Legionelloza – Patofizjologia i mechanizm

Legionelloza
Patofizjologia i mechanizm

Legionelloza, wywoływana głównie przez Legionella pneumophila, jest poważnym zapaleniem płuc przenoszonym przez inhalację skażonych aerozoli wodnych, szczególnie z systemów wodnych o temperaturze 20-50°C (optymalnie 35°C). Patogen ten jest Gram-ujemnym, wewnątrzkomórkowym bakteriem, który namnaża się w makrofagach pęcherzykowych, unikając fuzji fagosomów z lizosomami i tworząc niszę replikacyjną (LCV) o neutralnym pH. Kluczowym czynnikiem wirulencji jest system sekrecji typu IV (Dot/Icm), który transportuje około 300 białek efektorowych manipulujących szlakami komórkowymi gospodarza, hamując apoptozę i wspierając replikację. Wewnątrzkomórkowa proliferacja wymaga obecności amylazy LamB oraz żelaza (Fe³⁺), a odpowiedź immunologiczna gospodarza, zwłaszcza odporność komórkowa z udziałem limfocytów T i TNF-α, jest kluczowa dla kontroli infekcji. Patogeneza obejmuje silną odpowiedź zapalną, uszkodzenie pęcherzyków płucnych i potencjalne powikłania wielonarządowe, w tym niewydolność oddechową i wstrząs septyczny.

Patogeneza legionellozy

Legionelloza (choroba legionistów) jest poważną postacią zapalenia płuc wywoływaną przez bakterie z rodzaju Legionella, przy czym ponad 90% przypadków powoduje Legionella pneumophila. Bakterie te są Gram-ujemnymi, wewnątrzkomórkowymi patogenami, które naturalnie występują w środowiskach wodnych, takich jak jeziora, rzeki czy gleba.¹² Patogen ten został po raz pierwszy zidentyfikowany w 1976 roku podczas epidemii wśród uczestników konwencji Legionu Amerykańskiego w Filadelfii.³

Drogi transmisji

Zakażenie Legionella następuje głównie poprzez wdychanie skażonych aerozoli wodnych. Bakterie mogą namnażać się w sztucznych systemach wodnych, takich jak klimatyzatory, wieże chłodnicze, prysznice, jacuzzi czy fontanny, szczególnie w temperaturze 20-50°C (optymalna temperatura to 35°C).¹² Rzadziej infekcja może nastąpić poprzez aspirację (przypadkowe przedostanie się cieczy do płuc podczas połykania) wody zawierającej bakterie Legionella.³ Warto podkreślić, że legionelloza nie przenosi się z człowieka na człowieka.⁴

Dawka infekcyjna nie jest dokładnie znana, ale uważa się, że może być niska dla osób podatnych, ponieważ zachorowania odnotowywano nawet po krótkotrwałej ekspozycji i w odległości kilku kilometrów od źródła skażenia. Prawdopodobieństwo zachorowania zależy od stężenia bakterii Legionella w źródle wody, produkcji i rozprzestrzeniania się aerozoli, czynników związanych z gospodarzem (wiek, stan zdrowia) oraz zjadliwości określonego szczepu Legionella.⁵

Ewolucja i adaptacja Legionella

Bakterie Legionella wykazują oznaki długotrwałej koewolucji z ich naturalnymi gospodarzami – pierwotniakami. Żyją one i namnażają się wewnątrz ameb (np. Acanthamoeba, Hartmannella, Naegleria) oraz innych wolno żyjących pierwotniaków występujących w naturalnych i sztucznych systemach wodnych.¹² Ta zdolność do przeżycia i rozwoju w komórkach ameb pozwala bakteriom Legionella przetrwać w środowisku.³

Co istotne, mechanizmy, których Legionella używa do infekowania komórek ludzkich, są podobne do tych wykorzystywanych do infekowania pierwotniaków. Zdolność Legionella do namnażania się w różnych pierwotniaków wyposażyła bakterie w umiejętność replikacji w ludzkich makrofagach pęcherzykowych.⁴ Legionelloza jest dla bakterii ewolucyjnym ślepym zaułkiem – albo zostaje ona zwalczona przez układ odpornościowy, albo prowadzi do śmierci pacjenta.⁵

Mechanizm zakażenia makrofagów

Po przedostaniu się do układu oddechowego, bakterie Legionella docierają do pęcherzyków płucnych, gdzie są fagocytowane przez makrofagi pęcherzykowe – komórki stanowiące pierwszą linię obrony przeciwko infekcjom bakteryjnym w płucach.¹ W przeciwieństwie do typowego procesu fagocytozy, L. pneumophila szczep Philadelphia-1 jest pochłaniany przez makrofagi w wyjątkowy sposób, określany jako fagocytoza spiralna (coiling phagocytosis).²³

Proces inwazji komórki

Proces fagocytozy bakterii Legionella rozpoczyna się od przyłączenia składnika dopełniacza C3b do białka porynowego w błonie zewnętrznej bakterii. Następnie bakterie wiążą się z receptorami dopełniacza CR3 na jednojądrzastych fagocytach, po czym organizmy wnikają do komórki poprzez endocytozę.¹ Ten sposób wejścia wydaje się ograniczać wybuch tlenowy fagocyta, a tym samym zwiększa wewnątrzkomórkowe przeżycie bakterii Legionella.²

Legionella jest fakultatywnym pasożytem wewnątrzkomórkowym i swobodnie namnaża się w makrofagach. Po fagocytozie, bakterie znajdują się w wakuoli fagocytarnej, jednak poprzez nieznany mechanizm blokują fuzję lizosomów z fagosomem, zapobiegając normalnej acidyfikacji (zakwaszeniu) fagolizosomu i utrzymując toksyczny system mieloperoksydazy oddzielony od podatnych bakterii.³⁴

Formowanie wakuoli zawierającej Legionella

Po internalizacji przez komórkę gospodarza, wakuola bakteryjna przejściowo łączy się z mitochondriami, a następnie nabywa charakterystyki retikulum endoplazmatycznego (ER). Tworzy się specjalna nisza replikacyjna, nazywana wakuolą zawierającą Legionella (Legionella-containing vacuole, LCV).¹²

Unikalna biogeneza wakuoli Legionella wynika z jednoczesnego opóźnienia fuzji z endosomem oraz rekrutacji pęcherzyków i błon z sekrecyjnego szlaku komórki gospodarza. LCV rekrutuje specyficznie Rab1, ale nie Rab2 ani Rab6, do LCV w ciągu kilku minut od wchłonięcia, poprzedzając remodeling wakuoli.³ Wakuola utrzymuje neutralne pH, co umożliwia przeżycie i namnażanie się bakterii.⁴

W przeciwieństwie do normalnego procesu degradacji patogenów w fagolizosomie, kompartment, który powinien być pułapką śmierci, staje się niejako „inkubatorem” dla bakterii. Bakterie namnażają się wewnątrz fagosomu, aż do zniszczenia komórki, co prowadzi do uwolnienia nowej generacji mikrobów, które infekują kolejne komórki.⁵⁶

Systemy sekrecji i efektory bakteryjne

System sekrecji typu IV (Dot/Icm)

Kluczowym czynnikiem wirulencji L. pneumophila jest system sekrecji typu IV (T4SS), znany jako Dot/Icm. System ten transportuje około 300 białek efektorowych do cytoplazmy komórki gospodarza.¹² Efektory te stanowią około 10% proteomu L. pneumophila, co sugeruje, że są one głównym wyznacznikiem przeżycia bakterii, a presja selekcyjna na ich utrzymanie jest silna.³

System Dot/Icm jest niezbędny do wewnątrzkomórkowej replikacji i utworzenia LCV. Odgrywa również rolę w wejściu bakterii do komórki, hamowaniu apoptozy komórki gospodarza oraz wyjściu L. pneumophila z komórek gospodarza.⁴ Bakterie używają tego systemu do manipulowania szlakami sygnałowymi gospodarza na korzyść patogenu.⁵

Efektory bakteryjne i ich funkcje

Genom L. pneumophila koduje kilka efektorów Dot/Icm z motywami eukariotycznymi, które funkcjonują w szlaku ubikwitynacji eukariotów.¹ Bakterie posiadają również system sekrecji typu II (T2SS), określany jako Lsp (Legionella secretion pathway), który jest wymagany do pełnej wirulencji i przetrwania w środowisku.²

Jednym z interesujących mechanizmów odkrytych przez naukowców jest hamowanie odpowiedzi immunologicznej gospodarza przez małe regulatorowe RNA L. pneumophila. Bakteryjne RNA, nazwane RsmY i tRNA-Phe, działają w komórce gospodarza w sposób podobny do mikroRNA. Regulują one w dół ekspresję RIG-I, białka w komórce, które wykrywa obce cząsteczki RNA w celu zainicjowania odpowiedzi immunologicznej. Zmniejszenie ekspresji RIG-I prowadzi do osłabienia odpowiedzi immunologicznej gospodarza i lepszej replikacji L. pneumophila.³⁴

Inny mechanizm wirulencji związany jest z białkiem regulatorowym SidJ, które działa jako przeciwdziałanie dla enzymów SidE. SidJ jest glutamylazą, czyli posiada rzadką aktywność enzymatyczną, która pozwala na łączenie aminokwasów glutaminianowych w łańcuchy. W tym przypadku, SidJ atakuje centralny glutaminian enzymów SidE i hamuje ich aktywność, zapewniając precyzyjną kontrolę aktywności SidE.⁵⁶

Amylaza LamB i jej rola w patogenezie

Interesującym odkryciem jest kluczowa rola amylazy LamB w wewnątrzkomórkowej replikacji L. pneumophila. Mimo minimalnej roli glukozy w metabolizmie L. pneumophila, enzym ten jest niezbędny do namnażania się bakterii w amebách i ludzkich makrofagach.¹²

Gen lamB występuje tylko u L. pneumophila i L. steigerwaltii spośród ponad 60 gatunków Legionella. Utrata LamB lub ekspresja katalitycznie nieaktywnych wariantów LamB prowadzi do poważnego defektu wzrostu L. pneumophila w Acanthamoeba polyphaga i ludzkich makrofagach pochodzących z monocytów. Co istotne, mutant pozbawiony lamB wykazuje znaczne osłabienie proliferacji wewnątrzpłucnej w modelu mysim i jest wadliwy w rozprzestrzenianiu się do wątroby i śledziony.³⁴

