Bruceloza
Patofizjologia i mechanizm

Bruceloza jest chorobą odzwierzęcą wywoływaną przez Gram-ujemne bakterie z rodzaju Brucella, które wykazują zdolność do przeżywania i namnażania się wewnątrz komórek fagocytujących i niefagocytujących, co umożliwia im unikanie mechanizmów obronnych gospodarza i prowadzi do przewlekłego zakażenia. Drogi zakażenia obejmują uszkodzoną skórę, błony śluzowe, drogę pokarmową (spożycie niepasteryzowanych produktów mlecznych) oraz drogę oddechową. Po wniknięciu bakterie penetrują komórki nabłonkowe, są fagocytowane przez makrofagi i komórki dendrytyczne, a następnie transportowane do układu limfatycznego i narządów takich jak wątroba, śledziona, nerki, stawy czy ośrodkowy układ nerwowy. Kluczowe mechanizmy patogenne obejmują unikanie fuzji fagosomu z lizosomem dzięki systemowi sekrecji typu IV (T4SS) kodowanemu przez operon virB, a także modulację odpowiedzi immunologicznej gospodarza poprzez hamowanie apoptozy, dojrzewania komórek dendrytycznych i aktywacji limfocytów T. Lipopolisacharyd (LPS) Brucella ma nietypową strukturę, która osłabia rozpoznanie przez receptory TLR4, co sprzyja przewlekłości zakażenia.

  1. Patogeneza brucelozy
    1. Wnikanie i kolonizacja
    2. Przeżycie wewnątrzkomórkowe
    3. Główne czynniki wirulencji
    4. Modulacja odpowiedzi immunologicznej
  2. Mechanizmy patogenezy brucelozy
    1. Specyfika tkanek docelowych
    2. Fazy zakażenia
    3. Mechanizmy przetrwania wewnątrzkomórkowego
    4. Rola odpowiedzi immunologicznej
  3. Różnice między gatunkami Brucella
    1. Patogeneza w różnych gatunkach żywicieli
  4. Bruceloza – patogeneza u ludzi
    1. Neurobruceloza
    2. Immunopatogeneza brucelozy
    3. Kolejne rozdziały

Patogeneza brucelozy

Bruceloza jest chorobą odzwierzęcą wywoływaną przez bakterie z rodzaju Brucella, które są Gram-ujemnymi, małymi pałeczkami zdolnymi do zakażania ssaków. Najważniejszą cechą bakterii Brucella jest zdolność do przeżycia i namnażania się zarówno w komórkach fagocytujących, jak i niefagocytujących, co stanowi podstawę patogenezy tej choroby.12 Ta zdolność pozwala bakteriom na unikanie mechanizmów obronnych gospodarza i przyczynia się do rozwoju przewlekłego zakażenia.

Wnikanie i kolonizacja

Bakterie Brucella wnikają do organizmu gospodarza przez uszkodzoną skórę, błony śluzowe, drogą pokarmową (spożycie niepasteryzowanych produktów mlecznych) lub drogą oddechową.34 Po wniknięciu do organizmu, bakterie penetrują komórki nabłonkowe za pomocą mechanizmu przypominającego zapięcie na zamek (zipper-like mechanism).56 Następnie bakterie są fagocytowane przez makrofagi i komórki dendrytyczne, gdzie przeżywają i namnażają się.

Po wniknięciu do krwiobiegu, bakterie Brucella szybko stają się patogenami wewnątrzkomórkowymi zawartymi w krążących polimorfonuklearach i makrofagach. Bakterie, które przetrwały, są transportowane do układu limfatycznego i mogą replikować się lokalnie, a także w nerkach, wątrobie, śledzionie, tkance piersi lub stawach, powodując zarówno zakażenie miejscowe, jak i ogólnoustrojowe.7 Każdy układ narządów może zostać zajęty (np. ośrodkowy układ nerwowy, serce, stawy, układ moczowo-płciowy, układ oddechowy i skóra).

Przeżycie wewnątrzkomórkowe

Po wniknięciu do makrofagów, bakterie Brucella wykorzystują szereg mechanizmów umożliwiających im uniknięcie wewnątrzkomórkowego zniszczenia. Kluczowym elementem jest zdolność bakterii do manipulowania wewnątrzkomórkowym transportem, co pozwala im na uniknięcie fuzji fagosomu z lizosomem.8 Bakterie wykorzystują system sekrecji typu IV (T4SS kodowany przez operon virB), który jest odpowiedzialny za regulację wewnątrzkomórkowego transportu z autofagosomu do retikulum endoplazmatycznego (ER).9

Proces infekcji wewnątrzkomórkowej można podzielić na kilka etapów:

  1. Interakcja z wczesną siecią endocytarną, która trwa około 10 minut10
  2. Formowanie wczesnej wakuoli zawierającej Brucella (BCV – Brucella Containing Vacuole)11
  3. Tworzenie późnej BCV
  4. Interakcja z retikulum endoplazmatycznym, gdzie bakterie się namnażają12

Ostatnim etapem wewnątrzkomórkowego transportu Brucella jest pozyskanie markerów charakterystycznych dla retikulum endoplazmatycznego: kalneksyny, kalretikuliny i Sec61, chociaż na tym etapie BCV tracą LAMP-1.13 Mechanizm połączenia BCV z ER pozostaje niejasny.

Główne czynniki wirulencji

Główne czynniki wirulencji Brucella to:1415

  • Lipopolisacharyd (LPS) – pełni kluczową rolę w przeżyciu bakterii wewnątrz komórek fagocytujących. LPS Brucella ma nietypową strukturę, która zapobiega skutecznemu rozpoznaniu przez receptory TLR4, co prowadzi do słabszej aktywacji odpowiedzi immunologicznej.1617
  • System sekrecji typu IV (T4SS) – umożliwia transport białek i makrocząsteczek przez błony komórkowe i jest niezbędny do przeżycia wewnątrzkomórkowego.18
  • System dwuskładnikowy BvrR/BvrS – najlepiej scharakteryzowane komponenty systemu wirulencji; mutanty są niezdolne do inwazji, zapobiegania fuzji fagosomu z lizosomem i replikacji wewnątrzkomórkowej.1920
  • Cykliczne β-1,2-glukany – przyczyniają się do wirulencji bakterii21

W przeciwieństwie do innych bakterii, Brucella nie posiada klasycznych czynników wirulencji, takich jak egzotoksyny, otoczki, wydzielane proteazy, fimbrie, wici, plazmidy wirulencji, szczepy oporne i toksyny kodowane przez fagi.22 Zamiast tego, stosuje bardziej wyrafinowane strategie unikania odpowiedzi immunologicznej gospodarza.

Modulacja odpowiedzi immunologicznej

Brucella może modyfikować odpowiedź immunologiczną w komórkach gospodarza.23 Szczepy z S-LPS są w stanie hamować apoptozę zainfekowanych komórek poprzez interakcję łańcucha O z TNF-α (czynnikiem martwicy nowotworu). W ten sposób martwe komórki nie uwalniają specyficznych czynników, nie aktywują układu odpornościowego, a bakterie Brucella są w stanie uniknąć nadzoru immunologicznego gospodarza.24

Brucella hamuje dojrzewanie komórek dendrytycznych, prezentację antygenów i aktywację naiwnych limfocytów T, co zaburza rozwój skutecznej odpowiedzi immunologicznej.25 Bakterie wytwarzają białko TcpB, które naśladuje właściwości adaptora receptora Toll-like TIRAP. TcpB promuje degradację TIRAP i zakłóca sygnalizację TLR4, co prowadzi do zahamowania produkcji cytokin prozapalnych i dojrzewania komórek dendrytycznych.26

Chociaż Brucella może być rozpoznawana przez receptory TLR, to dzięki modyfikacjom jej interakcja z TLR jest 10-krotnie słabsza niż w przypadku bakterii z rodziny Enterobacteriaceae.27 To osłabione rozpoznanie przyczynia się do chroniczności zakażenia.