Rola żelaza w patogenezie

Obecność żelaza (żelazo transferrynowe) jest również niezbędna do wewnątrzkomórkowego wzrostu bakterii. L. pneumophila pozyskuje żelazo głównie poprzez aktywność chelatującą Fe³⁺ sideroforu, co jest najczęstszym czynnikiem pozyskiwania żelaza i promowania infekcji płuc.¹

Odpowiedź immunologiczna i zapalenie

Wzrost bakterii, aktywacja układu dopełniacza i/lub śmierć makrofagów pęcherzykowych wytwarzają silne czynniki chemotaktyczne, które wywołują napływ monocytów i polimorfojądrowych neutrofilów. Nieszczelne naczynia włosowate umożliwiają przesączanie się surowicy i odkładanie fibryny w pęcherzykach płucnych. W rezultacie powstaje niszczące zapalenie płuc, które obliteruje przestrzenie powietrzne i zaburza funkcję oddechową.¹

Rola odpowiedzi immunologicznej

Odporność komórkowa odgrywa kluczową rolę w kontroli infekcji Legionella. Aktywowane limfocyty T wytwarzają limfokiny, które stymulują zwiększoną aktywność przeciwbakteryjną makrofagów. Ta aktywacja zależna od komórek jest kluczowa do zatrzymania wewnątrzkomórkowego wzrostu bakterii Legionella. Znacząca rola odporności komórkowej wyjaśnia, dlaczego infekcje Legionella są częściej obserwowane u pacjentów z obniżoną odpornością.¹²

Limfocyty T są niezbędne do skutecznej kontroli przeciwko Legionella, ale dokładna rola limfocytów B jest niejasna.¹ Czynnik martwicy nowotworu alfa (TNF-α) jest kluczowy w ochronie organizmu przed infekcją L. pneumophila, a częstość występowania choroby legionistów jest wyższa u pacjentów otrzymujących antagonistów TNF-α w porównaniu do grup kontrolnych.²

Mechanizmy odpowiedzi zapalnej

Chemokiny i cytokiny uwalniane przez zakażone makrofagi stymulują silną odpowiedź zapalną, charakterystyczną dla zakażeń Legionella.¹ Objawy zakażenia Legionella wynikają niewątpliwie z kombinacji fizycznego zakłócenia utlenowania krwi, nierównowagi wentylacyjno-perfuzyjnej w pozostałej tkance płucnej oraz uwalniania toksycznych produktów z bakterii i komórek zapalnych.²

Badania na niewielkiej liczbie pacjentów wykazały, że intensywność odpowiedzi cytokinowej była większa u najciężej chorych pacjentów. Niedawne badanie prospektywnej kohorty wykazało, że pacjenci z ciężką postacią choroby legionistów pod respiratorem wykazywali początkowy wzrost wydzielania systemowego siedmiu mediatorów prozapalnych i hiporeaktywność leukocytów z niższą zdolnością wydzielania 16 cytokin, co sugeruje immunoparaliz.³

Czynniki bakteryjne w patogenezie

Wirulencja Legionella wydaje się być wieloczynnikowa. Białko błony zewnętrznej, które działa jako metaloproteaza, oraz białko szoku cieplnego błony cytoplazmatycznej wywołują ochronne odpowiedzi immunologiczne, ale nie są niezbędne do ekspresji wirulencji. Zidentyfikowano gen kodujący białko o masie 29 kDa, który odgrywa rolę w zakażeniu komórkowym. Mutacje tego genu są związane ze zmniejszoną zjadliwością.¹

Enzymy bakteryjne i toksyny

Bakteryjne czynniki wirulencji obejmują proteazę, która może być odpowiedzialna za uszkodzenie tkanki. Czynniki komórkowe obejmują interleukinę-1, która wywołuje gorączkę po uwolnieniu z monocytów, oraz czynnik martwicy nowotworów, który może być odpowiedzialny za niektóre objawy ogólnoustrojowe.¹

Organizmy namnażają się w swoich wewnątrzkomórkowych wakuolach i wytwarzają enzymy proteolityczne (fosfataza, lipaza i nukleaza), które ostatecznie zabijają komórkę gospodarza, gdy wakuola ulega lizie.¹ Bakterie zabijają fagocyty albo poprzez apoptozę, albo nekrozę, za pośrednictwem aktywności tworzącej pory, lub obu, a następnie przedostają się do środowiska pozakomórkowego, co może zainfekować inne makrofagi.²

Dwufazowy cykl wzrostu

L. pneumophila wykazuje dwufazowy cykl wzrostu: w warunkach bogatych w składniki odżywcze bakterie znajdują się w fazie replikacyjnej i wykazują niewiele cech wirulencji, ale w warunkach ograniczonych składników odżywczych, bakterie wchodzą w fazę transmisyjną i stają się wysoce ruchliwe i odporne na różne stresy.¹

W fazie ruchowej Legionella rozwija krótsze, grubsze ciało z wicią i przyjmuje niższą formę życia oddechowego. W fazie ruchowej Legionella jest najbardziej zjadliwa i niebezpieczna. Po uwolnieniu się z biofilmu i przedostaniu do ogólnego systemu wodnego, Legionella może zostać przeniesiona przez kropelki aerozolu i zainfekować człowieka.²

Powikłania i skutki zakażenia

Choroba legionistów może prowadzić do poważnych powikłań, w tym niewydolności płuc. Występuje ona, gdy płuca nie mogą dostarczyć organizmowi wystarczającej ilości tlenu lub nie mogą usunąć wystarczającej ilości dwutlenku węgla z krwi.¹ Gdy nie jest leczona szybko, choroba legionistów może zakończyć się śmiercią.²

Uszkodzenia wielonarządowe

Oprócz płuc, bakterie Legionella mogą zakażać węzły chłonne, mózg, nerki, wątrobę, śledzionę, szpik kostny i mięsień sercowy.¹ Zdolność L. pneumophila do przechodzenia przez barierę nabłonkową płuc prowadzi do bakteriemii, rozprzestrzeniania się i inwazji wielu narządów z późniejszymi objawami, powikłaniami i wstrząsem septycznym.²

Legionella jest rzadką, ale uznaną przyczyną rabdomiolizy. Mechanizm nie jest znany, ale teoretyzuje się, że jest to bezpośrednia inwazja Legionella do mięśni lub uwolnienie endotoksyny do krążenia, co powoduje uszkodzenie mięśni.³

Zmiany histopatologiczne

Histopatologia choroby legionistów może się różnić w zależności od stadium i ciężkości zakażenia. Stadium wysięku występuje w pierwszym tygodniu infekcji i charakteryzuje się obrzękiem pęcherzykowym, błonami szklistymi, wysiękiem wewnątrzpęcherzykowym i erytroleukosfagocytozą. Stadium proliferacyjne występuje między drugim a trzecim tygodniem infekcji i charakteryzuje się hiperplazją pneumocytów, proliferacją fibroblastów i odkładaniem kolagenu. Stadium włóknienia występuje po trzecim tygodniu infekcji i charakteryzuje się rozległym włóknieniem, zmianą plastra miodu i tworzeniem się torbieli.¹

Badania histopatologiczne płuc u zmarłych pacjentów z chorobą legionistów wykazały, że najbardziej dotknięte są oskrzeliki końcowe, z rozległym wewnątrzpęcherzykowym wysiękiem makrofagów, neutrofilów, erytrocytów i fibryny.²

Diagnoza i leczenie

Diagnoza choroby legionistów zwykle rozpoczyna się od diagnozy zapalenia płuc, potwierdzonej przez RTG klatki piersiowej i zweryfikowanej przez jeden lub więcej pozytywnych testów diagnostycznych na Legionella.¹

Metody diagnostyczne

Zakażenie Legionella jest diagnozowane poprzez hodowlę organizmu, która wymaga użycia specjalistycznego panelu mediów różnicujących i selektywnych. Pojawienie się testów na antygen w moczu w połowie lat 90. zapewniło po raz pierwszy prosty, szybki sposób identyfikacji zakażonych pacjentów. Idealnymi próbkami do hodowli są popłuczyny oskrzelowe, płukanie oskrzelowe lub wymazy z oskrzeli.²

Badania laboratoryjne często wykazują hiponatremię, hipofosfatemię oraz podwyższone poziomy aminotransferaz i białka C-reaktywnego.³

Skuteczność leczenia

Choroba legionistów jest leczona antybiotykami. Im wcześniej pacjent otrzyma terapię antybiotykową, tym większe prawdopodobieństwo, że będzie ona skuteczna.¹ Bez odpowiedniej terapii antybiotykowej infekcja może powodować poważne powikłania, a nawet śmierć.²

Uderzające jest to, że u większości pacjentów Legionella nie jest wykrywalna w płynie mózgowo-rdzeniowym, co skłoniło niektórych autorów do rozważenia, czy mechanizm leżący u podstaw objawów neurologicznych to reakcja immunologiczna lub toksyczna, a nie bezpośrednie uszkodzenie przez bakterie.³ Niemniej jednak stopniowa poprawa kliniczna, a także zanik hiperintensywności mózgu po dostosowaniu antybiotyków, skłaniają do wniosku, że choroba legionistów jest najbardziej prawdopodobnym źródłem stanu pacjenta.⁴

Zapobieganie i kontrola

Kluczem do zapobiegania chorobie legionistów jest zmniejszenie ryzyka wzrostu i rozprzestrzeniania się Legionella w systemach wodnych budynków i urządzeniach poprzez dobre strategie konserwacji. Strategie te obejmują monitorowanie temperatury wody i poziomów środków dezynfekujących oraz zapobieganie warunkom stagnacji wody.¹

Skuteczne środki kontroli

Skuteczne środki kontroli przeciwko bakteriom Legionella obejmują:

Zapewnienie regularnej konserwacji, czyszczenia i dezynfekcji systemów wodnych, w tym systemów hydraulicznych, wież chłodniczych, jacuzzi i fontann ozdobnych
Utrzymywanie systemów zimnej wody poniżej 20°C i systemów ciepłej wody powyżej 50°C, aby zapobiec wzrostowi bakterii
Zapewnienie właściwego przepływu i cyrkulacji wody w systemach wodnych, aby zminimalizować ryzyko stagnacji wody
Dezynfekcja systemów ciepłej wody wysokimi poziomami (50 mg/l) chloru przez 24 godziny po pracach nad systemem i podgrzewaczami wody oraz przed początkiem każdego ciepłego sezonu
Regularne czyszczenie i dezynfekcja filtrów wody, wież chłodniczych i powiązanych rur używanych w systemach klimatyzacji

Tymczasowa eliminacja lub redukcja kolonizacji Legionella w „ekosystemie” ciepłej wody jest możliwa, choć trudna. Sukces zależy od projektu i stanu systemu, a także zastosowanej metodologii rekultywacji. Jeśli system jest stary, czyszczenie i odkamienianie może być ważnym elementem programu kontroli Legionella.³⁴

Właściciele i zarządcy budynków powinni opracować i wdrożyć program zarządzania wodą zgodnie ze standardami ASHRAE (American Society of Heating, Refrigerating and Air-Conditioning Engineers).⁵