Mechanizmy patogenezy brucelozy

Specyfika tkanek docelowych

Brucella wykazuje wyraźny tropizm do określonych tkanek, w tym układu limfatyczno-siateczkowego i układu rozrodczego.2829 Szczególnie wysoki tropizm bakterie wykazują do trofoblastu łożyska w płucach płodu, ciężarnych samic lub układu rozrodczego. Ta preferencja tkankowa przyczynia się do charakterystycznych objawów klinicznych brucelozy, takich jak poronienia u zwierząt.

W zakażeniu B. abortus odpowiedź gospodarza charakteryzuje się rozwojem ziarniniaków tkankowych nieodróżnialnych od ziarniny sarkoidalnej. W przeciwieństwie do tego, zakażenie bardziej zjadliwymi gatunkami (B. melitensis i B. suis) częściej prowadzi do powstawania mikroropni w narządach wewnętrznych.30

Fazy zakażenia

Patogeneza brucelozy obejmuje trzy główne fazy:3132

  1. Faza inkubacji – okres przed wystąpieniem objawów klinicznych. Czas inkubacji brucelozy może być zmienny i trudny do ustalenia, ale zazwyczaj wynosi od 2 do 4 tygodni, z zakresem od 5 dni do 5 miesięcy.
  2. Faza ostra – charakteryzuje się pojawieniem się objawów i oznak takich jak gorączka, poty, zmęczenie, powiększenie wątroby i śledziony. W tej fazie patogen najeżdża i rozprzestrzenia się w tkankach gospodarza.
  3. Faza przewlekła – zdolność organizmu do utrzymywania się w komórkach gospodarza, prowadząca do rozproszenia bakterii przez układ limfatyczno-siateczkowy i ostatecznie powodująca chorobę sercowo-naczyniową, wątrobową, limfatyczno-siateczkową, neurologiczną i kostno-stawową.

Namnażanie Brucella w komórkach obejmuje dwie fazy: fazę stabilną i fazę wykładniczą.33 W fazie stabilnej bakterie adaptują się do środowiska wewnątrzkomórkowego, natomiast w fazie wykładniczej następuje intensywne namnażanie.

Mechanizmy przetrwania wewnątrzkomórkowego

Przeżycie Brucella wewnątrz komórek fagocytujących zależy od kilku kluczowych mechanizmów:3435

  • Hamowanie fuzji fagosomu z lizosomem – dzięki produkcji monofosforanu adeniny i guaniny, które hamują tę fuzję36
  • Hamowanie wybuchu tlenowego – ograniczenie aktywności bakteriobójczej makrofagów
  • Adaptacja do kwaśnego pH, niskiego poziomu tlenu i niskiego poziomu składników odżywczych37
  • Wykorzystanie systemu sekrecji typu IV (VirB) do regulacji transportu wewnątrzkomórkowego
  • Produkcja dysmutazy ponadtlenkowej Cu-Zn, która nadaje oporność na reaktywne formy tlenu38

Internalizacja Brucella abortus może zmieniać szlak transportu bakterii w komórkach gospodarza, zmieniać normalny proces dojrzewania fagosomów w komórkach gospodarza i zakłócać adhezję fagolizosomów do Brucella.39 Po replikacji w retikulum endoplazmatycznym, bakterie Brucella są uwalniane z pomocą hemolizyn i wywoływanej nekrozy komórek.40

Rola odpowiedzi immunologicznej

Rozwój odporności komórkowej jest głównym mechanizmem walki z zakażeniem Brucella.41 Chociaż zakażenie Brucella jest głównie kontrolowane przez odporność komórkową, a nie przez aktywność przeciwciał, pewną ochronę przed ponownym zakażeniem zapewniają immunoglobuliny surowicy.42

Początkowo wzrasta poziom IgM, a następnie miano IgG. IgM może pozostawać w surowicy na niskim poziomie przez kilka miesięcy, podczas gdy IgG ostatecznie spada. Trwale podwyższone miana IgG lub ponowny wzrost IgG zwykle wskazują na przewlekłe lub nawracające zakażenie. Przeciwciała IgA są wytwarzane późno i mogą utrzymywać się przez bardzo długi czas.4344

Brucella może hamować apoptozę makrofagów poprzez hamowanie wydzielania TNF-α, dzięki czemu może przetrwać w komórce i namnażać się w dużej liczbie, osłabiać funkcję fagocytarną makrofagów, tracić działanie zabijające i funkcję prezentacji antygenów makrofagów, a ostatecznie unikać nadzoru immunologicznego gospodarza.45

Brucella reguluje odpowiedź immunologiczną, indukując cytokiny regulacyjne (takie jak IL-10), co wskazuje, że szlak IL-10 odgrywa ważną rolę w przewlekłym zakażeniu wywołanym przez Brucella.46

Różnice między gatunkami Brucella

Różne gatunki Brucella wykazują zróżnicowaną zjadliwość i preferencje gospodarza:47

  • B. melitensis – najbardziej zjadliwy gatunek, powoduje najcięższe zakażenia u ludzi
  • B. abortus – związany z mniej częstymi zakażeniami i większą proporcją przypadków subklinicznych
  • B. suis – zjadliwość szczepów dla ludzi jest zróżnicowana, ale ogólnie o pośrednim nasileniu
  • B. canis – ma szorstki LPS w przeciwieństwie do gładkiego LPS pozostałych głównych gatunków

Fagocyty mogą łatwo zabijać B. abortus, co prowadzi do rozwoju ziarniniaków tkankowych, natomiast rzadko pochłaniają B. melitensis, co prowadzi do powstawania mikroropni w narządach; wyjaśnia to różnice w patogenności i objawach klinicznych u ludzi chorych na brucelozę.48

Patogeneza w różnych gatunkach żywicieli

Naturalne zakażenia przez Brucella spp. obserwowano w populacjach dzikich zwierząt. Ze względu na podobieństwo zmian i przebiegu choroby u różnych gatunków gospodarzy i patogenów, patogeneza brucelozy u dzikich zwierząt jest uważana za podobną do tej u zwierząt domowych, którą szczegółowo badano.49

Podobieństwa obejmują tropizm do tkanek rozrodczych i gruczołów sutkowych, kolonizację trofoblastu przez organizm oraz podobne zmiany histopatologiczne w narządach, zwłaszcza w układzie rozrodczym. Różnice w przebiegu choroby istnieją i prawdopodobnie są związane z różnicami immunologicznymi i behawioralnymi między gatunkami.50

U świń zakażonych B. suis, objawy niezwiązane z rozrodem obejmują zapalenie stawów, diskospondylitis, kulawiznę i porażenie tylnych kończyn. U bydła zakażonego B. abortus, byki są często bezobjawowe, ale rzadko rozwijają objawy ogólnoustrojowe obejmujące gorączkę, brak łaknienia i depresję.51

U świń duży odsetek, zwłaszcza samic, wraca do zdrowia po kilku miesiącach. Wskaźnik wyzdrowień u knurów jest niski, być może nigdy nie przekracza 50%. Wystarczająca liczba zwierząt pozostaje zakażona w stadzie, aby utrwalić chorobę. Co zaskakujące, większość prosiąt w zakażonych stadach jest wolna od zakażenia w momencie odsadzenia.52

Bruceloza – patogeneza u ludzi

Brucella spp. wykorzystują mechanizmy obronne gospodarza do ustanowienia przewlekłych zakażeń, prowadząc do spektrum objawów klinicznych, od gorączki, zmęczenia i bólu stawów po cięższe powikłania, takie jak zapalenie wsierdzia i zaburzenia neurologiczne.53