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Materiały źródłowe

#1 Legionnaires’ disease – Wikipedia
https://en.wikipedia.org/wiki/Legionnaires%27_disease
Over 90% of cases of Legionnaires’ disease are caused by Legionella pneumophila. Legionnaires’ disease is usually spread by the breathing in of aerosolized water or soil contaminated with the Legionella bacteria. Experts have stated that Legionnaires’ disease is not transmitted from person to person. Legionella spp. enter the lungs either by aspiration of contaminated water or inhalation of aerosolized contaminated water or soil. In the lung, the bacteria are consumed by macrophages, a type of white blood cell, inside of which the Legionella bacteria multiply, causing the death of the macrophage. Once the macrophage dies, the bacteria are released from the dead cell to infect other macrophages. Virulent strains of Legionella kill macrophages by blocking the fusion of phagosomes with lysosomes inside the host cell; normally, bacteria are contained inside the phagosome, which merges with a lysosome, allowing enzymes and other chemicals to break down the invading bacteria.
#1
https://www.who.int/news-room/fact-sheets/detail/legionellosis
The bacteria live and grow in water systems at temperatures of 20 to 50 degrees Celsius (optimal 35 degrees Celsius). Legionella can survive and grow as parasites within free-living protozoa and within biofilms which develop in water systems. They can cause infections by infecting human cells using a similar mechanism to that used to infect protozoa. […] The most common form of transmission of Legionella is inhalation of contaminated aerosols from contaminated water. Sources of aerosols that have been linked with transmission of Legionella include air conditioning cooling towers, hot and cold water systems, humidifiers and whirlpool spas. […] The causative agents are Legionella bacteria from water or potting mix. The most common cause of illness is the freshwater species L. pneumophila, which is found in natural aquatic environments worldwide. However, artificial water systems which provide environments conducive to the growth and dissemination of Legionella represent the most likely sources of disease.
#1 Legionnaires Disease: Background, Pathophysiology, Etiology
https://emedicine.medscape.com/article/220163-overview
Legionella species are obligate or facultative intracellular parasites. Water is the major environmental reservoir for Legionella; the bacteria can infect and replicate within protozoa such as Acanthamoeba and Hartmannella, which are free-living amoebae found in natural and manufactured water systems. (Legionellae can resist low levels of chlorine used in water distribution systems.) […] Within the amebic cells, Legionella species can avoid the endosomal-lysosomal pathway and can replicate within the phagosome. Surviving and growing in amebic cells allows Legionella to persist in nature. […] Legionella species infect human macrophages and monocytes; intracellular replication of the bacterium is observed within these cells in the alveoli. The intracellular infections of protozoa and macrophages have many similarities.
#1 Legionella – Medical Microbiology – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK7619/
Legionella bacilli reside in surface and drinking water and are usually transmitted to humans in aerosols. The bacteria multiply intracellularly in alveolar macrophages. Recruited neutrophils and monocytes, as well as bacterial enzymes, produce destructive alveolar inflammation. […] The pathogenesis of Legionella infections begins with a supply of water containing virulent bacteria and with a means for dissemination to humans. Person-to-person transmission has never been demonstrated, and Legionella is not a member of the bacterial flora of humans. […] Infection begins in the lower respiratory tract. Alveolar macrophages, which are the primary defense against bacterial infection of the lungs, engulf the bacteria; however, Legionella is a facultative intracellular parasite and multiplies freely in macrophages. The bacteria bind to alveolar macrophages via the complement receptors and are engulfed into a phagosomal vacuole. However, by an unknown mechanism, the bacteria block the fusion of lysosomes with the phagosome, preventing the normal acidification of the phagolysosome and keeping the toxic myeloperoxidase system segregated from the susceptible bacteria. The bacilli multiply within the phagosome. Thus, a cellular compartment that should be a death trap instead becomes a nursery. Eventually, the cell is destroyed, releasing a new generation of microbes to infect other cells.
#1 Virulence factors, Pathogenesis and Clinical manifestations of Legionella pneumophila
https://microbenotes.com/virulence-factors-pathogenesis-and-clinical-manifestations-of-legionella-pneumophila/
L. pneumophila is considered a facultative intracellular pathogen. […] Infection in humans follows the inhalation of fine aerosol (5 m particle size) containing organisms that are both viable and virulent. […] Once within the alveoli the legionellae are taken up by resident alveolar macrophages where they survive and replicate within a specialized, membrane-bound vacuole by resisting acidification and evading fusion with lysosomes. […] This ability to infect and replicate in macrophages is critical for pathogenesis. […] The replicative cycle is initiated by binding complement component C3b to an outer membrane porin protein on the bacterial surface. […] The bacteria then binds to the CR3 complement receptors on mononuclear phagocytes, after which the organisms penetrate the cell through endocytosis.
#1
https://pmc.ncbi.nlm.nih.gov/articles/PMC2863363/
In all models, following internalization by the host cell, the bacterial vacuole associates transiently with mitochondria and then acquires characteristics of the endoplasmic reticulum (ER). […] The unusual biogenesis of the Legionella vacuole arises from the simultaneous delay of endosome fusion and the recruitment of vesicles and membrane from the host cell secretory pathway. […] The LCV specifically recruits Rab1, but not Rab2 or Rab6, to the LCV within minutes of uptake, preceding any remodeling of the vacuole. […] The ability of L. pneumophila to establish and maintain this intracellular niche indicates that the bacteria actively and continually manipulate host cell trafficking from within the replicative vacuole. […] Replication of L. pneumophila bacteria then commences between 4 and 10 h after phagocytosis, and the bacteria continue to replicate within a vacuole that maintains a neutral pH.
#1
https://pmc.ncbi.nlm.nih.gov/articles/PMC2863363/
Other evidence suggests that the manipulation of autophagy by L. pneumophila is important for bacterial replication. […] The Dot/Icm system is required for intracellular replication and the establishment of the LCV, it is also involved in bacterial entry, the inhibition of host cell apoptosis, and the egress of L. pneumophila from host cells. […] The Dot/Icm effectors therefore constitute around 10% of the L. pneumophila proteome, which suggests that the effectors are a major determinant of L. pneumophila survival and that the selection for their retention is strong. […] The L. pneumophila genome encodes several putative Dot/Icm effector proteins with eukaryotic motifs that function in the eukaryotic ubiquitination pathway. […] The L. pneumophila type II secretion system (T2SS) termed Lsp, for Legionella secretion pathway, which is required for full virulence and environmental persistence.
#1 A Legionella pneumophila amylase is essential for intracellular replication in human macrophages and amoebae | Scientific Reports
https://www.nature.com/articles/s41598-018-24724-1
Legionella pneumophila invades protozoa with an accidental ability to cause pneumonia upon transmission to humans. To support its nutrition during intracellular residence, L. pneumophila relies on host amino acids as the main source of carbon and energy to feed the TCA cycle. […] Loss of LamB or expression of catalytically-inactive variants of LamB results in a severe growth defect of L. pneumophila in Acanthamoeba polyphaga and human monocytes-derived macrophages. Importantly, the lamB null mutant is severely attenuated in intra-pulmonary proliferation in the mouse model and is defective in dissemination to the liver and spleen. Our data show an essential role for LamB in intracellular replication of L. pneumophila in amoeba and human macrophages and in virulence in vivo.
#1 Virulence factors, Pathogenesis and Clinical manifestations of Legionella pneumophila
https://microbenotes.com/virulence-factors-pathogenesis-and-clinical-manifestations-of-legionella-pneumophila/
Following replication, the organisms will kill the phagocyte releasing them into the lungs and will again be phagocytized by a mononuclear cell, and multiplication of the organism will increase. […] The presence of iron (transferrin iron) is also essential for the process of intracellular growth of the bacteria. […] The first means by which L. pneumophila acquires iron is through the Fe3+-chelating activity of a siderophore, the most common factor for iron acquisition and promoting lung infection.
#1 Legionella – Medical Microbiology – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK7619/
Bacterial growth, activation of the complement system, and/or the death of alveolar macrophages produce powerful chemotactic factors that elicit an influx of monocytes and polymorphonuclear neutrophils. Leaky capillaries allow the transudation of serum and deposition of fibrin in the alveoli. The result is a destructive pneumonia that obliterates the air spaces and compromises respiratory function. […] The symptoms of Legionella infection undoubtedly result from a combination of physical interference with oxygenation of blood, ventilation-perfusion imbalance in the remaining lung tissue, and release of toxic products from bacteria and inflammatory cells. Bacterial factors include a protease that may be responsible for tissue damage. Cellular factors include interleukin-1, which produces fever after it is released from monocytes, and tumor necrosis factor, which may be responsible for some of the systemic symptoms.
#1 Legionnaires Disease: Background, Pathophysiology, Etiology
https://emedicine.medscape.com/article/220163-overview
Activated T cells produce lymphokines that stimulate increased antimicrobial activity of macrophages. This cell-mediated activation is key to halting the intracellular growth of legionellae. The significant role of cellular immunity explains why legionellae are observed more frequently in immunocompromised patients. Humoral immunity is thought to play a secondary role in the host response to Legionella infection.
#1 Legionnaires Disease in Immunocompromised Host | IntechOpen
https://www.intechopen.com/chapters/69331
T lymphocytes are essential for effective anti-legionella control but the exact role of B lymphocytes is unclear. […] In conclusion while Legionella infection can occur in both immunocompetent and immunocompromised patients, certain risk factors in the immunocompromised are associated with an increased incidence. T cell and cell mediated immunity play a key role in bodys defense against the bacteria.
#1 Virulence factors, Pathogenesis and Clinical manifestations of Legionella pneumophila
https://microbenotes.com/virulence-factors-pathogenesis-and-clinical-manifestations-of-legionella-pneumophila/
This mode of entry appears to limit the oxidative burst of the phagocyte and hence enhances the intracellular survival of the legionellae. […] Chemokines and cytokines released by the infected macrophages stimulate a robust inflammatory response that is characteristic of infections with Legionella. […] The organisms proliferate in their intracellular vacuole, phagosomal vacuoles (Legionella-containing vacuole, LCV), and produce proteolytic enzymes (phosphatase, lipase, and nuclease) that eventually kill the host cell when the vacuole is lysed. […] During the late replicative phase the legionella-containing phagosome merges with lysosomes, but replication continues until the host cell is packed with organisms and finally disrupts releasing bacteria to infect further host cells. […] In addition to this process, phagosome survival and organism replication are facilitated by the elaboration of a type IV secretion system call Dot/Icm which is essential for L. pneumophila.
#1 Legionella – Medical Microbiology – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK7619/
Virulence appears to be multifactorial. An outer membrane protein that functions as a metalloprotease and a cytoplasmic membrane heat-shock protein elicit protective immune responses, but are not essential for expression of virulence. A gene that encodes a 29 Kd protein and plays a role in cellular infection has been identified. Mutations of the gene are associated with decreased virulence.
#1
https://pmc.ncbi.nlm.nih.gov/articles/PMC2863363/
The ability of L. pneumophila to remain viable under a wide range of conditions is fundamental to its environmental persistence. […] The biphasic growth cycle where, under nutrient-rich conditions, the bacteria are in a replicative phase and express few virulence traits, but under nutrient-limited conditions, the bacteria enter a transmissive phase and become highly motile and resistant to various stresses. […] The rapid advances made in the understanding of L. pneumophila molecular pathogenesis have resulted largely from the availability of genome sequences that have uncovered unusual features of the pathogen, such as the presence of virulence determinants with similarity to eukaryotic proteins.
#1 Legionnaires’ disease – Symptoms & causes – Mayo Clinic
https://www.mayoclinic.org/diseases-conditions/legionnaires-disease/symptoms-causes/syc-20351747