Bakterie Brucella po wniknięciu do organizmu ulegają opsonizacji i są fagocytowane przez granulocyty i monocyty. Jako fakultatywne patogeny wewnątrzkomórkowe, przeżywają i namnażają się wewnątrz granulocytów. Bakterie Brucella prawdopodobnie początkowo namnażają się wewnątrz komórek węzłów chłonnych zlokalizowanych w pobliżu wrót zakażenia. Stamtąd są transportowane przez krew do różnych narządów, które kolonizują.54

Bakterie wykazują szczególne powinowactwo do tkanek bogatych w komórki siateczkowo-śródbłonkowe, takich jak wątroba, śledziona lub szpik kostny, a także do tkanek mięśniowo-szkieletowych i moczowo-płciowych. W tkankach tworzą się ropnie i ziarniniaki z nekrozą lub bez, a tkanki ulegają serowaceniu.55

Konsekwencje zakażenia Brucella są bardzo zmienne i mogą obejmować zapalenie stawów, zapalenie kręgosłupa, małopłytkowość, zapalenie opon mózgowo-rdzeniowych, zapalenie błony naczyniowej oka, zapalenie nerwu wzrokowego, zapalenie wsierdzia i różne zaburzenia neurologiczne znane zbiorczo jako neurobruceloza.56

Bruceloza wywołuje nieregularne gorączki, poronienia (u zwierząt), pocenie się, osłabienie, anemię, bóle głowy, depresję oraz bóle mięśniowe i ogólne.57 Dwie główne przyczyny samoistnych poronień u zwierząt to erytrytol, który może promować zakażenia płodu i łożyska, oraz brak aktywności przeciw-Brucella w płynie owodniowym.58

Ogólnie wskaźnik śmiertelności wynosi 2%. Wczesna diagnoza i leczenie są ważne dla ograniczenia czasu trwania choroby i zapobiegania powikłaniom. Nieleczona choroba może trwać miesiące lub lata. Pomimo odpowiednich antybiotyków nawrót występuje u około 10% wszystkich pacjentów i zwykle występuje w ciągu pierwszego roku po zakażeniu.59

Neurobruceloza

Objawy neurologiczne neurobrucelozy są przypisywane procesowi zapalnemu w ośrodkowym układzie nerwowym, prowadzącemu do uszkodzenia neuronów. Badania nad tym, jak Brucella przenika do OUN, są nadal w toku. Jednym z proponowanych mechanizmów jest replikacja bakterii w makrofagach rezydujących w OUN, a mianowicie w mikrogleju. Innym możliwym mechanizmem jest inwazja komórek śródbłonka, która ułatwia przejście komórek zapalnych przez barierę krew-mózg.60

Wykazano, że obecność Brucella abortus w OUN prowadzi do reaktywnej mikrogliozy i astrogliozy, które są cechami charakterystycznymi odpowiedzi zapalnej w neurobrucelozie. Astrocyty i mikroglej, aktywowane przez obecność B. abortus, wydzielają różne cytokiny, które prowadzą do zapalenia i uszkodzenia tkanki neuronalnej: TNF-alfa, interleukina (IL)-1beta i IL-6 oraz chemokiny i białko chemotaktyczne monocytów-1 (MCP-1).61

Immunopatogeneza brucelozy

Najnowsze badania wskazują na istotną rolę limfocytów B w patogenezie przewlekłej brucelozy. W badaniach wstępnych stwierdzono, że komórki B zawierały 90% żywotnych, odzyskiwalnych, wewnątrzkomórkowych bakterii Brucella z zakażonych śledzion myszy typu dzikiego.62 Rola specyficznych podtypów komórek B (B1a i komórki B strefy brzeżnej) w patogenezie przewlekłej brucelozy jest również badana.63

Patogeneza brucelozy stawowej jest nadal słabo poznana. Badacze wciąż badają immunologiczne podstawy patologii kostno-stawowej wywołanej przez Brucella, mając na celu identyfikację patogennych odpowiedzi immunologicznych, które mogą być celem w celu wspomagania antybiotykowego leczenia zapalenia stawów w brucelozie kostno-stawowej.64