Legionnaires’ disease is a severe form of a lung infection called pneumonia. It’s caused by a bacterium known as legionella. […] The bacterium Legionella pneumophila causes most cases of Legionnaires’ disease. Outdoors, legionella bacteria live in soil and water. In those places the bacteria rarely cause infections. But legionella bacteria can grow in water systems made by humans, such as air conditioners. […] Most people become infected when they breathe in tiny water droplets that have legionella bacteria. This might be from the spray from a shower, sink or hot tub. Or it might be from water from the system that cools large buildings. […] The infection can spread in other ways besides breathing in water droplets. The infection can spread by: Aspiration. This occurs when liquids enter the lungs by accident, most often because of coughing or choking while drinking. Aspirating water that has legionella bacteria can cause Legionnaires’ disease. […] Legionnaires’ disease can lead to serious complications, including: Lung failure. This occurs when the lungs can’t provide the body with enough oxygen or can’t remove enough carbon dioxide from the blood. […] When not treated promptly, Legionnaires’ disease can kill.
#1 Legionella Infection: Practice Essentials, Pathophysiology, Etiology
https://emedicine.medscape.com/article/965492-overview
Organisms that reach the alveoli undergo phagocytosis by the alveolar macrophages but are not actively killed. Macrophages may actually support the growth of Legionella organisms. The bacteria multiply intracellularly until the cell ruptures. Liberated bacteria then infect other macrophages. Additional virulence factors include genes that potentiate infection of macrophages and inhibit phagosomal fusion, allowing intracellular growth. […] Cell-mediated immunity appears to be the primary host defense mechanism against Legionella infection. Activation of macrophages produces cytokines that regulate antimicrobial activity against Legionella organisms. Individuals with certain deficiencies in cell-mediated immunity are at increased risk for legionellosis. […] Once infection is established, Legionella organisms cause an acute fibrinopurulent pneumonia with alveolitis and bronchiolitis. In addition to the lungs, Legionella organisms may infect the lymph nodes, brain, kidney, liver, spleen, bone marrow, and myocardium.
#1 Legionnaires Disease | Treatment & Management | Point of Care
https://www.statpearls.com/point-of-care/24176
The immune response to legionellae infection is complex and involves innate and adaptive immunity. […] The natural inflammatory response further exacerbates legionellae-associated cellular damage. […] Legionellae infection is confirmed by immunohistochemical staining or molecular techniques identifying bacterial antigens or DNA in the lung tissue. […] The histopathology of Legionnaires disease may vary with the stage and severity of the infection. […] The exudative stage occurs within the first week of infection and is characterized by alveolar edema, hyaline membranes, intra-alveolar exudate, and erythroleukophagocytosis. […] The proliferative stage occurs between the second and third weeks of infection and is characterized by pneumocyte hyperplasia, fibroblast proliferation, and collagen deposition. […] The fibrotic stage occurs after the third week of infection and is characterized by extensive fibrosis, honeycomb change, and cyst formation.
#1 Legionellosis (Legionnaires’ Disease and Pontiac Fever) – Medical information | Occupational Safety and Health Administration
http://www.osha.gov/legionnaires-disease/medical-Information
Diagnosing Legionnaires’ disease usually begins with a pneumonia diagnosis, confirmed by chest x-ray, and verified by one or more positive diagnostic tests for Legionella. […] Legionnaires’ disease is treatable with antibiotics. The earlier a patient receives antibiotic therapy, the more likely it will be successful.
#1 About Legionnairesâ Disease – MN Dept. of Health
https://www.health.state.mn.us/diseases/legionellosis/basics.html
The key to preventing Legionnaires disease is to reduce the risk of Legionella growth and spread in building water systems and devices through good maintenance strategies. These strategies include monitoring water temperatures and disinfectant levels and preventing stagnant water conditions. […] Building owners and managers should develop and implement a water management program using ASHRAE (American Society of Heating, Refrigerating and Air-Conditioning Engineers) standards.
#2 Legionella Infection: Practice Essentials, Pathophysiology, Etiology
https://emedicine.medscape.com/article/965492-overview
Legionella organisms are aerobic, motile, and nutritionally fastidious pleomorphic gram-negative rods. The growth of the organisms depends on the presence of L-cysteine and iron in special media. The organism has been isolated in natural aquatic habitats (freshwater streams and lakes, water reservoirs) and artificial sources (cooling towers, potable water distribution systems). Freshwater amoebae appear to be the natural reservoir for the organisms. Optimal growth temperature is 28-40C; organisms are dormant below 20C and are killed at temperatures above 60C. […] Although more than 70 Legionella serogroups have been identified among 50 species, L pneumophila causes most legionellosis. L pneumophila serogroup 1 alone is responsible for 70-90% of cases in adults. In a pediatric series, L pneumophila serogroup 1 accounted for only 48% of cases, serogroup 6 accounted for 33%, and the remaining cases involved other serotypes and species. Legionella micdadei and L dumoffii are the second and third most common species to cause Legionnaires disease in children, respectively.
#2 Legionella Infection: Practice Essentials, Pathophysiology, Etiology
https://emedicine.medscape.com/article/965492-overview
Transmission occurs by means of aerosolization or aspiration of water contaminated with Legionella organisms. Wounds may become infected after contact with contaminated water. The following systems are linked to transmission of Legionella organisms: Cooling towers, Humidifiers, Respiratory therapy equipment, Whirlpool spas, Evaporative condensers, Potable water distribution systems (eg, showers, faucets). […] Most nosocomial infections and hospital outbreaks have been linked to contaminated hot water supply. However, contamination of cold-water supply has also been reported. Person-to-person transmission has not been demonstrated. […] Mucociliary action clears Legionella organisms from the upper respiratory tract. Any process that compromises mucociliary clearance (eg, smoking tobacco) increases risk of infection. Virulence varies between strains of L pneumophila. For example, some strains can adhere to the respiratory epithelial cells via pili, whereas strains with a mutated gene that encodes for the pili show reduced adherence in vitro.
#2 Legionella – Wikipedia
https://en.wikipedia.org/wiki/Legionella
Legionella bacteria live inside tiny organisms, like amoebae (examples:Acanthamoebaspp.,Naegleriaspp.,Vermamoebaspp., or other protozoa such asTetrahymena pyriformis). […] Legionella is spread through inhaling contaminated water droplets, which can come from mists, sprays, or other sources that release tiny droplets into the air. […] After inhaling or accidentally swallowing small aerosol particles, Legionella bacteria attach to immune cells and are taken up by them through a process called phagocytosis. Inside the body, the bacteria can grow and multiple in lung cells, specifically alveolar macrophages and monocytes. […] Legionella has several ways to evade the immune system, increasing the chance that a person develops symptoms of infection. It creates special vacuoles, or protective bubbles, inside immune cells to hide from the body’s defenses. It also reduces the activity of cytokine receptors (which play a role in immune response), blocks the production of certain proteins needed by the host, and avoids being broken down by lysosomes, which are cell structures meant to digest harmful particles.
#2
https://journals.lww.com/joad/fulltext/2019/08060/legionella_and_legionnaires__disease__an_overview.1.aspx
As a result of this intracellular multiplication, macrophages, neutrophils, and peripheral blood monocytes penetrate the alveoli and capillary leakage and leads to severe inflammatory response and edema. […] During the process of Legionella phagocytosis, a complex cascade of processes occur, such as interdiction of phagosome-lysosome fusion, decrease of phagosome acidification, prevention of the oxidative burst, alteration in organelle trafficking and inhibition of phagosome maturation. […] In contrast to common symmetrical and conventional uptake of pathogens, L. pneumophila Philadelphia-1 strain is phagocytosed by macrophage through an exclusive uptake process called coiling phagocytosis. […] Some investigations have ascertained that the other serotypes of L. pneumophila and non -L. pneumophila species can enter host cells by conventional phagocytosis.
#2 Virulence factors, Pathogenesis and Clinical manifestations of Legionella pneumophila
https://microbenotes.com/virulence-factors-pathogenesis-and-clinical-manifestations-of-legionella-pneumophila/
This mode of entry appears to limit the oxidative burst of the phagocyte and hence enhances the intracellular survival of the legionellae. […] Chemokines and cytokines released by the infected macrophages stimulate a robust inflammatory response that is characteristic of infections with Legionella. […] The organisms proliferate in their intracellular vacuole, phagosomal vacuoles (Legionella-containing vacuole, LCV), and produce proteolytic enzymes (phosphatase, lipase, and nuclease) that eventually kill the host cell when the vacuole is lysed. […] During the late replicative phase the legionella-containing phagosome merges with lysosomes, but replication continues until the host cell is packed with organisms and finally disrupts releasing bacteria to infect further host cells. […] In addition to this process, phagosome survival and organism replication are facilitated by the elaboration of a type IV secretion system call Dot/Icm which is essential for L. pneumophila.
#2 Severe Legionnairesâ disease | Annals of Intensive Care | Full Text
https://annalsofintensivecare.springeropen.com/articles/10.1186/s13613-024-01252-y
Lung histopathological studies of LD in deceased patients have reported that terminal bronchioles are predominantly affected by an extensive intra-alveolar exudation of macrophages, neutrophils, erythrocytes, and fibrin. […] The lung cells, in particular macrophages, infected by Lp not only provide intracellular niches that facilitate its pathogenesis, but also contribute to the immune response against it. […] To establish an infection, Lp uses its type IV secretion system (T4SS), one of the key virulence factors, which translocates approximately 300 effector proteins into the host cell cytosol. […] The pathogenesis of severe LD remains poorly understood. Several virulence factors involved at different stages of pathogenesis have been described in the literature. […] In particular, ProA may contribute to bacterial proliferation and dissemination in the human lung, as well as to the formation and progression of lung damage, through a protease extracellular activity against the host lung tissue.
#2
https://pmc.ncbi.nlm.nih.gov/articles/PMC2863363/
Other evidence suggests that the manipulation of autophagy by L. pneumophila is important for bacterial replication. […] The Dot/Icm system is required for intracellular replication and the establishment of the LCV, it is also involved in bacterial entry, the inhibition of host cell apoptosis, and the egress of L. pneumophila from host cells. […] The Dot/Icm effectors therefore constitute around 10% of the L. pneumophila proteome, which suggests that the effectors are a major determinant of L. pneumophila survival and that the selection for their retention is strong. […] The L. pneumophila genome encodes several putative Dot/Icm effector proteins with eukaryotic motifs that function in the eukaryotic ubiquitination pathway. […] The L. pneumophila type II secretion system (T2SS) termed Lsp, for Legionella secretion pathway, which is required for full virulence and environmental persistence.
#2 A Legionella pneumophila amylase is essential for intracellular replication in human macrophages and amoebae | Scientific Reports
https://www.nature.com/articles/s41598-018-24724-1
Essential to intracellular replication is the Dot/Icm Type 4b secretion system (T4SS), which inject proteins, known as effectors, from the bacterium to the host cytoplasm to modulate host processes. […] The primary food source for L. pneumophila is amino acids which are used for carbon and energy through feeding the TCA cycle. […] The predicted putative amylase, Lpg2528, has been designated as LamB. Among the 60 Legionella species, L. pneumophila and L. steigerwaltii are the only two Legionella species to harbor lamB. […] Here we show that despite the minimal role of glucose in L. pneumophila metabolism, the LamB amylase is surprisingly necessary for intracellular replication in amoebae and human macrophages, and is required for virulence in vivo, in the A/J mouse model.
#2 Legionnaires Disease in Immunocompromised Host | IntechOpen
https://www.intechopen.com/chapters/69331
Legionella bacteria are aerobic, pleomorphic, gram negative bacilli found in fresh water environments and are usually transmitted through inhalation aerosols from contaminated water or soil. […] The pathogenesis of legionnaires disease involves invasion of alveolar macrophages and cell mediated immunity is the primary means of immune control. […] Legionella pneumophila is an intracellular pathogen that replicates within alveolar macrophages. […] Bacteria are initially engulfed by phagocytes from a vacuole that blocks phagolysosome fusion by delivering bacterial proteins into host cell cytosol. […] These proteins subsequently modulate endoplasmic reticulum and prevent lysosomal mediated killing of the bacteria. […] Tumor necrosis factor alpha is vital in protecting the body from L. pneumophila infection and the incidence of Legionnaires disease is reported to be higher in patients receiving TNF-alpha antagonists when compared to controls.
#2 Legionella – Medical Microbiology – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK7619/
Bacterial growth, activation of the complement system, and/or the death of alveolar macrophages produce powerful chemotactic factors that elicit an influx of monocytes and polymorphonuclear neutrophils. Leaky capillaries allow the transudation of serum and deposition of fibrin in the alveoli. The result is a destructive pneumonia that obliterates the air spaces and compromises respiratory function. […] The symptoms of Legionella infection undoubtedly result from a combination of physical interference with oxygenation of blood, ventilation-perfusion imbalance in the remaining lung tissue, and release of toxic products from bacteria and inflammatory cells. Bacterial factors include a protease that may be responsible for tissue damage. Cellular factors include interleukin-1, which produces fever after it is released from monocytes, and tumor necrosis factor, which may be responsible for some of the systemic symptoms.
#2
https://journals.lww.com/joad/fulltext/2019/08060/legionella_and_legionnaires__disease__an_overview.1.aspx
Legionella species are considered opportunistic pathogens, which accidentally cause disease in humans. […] The infection in humans is initiated by direct inhalation or microaspiration of fine aerosol containing both virulent and non-virulent strains. Once within the alveoli, the virulent strains are taken up by alveolar phagocytes where they multiply and inhibit the fusion of phagosomes with lysosomes and acidification of the phagosome. […] The bacterial growth within infected macrophages has been estimated at 100 to 1 000 fold within 48 to 72 h of infection, which is considered remarkable compared to other intracellular opportunistic bacteria (e.g., Salmonella, Mycobacterium, Listeria). […] After adequate intracellular multiplications, the bacteria kill alveolar macrophages by either apoptosis or necrosis mediated by a pore-forming activity or both, and then transfer into the extracellular environment, which can infect other macrophages.
#2 The Lifecycle of Legionella – The impact on detection and Legionnaires’ disease control
https://blog.hydrosense-legionella.com/the-lifecycle-of-legionella-the-impact-on-detection-and-legionnaires-disease-control
Within the amoebic host environment, the Legionella quickly uses up the available resources. Having exhausted the resources of its host, the Legionella reverts to the motile dispersal phase and breaks through the amoeba cell wall to seek a new host. […] In the motile phase, Legionella develops a shorter, thicker body with a flagellum and takes on a lower respiratory life form. […] In the motile phase, Legionella is at its most virulent and dangerous. Once free of the biofilm and in the general water system, Legionella can be taken up by aerosol droplets – caused by any agitation of the water near a water/air interface, e.g. a showerhead or cooling tower. […] Humans can inhale the Legionella in the aerosol droplets and once in the respiratory system, the Legionella will attack human lung cells, in the same way that it attacks an amoebic cell, which it resembles.
#2 Legionnaires’ disease – Symptoms & causes – Mayo Clinic
https://www.mayoclinic.org/diseases-conditions/legionnaires-disease/symptoms-causes/syc-20351747
Legionnaires’ disease is a severe form of a lung infection called pneumonia. It’s caused by a bacterium known as legionella. […] The bacterium Legionella pneumophila causes most cases of Legionnaires’ disease. Outdoors, legionella bacteria live in soil and water. In those places the bacteria rarely cause infections. But legionella bacteria can grow in water systems made by humans, such as air conditioners. […] Most people become infected when they breathe in tiny water droplets that have legionella bacteria. This might be from the spray from a shower, sink or hot tub. Or it might be from water from the system that cools large buildings. […] The infection can spread in other ways besides breathing in water droplets. The infection can spread by: Aspiration. This occurs when liquids enter the lungs by accident, most often because of coughing or choking while drinking. Aspirating water that has legionella bacteria can cause Legionnaires’ disease. […] Legionnaires’ disease can lead to serious complications, including: Lung failure. This occurs when the lungs can’t provide the body with enough oxygen or can’t remove enough carbon dioxide from the blood. […] When not treated promptly, Legionnaires’ disease can kill.
#2 Legionella pneumophila: The Journey from the Environment to the Blood
https://www.mdpi.com/2077-0383/11/20/6126
An outbreak of a potentially fatal form of pneumonia in 1976 and in the annual convention of the American Legion was the first time that Legionella spp. was identified. […] The pathogenesis of LD infection initiates with the attachment of the bacterial cells to the host cells, and subsequent intracellular replication. Following invasion, Legionella spp. activates its virulence mechanisms: generation of specific compartments of Legionella-containing vacuole (LCV), and expression of genes that encode a type IV secretion system (T4SS) for the translocation of proteins. […] The ability of L. pneumophila to transmigrate across the lungâs epithelium barrier leads to bacteremia, spread, and invasion of many organs with subsequent manifestations, complications, and septic shock. […] The mechanisms involved include: apoptosis, autophagy, mitochondrial dynamics, and phospholipid biosynthesis.
#2 Texas DSHS Report of the Texas Legionnairesâ Disease Task Force | Texas DSHS
https://www.dshs.texas.gov/legionellosis-legionnaires-disease/legionellosis-legionnaires-disease-task-force-recommendations/texas-dshs-report-the
The most important host risk factors for developing illness include 1) immunosuppressive therapy (anti-rejection therapy to prevent graft rejection in bone marrow and solid organ transplant patients), 2) chemotherapy for neoplastic disease, current steroid therapy, and 3) chronic underlying illnesses such as hematologic malignancies or end-stage renal disease. […] The disease is extremely rare in children. […] Legionnaires disease is characterized by fever, myalgias, cough, and pneumonia. […] Legionella infection is diagnosed through culture of the organism, which requires use of a specialized panel of differential and selective media. […] The advent of urine antigen testing in the mid 1990s provided for the first time a simple, rapid means of identifying infected patients. […] The ideal specimens for culture are bronchial washings, bronchial lavages, or bronchial brushings.
#2 Texas DSHS Report of the Texas Legionnairesâ Disease Task Force | Texas DSHS
https://www.dshs.texas.gov/legionellosis-legionnaires-disease/legionellosis-legionnaires-disease-task-force-recommendations/texas-dshs-report-the
Legionnaires disease in Texas is highly variable and that the method of water treatment in a given community may influence the risk of Legionella bacterial contamination in the hospital setting. […] The incubation period for Legionnaires disease is usually 2-10 days. Based on studies in several parts of the country, Legionnaires disease may account for 5-15% of all community-acquired pneumonias. […] Without appropriate antibiotic therapy, infection can cause serious complications and even death. Patients with Legionnaires disease have signs and symptoms that resemble other bacterial pneumonias, and the diagnosis generally cannot be made by a physician in the absence of specialized laboratory testing. […] Certain populations are clearly at greater risk than others for developing severe Legionella infections.
#2 Legionnairesâ disease
https://www.ecdc.europa.eu/en/legionnaires-disease
People can get infected when they breathe in tiny water droplets called aerosols that carry the Legionella bacteria. If these bacteria go into the lungs, they can cause an infection. […] Legionella bacteria are quite common in the environment and naturally exist in water sources such as rivers, lakes, and reservoirs. They may also be found in soil and compost. These bacteria can survive in different temperatures in the environment. They may also grow in engineered water systems, most often associated with buildings and plumbing such as hot and cold water systems, cooling towers, humidifiers, fountains and hot tubs. […] The main protective measure is to reduce risk of Legionella growth in places that produce aerosol droplets that can be breathed in. Regular checks for the presence of Legionella bacteria and appropriate control measures can help prevent cases of Legionnaires disease in places where people who may be at higher risk of the disease might be more likely to be exposed. Effective control measures against legionella bacteria include: Ensuring regular maintenance, cleaning, and disinfection of water systems, including plumbing systems, cooling towers, hot tubs, and decorative fountains. Maintaining cold-water systems below 20C, and hot-water systems above 50C to prevent bacterial growth. Ensuring proper water flow and circulation in water systems to minimize the risk of stagnant water. Disinfecting hot water systems with high levels of (50mg/l) chlorine for 24 hours after work on the system and water heaters, and before the beginning of every warm season. Regularly cleaning and disinfecting water filters, cooling towers and associated pipes used in air conditioning systems.
#3 Legionnairesâ Disease | SpringerLink
https://link.springer.com/10.1007/978-3-642-30144-5_94?fromPaywallRec=true
Legionella pneumophila, the etiological agent of Legionnaires disease was first recognized in 1976, during an outbreak of severe pneumonia at the convention of the American Legion in Philadelphia. […] However, L. pneumophila remains the major cause of human disease, as it is responsible for over 90 % of legionellosis cases worldwide. […] In the second part, we focus on the pathogenesis, the virulence factors, and the immune response of the host. Special emphasis is placed on the implication of the literally hundreds of different effector proteins secreted by the Dot/Icm type IV secretion system. […] In the third section we discuss recent knowledge acquired on genomics, transcriptomics, and the metabolic features of Legionella, and, particularly, we present new insight on comparative genomics, evolution, horizontal gene transfer, and the regulation of the life cycle of L. pneumophila.
#3 Legionnaires’ disease – Symptoms & causes – Mayo Clinic
https://www.mayoclinic.org/diseases-conditions/legionnaires-disease/symptoms-causes/syc-20351747
Legionnaires’ disease is a severe form of a lung infection called pneumonia. It’s caused by a bacterium known as legionella. […] The bacterium Legionella pneumophila causes most cases of Legionnaires’ disease. Outdoors, legionella bacteria live in soil and water. In those places the bacteria rarely cause infections. But legionella bacteria can grow in water systems made by humans, such as air conditioners. […] Most people become infected when they breathe in tiny water droplets that have legionella bacteria. This might be from the spray from a shower, sink or hot tub. Or it might be from water from the system that cools large buildings. […] The infection can spread in other ways besides breathing in water droplets. The infection can spread by: Aspiration. This occurs when liquids enter the lungs by accident, most often because of coughing or choking while drinking. Aspirating water that has legionella bacteria can cause Legionnaires’ disease. […] Legionnaires’ disease can lead to serious complications, including: Lung failure. This occurs when the lungs can’t provide the body with enough oxygen or can’t remove enough carbon dioxide from the blood. […] When not treated promptly, Legionnaires’ disease can kill.
#3 Severe Legionnairesâ disease | Annals of Intensive Care | Full Text
https://annalsofintensivecare.springeropen.com/articles/10.1186/s13613-024-01252-y
All Legionella species show evidence of long-lasting coevolution with their protozoan hosts. […] Legionella is an opportunistic pathogen that incidentally infects humans. LD is an evolutionary dead-end for Legionella; it is either cleared by the immune system or results in the death of the patient.
#3 Phagocytosis of the legionnaires’ disease bacterium (legionella pneumophila) occurs by a novel mechanism: Engulfment within a Pseudopod coil
https://escholarship.org/uc/item/258844f0
Phagocytosis of Legionella pneumophila, a bacterial pathogen that multiplies intracellularly in human mononuclear phagocytes and causes Legionnaires’ disease, occurs by a novel mechanism. […] Human monocytes, alveolar macrophages, and polymorphonuclear leukocytes all phagocytize L. pneumophila by this unusual process, termed „coiling phagocytosis,” and these leukocytes phagocytize not only live L. pneumophila in this way, but also formalin-killed, glutaraldehyde-killed, and heat-killed L. pneumophila. […] Treatment of L. pneumophila with high-titer anti-L. pneumophila antibody abolishes coiling phagocytosis; such bacteria are internalized by conventional phagocytosis. […] These experiments raise the possibility that a surface component of L. pneumophila mediates the unusual response by the phagocyte. […] Such a component, if elaborated in vivo, might be responsible for extrapulmonary manifestations of Legionnaires’ disease suspected of being toxin-mediated.
#3 Legionella – Medical Microbiology – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK7619/