Pomimo znacznych postępów w zrozumieniu patogenezy brucelozy, wiele aspektów interakcji Brucella-gospodarz pozostaje niewyjaśnionych. Dalsze badania powinny skupić się na wyjaśnieniu, w jaki sposób Brucella moduluje odpowiedź immunologiczną gospodarza, co może prowadzić do opracowania skuteczniejszych szczepionek i strategii leczenia.6566

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  1. 10.04.2026
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Materiały źródłowe

  • #1
    https://pmc.ncbi.nlm.nih.gov/articles/PMC7256693/
    Brucellae are Gram-negative, small rods infecting mammals and capable of causing disease called brucellosis. […] The most important feature of Brucella is the ability to survive and multiply within both phagocytic and non-phagocytic cells. […] Major virulence factors are: lipopolysaccharide (LPS), T4SS secretion system and BvrR/BvrS system, which allow interaction with host cell surface, formation of an early, late BCV (Brucella Containing Vacuole) and interaction with endoplasmic reticulum (ER) when the bacteria multiply. […] Pathogenicity of Brucella is dependent on their ability to multiply and survive within macrophages. […] Brucella is an intracellular pathogen, during an infection it survives and multiplies in macrophages; the bacteria adapt to the acidic pH, low levels of oxygen, and low levels of nutrients.
  • #2 Brucella – Virulence Factors, Pathogenesis and Treatment
    https://sciendo.com/article/10.21307/pjm-2018-029
    Brucellae are Gram-negative, small rods infecting mammals and capable of causing disease called brucellosis. […] The most important feature of Brucella is the ability to survive and multiply within both phagocytic and non-phagocytic cells. […] Major virulence factors are: lipopolysaccharide (LPS), T4SS secretion system and BvrR/BvrS system, which allow interaction with host cell surface, formation of an early, late BCV (Brucella Containing Vacuole) and interaction with endoplasmic reticulum (ER) when the bacteria multiply.
  • #3 Brucellosis of the nervous system | MedLink Neurology
    https://www.medlink.com/articles/brucellosis-of-the-nervous-system
    Brucella is a zoonosis, meaning that it is transmitted from animals to humans. Brucella spp initially exist in animal hosts: Brucella abortus infects cattle, Brucella suis infects pigs, Brucella melitensis infects goats, and Brucella ovis infects sheep. These gram-negative rods can be transmitted to human hosts by multiple routes, including cutaneous and mucous routes (through abrasions), as well as gastrointestinal (as in consuming unpasteurized dairy products) and respiratory. Humans who consume or handle unpasteurized milk and its derivatives, as well as those working in close contact with livestock, are the most prone to infection with brucellosis. Once the Brucella bacilli have entered the human body, the coccobacilli migrate through the mucosal and epithelial cell layers, and they enter nonphagocytic mucosal epithelial cells via a zipper-like mechanism, where the pathogen binds multiple cell-surface receptors that contain sialic acid and sulfated residues. Brucella rods survive for up to 72 hours inside these epithelial cells, allowing them to break through the epithelial barrier. Then the surviving brucella rods are phagocytosed by macrophages and dendritic cells. This happens either via opsonization (involving complement and Fc receptors) or via fibronectin and lectin receptors. To note, the Brucella microbes that were phagocytosed via the fibronectin/lectin receptors are more likely to survive within the phagocytic cell than the opsonized bacteria.
  • #4 Brucellosis – Traveler Summary – TripPrep.com
    https://tripprep.com/library/brucellosis/traveler-summary
    Brucellosis is a bacterial disease that is transmitted to humans primarily from cattle, hogs, and goats; it can also be transmitted from sheep, camel, buffalo, yak, reindeer, caribou, dogs, and rats. […] The organisms infect humans through the skin or mucous membranes or through the respiratory tract. […] In travelers, the most common mechanism of acquisition is through eating or drinking unpasteurized dairy products, especially fresh goat cheese and other goat products. […] There is no clear seasonal pattern in the transmission of brucellosis. […] Risk factors for travelers include eating meals prepared with undercooked or unpasteurized products from infected animals or close contact with the animals or their tissues. […] The acute symptoms of brucellosis can include headache, fever, chills, profuse sweating, and abdominal and joint pains.