Legionella bacilli reside in surface and drinking water and are usually transmitted to humans in aerosols. The bacteria multiply intracellularly in alveolar macrophages. Recruited neutrophils and monocytes, as well as bacterial enzymes, produce destructive alveolar inflammation. […] The pathogenesis of Legionella infections begins with a supply of water containing virulent bacteria and with a means for dissemination to humans. Person-to-person transmission has never been demonstrated, and Legionella is not a member of the bacterial flora of humans. […] Infection begins in the lower respiratory tract. Alveolar macrophages, which are the primary defense against bacterial infection of the lungs, engulf the bacteria; however, Legionella is a facultative intracellular parasite and multiplies freely in macrophages. The bacteria bind to alveolar macrophages via the complement receptors and are engulfed into a phagosomal vacuole. However, by an unknown mechanism, the bacteria block the fusion of lysosomes with the phagosome, preventing the normal acidification of the phagolysosome and keeping the toxic myeloperoxidase system segregated from the susceptible bacteria. The bacilli multiply within the phagosome. Thus, a cellular compartment that should be a death trap instead becomes a nursery. Eventually, the cell is destroyed, releasing a new generation of microbes to infect other cells.
#3
https://pmc.ncbi.nlm.nih.gov/articles/PMC2863363/
In all models, following internalization by the host cell, the bacterial vacuole associates transiently with mitochondria and then acquires characteristics of the endoplasmic reticulum (ER). […] The unusual biogenesis of the Legionella vacuole arises from the simultaneous delay of endosome fusion and the recruitment of vesicles and membrane from the host cell secretory pathway. […] The LCV specifically recruits Rab1, but not Rab2 or Rab6, to the LCV within minutes of uptake, preceding any remodeling of the vacuole. […] The ability of L. pneumophila to establish and maintain this intracellular niche indicates that the bacteria actively and continually manipulate host cell trafficking from within the replicative vacuole. […] Replication of L. pneumophila bacteria then commences between 4 and 10 h after phagocytosis, and the bacteria continue to replicate within a vacuole that maintains a neutral pH.
#3
https://pmc.ncbi.nlm.nih.gov/articles/PMC2863363/
Other evidence suggests that the manipulation of autophagy by L. pneumophila is important for bacterial replication. […] The Dot/Icm system is required for intracellular replication and the establishment of the LCV, it is also involved in bacterial entry, the inhibition of host cell apoptosis, and the egress of L. pneumophila from host cells. […] The Dot/Icm effectors therefore constitute around 10% of the L. pneumophila proteome, which suggests that the effectors are a major determinant of L. pneumophila survival and that the selection for their retention is strong. […] The L. pneumophila genome encodes several putative Dot/Icm effector proteins with eukaryotic motifs that function in the eukaryotic ubiquitination pathway. […] The L. pneumophila type II secretion system (T2SS) termed Lsp, for Legionella secretion pathway, which is required for full virulence and environmental persistence.
#3 Legionellosis: a novel mechanism by which the bacterium Legionella pneumophila regulates the immune response of its host cells | EurekAlert!
https://www.eurekalert.org/news-releases/943972
Legionellosis or Legionnaires disease affected more than 1 800 people in France in 2019 and caused 160 deaths. This emerging disease is caused by Legionella pneumophila, an environmental bacterium that thrives in hot water systems. Researchers from the Institut Pasteur, the CNRS, the University of Paris have discovered a mechanism that allows Legionella pneumophila to target the immune response of the cells it infects by secreting a small regulatory RNA. This mechanism, not described before, facilitates the survival and proliferation of Legionella pneumophila during infection. […] Legionella pneumophila has a large repository of effector proteins that mimic host cell functions and are used by the pathogen to manipulate host signaling pathways to the pathogens advantage. […] The researchers have discovered that these two bacterial RNAs, named RsmY and tRNA-Phe, function in the host cell in a microRNA-like manner. They downregulate RIG-I, a protein in the cell that detects foreign RNA molecules in order to initiate an immune response. The down regulation of the expression of RIG-I leads to a diminished host immune response and a better replication of Legionella pneumophila. […] This work sheds new light on the diverse, sophisticated strategies employed by intracellular pathogens for survival and development during infection.
#3 A Legionella pneumophila amylase is essential for intracellular replication in human macrophages and amoebae | Scientific Reports
https://www.nature.com/articles/s41598-018-24724-1
Legionella pneumophila invades protozoa with an accidental ability to cause pneumonia upon transmission to humans. To support its nutrition during intracellular residence, L. pneumophila relies on host amino acids as the main source of carbon and energy to feed the TCA cycle. […] Loss of LamB or expression of catalytically-inactive variants of LamB results in a severe growth defect of L. pneumophila in Acanthamoeba polyphaga and human monocytes-derived macrophages. Importantly, the lamB null mutant is severely attenuated in intra-pulmonary proliferation in the mouse model and is defective in dissemination to the liver and spleen. Our data show an essential role for LamB in intracellular replication of L. pneumophila in amoeba and human macrophages and in virulence in vivo.
#3 Severe Legionnairesâ disease | Annals of Intensive Care | Full Text
https://annalsofintensivecare.springeropen.com/articles/10.1186/s13613-024-01252-y
Studies have shown an association between initial Legionella DNA load in respiratory samples and initial high pneumonia severity score, ICU admission or prolonged hospitalisation. […] The respiratory tract microbiome (RTM) balance is impaired in the case of severe LD. […] The interaction between the balance of the respiratory microbiome, the dynamics of the pathogen load and the interventions associated with hospitalisation (mechanical ventilation, antibiotics, etc.) plays an essential role in the recovery of patients with pneumonia. […] In humans, the data are sparse; one study in a small number of patients showed that the intensity of the inflammatory cytokine response was greater in the most severe patients. […] A recent study of a prospective cohort found that severe LD patients under mechanical ventilation presented an initial increase in the systemic secretion of seven pro-inflammatory mediators and a leukocyte hypo-responsiveness with a lower secretion capacity for 16 cytokines, suggesting immunoparalysis.
#3
https://journals.lww.com/ajg/fulltext/2018/10001/legionella_and_the_liver__severe_hepatic_injury.2170.aspx
Legionella is a rare, but recognized, cause of rhabdomyolysis. The mechanism is unknown, but theorized to be a direct invasion of Legionella into the muscle or release of endotoxin into circulation that causes muscle injury. […] While elevated aminotransaminases have been reported to occur with Legionella pneumonia in the absence of significant liver injury, this case illustrates that severe hepatic injury can occur with this infection. Elevated INR with ALT can be important indicators for associated hepatic injury. Heightened awareness of this potential complication can guide management and potentially improve clinical outcome.
#3 Legionella Infections – Infectious Diseases – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/infectious-diseases/gram-negative-bacilli/legionella-infections
Slow growth on laboratory media may delay identification for 3 to 5 days. […] Laboratory abnormalities often include hyponatremia, hypophosphatemia, and elevated aminotransferase and C-reactive protein levels. […] L. pneumophila usually causes pulmonary infection; it rarely causes extrapulmonary infections (most often involving the heart). […] L. pneumophila infection is typically acquired by inhaling aerosols (or less often by aspiration) of contaminated water; it is not transmitted from person to person.
#3 Legionnaire’s-disease-associated meningoencephalitis: A case report | Pulmonology
https://journalpulmonology.org/en-legionnaire39s-disease-associated-meningoencephalitis-a-case-report-articulo-S2531043719300042
Legionnaire’s disease is a pneumonia caused by the gram-negative bacteria Legionella spp. which contaminate artificial freshwater systems. […] Although primarily a lung disease, the central nervous system (CNS) may also be affected. […] Legionnaire’s disease, a primarily pulmonary pathology, can also manifest neurological symptoms. […] In addition, brainstem and cerebellar symptoms such as ataxi or dysarthria, from which our patient also suffered, are also frequently observed. […] The characteristics of these lesions is their full reversibility after initiation of an appropriate antibiotic therapy. […] It is hypothesized that this phenomenon is caused by a reversible sinus vein thrombosis. […] The striking fact that in most patients Legionella spp. was not detectable in the CSF has led some authors to consider the underlying mechanism to be an immune- or toxin-mediated reaction rather than direct damage by the bacteria.
#3 Texas DSHS Report of the Texas Legionnairesâ Disease Task Force | Texas DSHS
https://www.dshs.texas.gov/legionellosis-legionnaires-disease/legionellosis-legionnaires-disease-task-force-recommendations/texas-dshs-report-the
In hospitals and other institutions, Legionella are found primarily in two locations, 1) potable hot water systems and 2) water in cooling towers. […] Ingestion/aspiration and aerosolization of potable water from hot water systems are thought to represent the major routes by which the organism is transmitted to patients in nosocomial Legionella cases. […] Factors which determine whether a specific hospital water system will be colonized with Legionella are not well understood, but probably include the type of disinfection used, age and condition of the pipes, the degree of scaling and sediment, and the potential for biofilm formation within the system. […] Temporary elimination or reduction of Legionella colonization in a hot water „ecosystem” is possible, although difficult. […] Success depends on the design and condition of the system, as well as the remediation methodology used.
#4 Legionellosis (Legionnaires’ Disease and Pontiac Fever) – Medical information | Occupational Safety and Health Administration
http://www.osha.gov/legionnaires-disease/medical-Information
Legionellosis is not contagious, meaning it is not spread from person-to-person. Disease transmission primarily occurs through inhaling Legionella-contaminated, aerosolized water. While rare, exposure is also possible from breathing in (i.e., aspirating) Legionella contaminated soil or while drinking water. An exposed person’s physical condition (general health), the Legionella concentration in an aerosol (bacteria suspended in air, including in droplets), and contamination levels at a source all contribute to whether an exposure results in disease and how severe the disease is. […] When Legionnaires’ disease progresses to pneumonia, it is frequently severe and can be fatal. It is important to recognize Legionnaires’ disease symptoms because early medical treatment can save lives. […] The reason for illness in Legionnaires’ disease is a bacterial infection, while Pontiac Fever is a reaction to endotoxin production by Legionella bacteria.
#4
https://pmc.ncbi.nlm.nih.gov/articles/PMC2863363/
The genus Legionella contains more than 50 species, of which at least 24 have been associated with human infection. The best-characterized member of the genus, Legionella pneumophila, is the major causative agent of Legionnaires’ disease, a severe form of acute pneumonia. L. pneumophila is an intracellular pathogen, and as part of its pathogenesis, the bacteria avoid phagolysosome fusion and replicate within alveolar macrophages and epithelial cells in a vacuole that exhibits many characteristics of the endoplasmic reticulum (ER). […] The formation of the unusual L. pneumophila vacuole is a feature of its interaction with the host, yet the mechanisms by which the bacteria avoid classical endosome fusion and recruit markers of the ER are incompletely understood. […] The innate ability of Legionella to replicate within different protozoa has equipped the bacteria with the capacity to replicate in human alveolar macrophages. The interaction of L. pneumophila with eukaryotic cells is therefore key to understanding the ability of the pathogen to cause disease.
#4 Legionella Infection: Practice Essentials, Pathophysiology, Etiology
https://emedicine.medscape.com/article/965492-overview
Organisms that reach the alveoli undergo phagocytosis by the alveolar macrophages but are not actively killed. Macrophages may actually support the growth of Legionella organisms. The bacteria multiply intracellularly until the cell ruptures. Liberated bacteria then infect other macrophages. Additional virulence factors include genes that potentiate infection of macrophages and inhibit phagosomal fusion, allowing intracellular growth. […] Cell-mediated immunity appears to be the primary host defense mechanism against Legionella infection. Activation of macrophages produces cytokines that regulate antimicrobial activity against Legionella organisms. Individuals with certain deficiencies in cell-mediated immunity are at increased risk for legionellosis. […] Once infection is established, Legionella organisms cause an acute fibrinopurulent pneumonia with alveolitis and bronchiolitis. In addition to the lungs, Legionella organisms may infect the lymph nodes, brain, kidney, liver, spleen, bone marrow, and myocardium.
#4
https://pmc.ncbi.nlm.nih.gov/articles/PMC2863363/
In all models, following internalization by the host cell, the bacterial vacuole associates transiently with mitochondria and then acquires characteristics of the endoplasmic reticulum (ER). […] The unusual biogenesis of the Legionella vacuole arises from the simultaneous delay of endosome fusion and the recruitment of vesicles and membrane from the host cell secretory pathway. […] The LCV specifically recruits Rab1, but not Rab2 or Rab6, to the LCV within minutes of uptake, preceding any remodeling of the vacuole. […] The ability of L. pneumophila to establish and maintain this intracellular niche indicates that the bacteria actively and continually manipulate host cell trafficking from within the replicative vacuole. […] Replication of L. pneumophila bacteria then commences between 4 and 10 h after phagocytosis, and the bacteria continue to replicate within a vacuole that maintains a neutral pH.
#4
https://pmc.ncbi.nlm.nih.gov/articles/PMC2863363/
Other evidence suggests that the manipulation of autophagy by L. pneumophila is important for bacterial replication. […] The Dot/Icm system is required for intracellular replication and the establishment of the LCV, it is also involved in bacterial entry, the inhibition of host cell apoptosis, and the egress of L. pneumophila from host cells. […] The Dot/Icm effectors therefore constitute around 10% of the L. pneumophila proteome, which suggests that the effectors are a major determinant of L. pneumophila survival and that the selection for their retention is strong. […] The L. pneumophila genome encodes several putative Dot/Icm effector proteins with eukaryotic motifs that function in the eukaryotic ubiquitination pathway. […] The L. pneumophila type II secretion system (T2SS) termed Lsp, for Legionella secretion pathway, which is required for full virulence and environmental persistence.
#4 Legionellosis: A novel mechanism by which the bacterium Legionella pneumophila regulates the immune response of its host cells | ScienceDaily
https://www.sciencedaily.com/releases/2022/02/220218100648.htm
Legionellosis or Legionnaires’ disease affected more than 1,800 people in France in 2019 and caused 160 deaths. […] Researchers have discovered a mechanism that allows Legionella pneumophila to target the immune response of the cells it infects by secreting a small regulatory RNA. This mechanism, not described before, facilitates the survival and proliferation of Legionella pneumophila during infection. […] Legionella pneumophila has a large repository of effector proteins that mimic host cell functions and are used by the pathogen to manipulate host signaling pathways to the pathogens advantage. […] The researchers have discovered that these two bacterial RNAs, named RsmY and tRNA-Phe, function in the host cell in a microRNA-like manner. They downregulate RIG-I, a protein in the cell that detects foreign RNA molecules in order to initiate an immune response. The down regulation of the expression of RIG-I leads to a diminished host immune response and a better replication of Legionella pneumophila. […] This work sheds new light on the diverse, sophisticated strategies employed by intracellular pathogens for survival and development during infection.
#4 A Legionella pneumophila amylase is essential for intracellular replication in human macrophages and amoebae | Scientific Reports
https://www.nature.com/articles/s41598-018-24724-1
These data show that LamB is necessary for intracellular replication of L. pneumophila in both hMDMs and A. polyphaga. Indeed, it is the amylase activity of LamB that contributes to its essential role in intracellular growth, indicating the requirement for degradation of polysaccharides by L. pneumophila. […] Given that A. polyphaga and hMDMs restrict the lamB mutant, we sought to determine the role of LamB in intrapulmonary growth in the mouse model, in vivo. […] The defective phenotype was completely recovered by complementation, indicating minimal loss of plasmid in vivo compared to ex vivo infection. […] In summary, we report an amylase essential for intracellular proliferation of L. pneumophila within the two evolutionarily distant hosts, human macrophages and amoebae. Given its uniqueness to L. pneumophila, LamB serves as an interesting enzyme that may contribute to the prevalence and virulence of L. pneumophila compared to other Legionella species.
#4 Legionnaire’s-disease-associated meningoencephalitis: A case report | Pulmonology
https://journalpulmonology.org/en-legionnaire39s-disease-associated-meningoencephalitis-a-case-report-articulo-S2531043719300042
Nevertheless, the gradual clinical improvement, as well as the disappearance of the brain hyperintensities after adjusting the antibiotics, encourage us to conclude that Legionnaire’s disease is the most probable source for the patient’s condition and that the water appliances for the animals he raised were the source of contamination. […] As these symptoms are uncommon, physicians might easily overlook this pathogen in cases presenting primarily with extra-pulmonary signs and symptoms.
#4 Texas DSHS Report of the Texas Legionnairesâ Disease Task Force | Texas DSHS
https://www.dshs.texas.gov/legionellosis-legionnaires-disease/legionellosis-legionnaires-disease-task-force-recommendations/texas-dshs-report-the
If a system is old, cleaning and descaling may be an important component of a Legionella control program. […] As Legionella is killed by temperatures over 50oC (122oF), superheating of water may be efficacious. […] Continuous hyperchlorination has been attempted by several institutions, but has generally been discontinued because of its corrosive effect on plumbing. […] A new hospital at the University of Virginia built in 1989 had a UV light disinfection system installed on the municipal water intake upon completion. […] There are also now intriguing data suggesting that use of monochloramine as a disinfectant in municipal and hospital systems is effective in eradicating Legionella. […] The link between specific levels of colonization and risk of nosocomial Legionella infection remains uncertain. […] The Texas Department of State Health Services has investigated three legionellosis outbreaks since 1989, involving from 3 to 20 patients each. […] The Task Force recommends that each facility consider these factors in determining whether there is an increased risk of nosocomial transmission.
#5
https://www.who.int/news-room/fact-sheets/detail/legionellosis
The infective dose is unknown but can be assumed to be low for susceptible people, as illnesses have occurred after short exposures and 3 or more kilometres from the source of outbreaks. The likelihood of illness depends on the concentrations of Legionella in the water source, the production and dissemination of aerosols, host factors such as age and pre-existing health conditions and the virulence of the particular strain of Legionella. Most infections do not cause illness.
#5 Severe Legionnairesâ disease | Annals of Intensive Care | Full Text
https://annalsofintensivecare.springeropen.com/articles/10.1186/s13613-024-01252-y
All Legionella species show evidence of long-lasting coevolution with their protozoan hosts. […] Legionella is an opportunistic pathogen that incidentally infects humans. LD is an evolutionary dead-end for Legionella; it is either cleared by the immune system or results in the death of the patient.
#5 Legionella – Medical Microbiology – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK7619/
Legionella bacilli reside in surface and drinking water and are usually transmitted to humans in aerosols. The bacteria multiply intracellularly in alveolar macrophages. Recruited neutrophils and monocytes, as well as bacterial enzymes, produce destructive alveolar inflammation. […] The pathogenesis of Legionella infections begins with a supply of water containing virulent bacteria and with a means for dissemination to humans. Person-to-person transmission has never been demonstrated, and Legionella is not a member of the bacterial flora of humans. […] Infection begins in the lower respiratory tract. Alveolar macrophages, which are the primary defense against bacterial infection of the lungs, engulf the bacteria; however, Legionella is a facultative intracellular parasite and multiplies freely in macrophages. The bacteria bind to alveolar macrophages via the complement receptors and are engulfed into a phagosomal vacuole. However, by an unknown mechanism, the bacteria block the fusion of lysosomes with the phagosome, preventing the normal acidification of the phagolysosome and keeping the toxic myeloperoxidase system segregated from the susceptible bacteria. The bacilli multiply within the phagosome. Thus, a cellular compartment that should be a death trap instead becomes a nursery. Eventually, the cell is destroyed, releasing a new generation of microbes to infect other cells.
#5 Legionellosis: a novel mechanism by which the bacterium Legionella pneumophila regulates the immune response of its host cells | EurekAlert!
https://www.eurekalert.org/news-releases/943972
Legionellosis or Legionnaires disease affected more than 1 800 people in France in 2019 and caused 160 deaths. This emerging disease is caused by Legionella pneumophila, an environmental bacterium that thrives in hot water systems. Researchers from the Institut Pasteur, the CNRS, the University of Paris have discovered a mechanism that allows Legionella pneumophila to target the immune response of the cells it infects by secreting a small regulatory RNA. This mechanism, not described before, facilitates the survival and proliferation of Legionella pneumophila during infection. […] Legionella pneumophila has a large repository of effector proteins that mimic host cell functions and are used by the pathogen to manipulate host signaling pathways to the pathogens advantage. […] The researchers have discovered that these two bacterial RNAs, named RsmY and tRNA-Phe, function in the host cell in a microRNA-like manner. They downregulate RIG-I, a protein in the cell that detects foreign RNA molecules in order to initiate an immune response. The down regulation of the expression of RIG-I leads to a diminished host immune response and a better replication of Legionella pneumophila. […] This work sheds new light on the diverse, sophisticated strategies employed by intracellular pathogens for survival and development during infection.
#5
https://www.goethe-university-frankfurt.de/80811091/Surprising_insight_into_Legionnaires__disease
Frankfurt researchers have explained the mechanism of regulator SidJ in detail / Accelerated publication in Nature. […] In order to control cellular processes and thwart the immune system, the bacterium Legionella pneumophilia, the cause of the notorious Legionnaires’ disease, releases hundreds of enzymes. […] They discovered how the regulatory enzyme SidJ keeps other dangerous virulence factors in check. […] What makes Legionella so dangerous is its ability to multiply in phagocytes of the immune system by secreting virulence factors. […] However, since Legionella needs the host cells in order to multiply, it has developed a sophisticated mechanism for the precise metering of SidE enzyme activity. […] They have shown that the regulator SidJ also released by Legionella works as an antidote to SidE enzymes, thus ensuring accurate control of SidE activity.
#5 About Legionnairesâ Disease – MN Dept. of Health
https://www.health.state.mn.us/diseases/legionellosis/basics.html
The key to preventing Legionnaires disease is to reduce the risk of Legionella growth and spread in building water systems and devices through good maintenance strategies. These strategies include monitoring water temperatures and disinfectant levels and preventing stagnant water conditions. […] Building owners and managers should develop and implement a water management program using ASHRAE (American Society of Heating, Refrigerating and Air-Conditioning Engineers) standards.
#6 Virulence factors, Pathogenesis and Clinical manifestations of Legionella pneumophila
https://microbenotes.com/virulence-factors-pathogenesis-and-clinical-manifestations-of-legionella-pneumophila/
This mode of entry appears to limit the oxidative burst of the phagocyte and hence enhances the intracellular survival of the legionellae. […] Chemokines and cytokines released by the infected macrophages stimulate a robust inflammatory response that is characteristic of infections with Legionella. […] The organisms proliferate in their intracellular vacuole, phagosomal vacuoles (Legionella-containing vacuole, LCV), and produce proteolytic enzymes (phosphatase, lipase, and nuclease) that eventually kill the host cell when the vacuole is lysed. […] During the late replicative phase the legionella-containing phagosome merges with lysosomes, but replication continues until the host cell is packed with organisms and finally disrupts releasing bacteria to infect further host cells. […] In addition to this process, phagosome survival and organism replication are facilitated by the elaboration of a type IV secretion system call Dot/Icm which is essential for L. pneumophila.
#6
https://www.goethe-university-frankfurt.de/80811091/Surprising_insight_into_Legionnaires__disease
The SidJ regulator is a glutamylase, i.e. it has a rare enzyme activity that allows amino acid glutamates to be linked together to form chains. […] In this case, SidJ attacks the central glutamate of SidE enzymes and inhibits their activity. […] Our finding that Legionella pneumophilia uses exactly this mechanism to sustain the infection certainly argues for more research in this field. […] This so far unknown mechanism opens up new possibilities for research to inhibit the spread of Legionella in the host organism. […] We’re currently working on eliminating SidJ selectively by developing inhibitors for the glutamylase domain.