  • #5
    https://pmc.ncbi.nlm.nih.gov/articles/PMC7256693/
    Brucella strains penetrate the host cells through a zipper-like mechanism. […] The Brucella strains survive and multiply within both phagocytic and non-phagocytic cells. […] The interaction with early endocytic network last about 10 minutes. […] Brucella type IV secretion (T4SS encoded by virB operon) is responsible for regulation of intracellular trafficking from autophagosome to endoplasmatic reticulum (ER). […] The final step of Brucella intercellular trafficking is an acquisition of the markers characteristic of the endoplasmic reticulum: calnexin, calreticulin and Sec61, although in this step BCV lose the LAMP-1. […] The mechanism of BCV-ER connection remains unclear. […] Brucella can modify immune response in host cells; it has an affinity to the cells of specific tissues, e.g. placental trophoblast in fetal lung, pregnant females or reproductive system.
  • #6 Brucellosis of the nervous system | MedLink Neurology
    https://www.medlink.com/articles/brucellosis-of-the-nervous-system
    Brucella is a zoonosis, meaning that it is transmitted from animals to humans. Brucella spp initially exist in animal hosts: Brucella abortus infects cattle, Brucella suis infects pigs, Brucella melitensis infects goats, and Brucella ovis infects sheep. These gram-negative rods can be transmitted to human hosts by multiple routes, including cutaneous and mucous routes (through abrasions), as well as gastrointestinal (as in consuming unpasteurized dairy products) and respiratory. Humans who consume or handle unpasteurized milk and its derivatives, as well as those working in close contact with livestock, are the most prone to infection with brucellosis. Once the Brucella bacilli have entered the human body, the coccobacilli migrate through the mucosal and epithelial cell layers, and they enter nonphagocytic mucosal epithelial cells via a zipper-like mechanism, where the pathogen binds multiple cell-surface receptors that contain sialic acid and sulfated residues. Brucella rods survive for up to 72 hours inside these epithelial cells, allowing them to break through the epithelial barrier. Then the surviving brucella rods are phagocytosed by macrophages and dendritic cells. This happens either via opsonization (involving complement and Fc receptors) or via fibronectin and lectin receptors. To note, the Brucella microbes that were phagocytosed via the fibronectin/lectin receptors are more likely to survive within the phagocytic cell than the opsonized bacteria.
  • #7 Brucellosis: Background, Pathophysiology, Etiology
    https://emedicine.medscape.com/article/213430-overview
    Brucellae that survive are transported into the lymphatic system and may replicate there locally; they also may replicate in the kidney, liver, spleen, breast tissue, or joints, causing both localized and systemic infection. Any organ system can be involved (eg, central nervous system [CNS], heart, joints, genitourinary system, pulmonary system, and skin); localization of the process may cause focal symptoms or findings. After replication in the endoplasmic reticulum, the brucellae are released with the help of hemolysins and induced cell necrosis. […] Development of cell-mediated immunity is the principal mechanism of recovery. The host response to infection with B abortus is characterized by the development of tissue granulomas indistinguishable from those of sarcoidosis. In contrast, infection with the more virulent species (B melitensis and B suis) more commonly results in visceral microabscesses.
  • #8
    https://pmc.ncbi.nlm.nih.gov/articles/PMC7256693/
    Brucella strains penetrate the host cells through a zipper-like mechanism. […] The Brucella strains survive and multiply within both phagocytic and non-phagocytic cells. […] The interaction with early endocytic network last about 10 minutes. […] Brucella type IV secretion (T4SS encoded by virB operon) is responsible for regulation of intracellular trafficking from autophagosome to endoplasmatic reticulum (ER). […] The final step of Brucella intercellular trafficking is an acquisition of the markers characteristic of the endoplasmic reticulum: calnexin, calreticulin and Sec61, although in this step BCV lose the LAMP-1. […] The mechanism of BCV-ER connection remains unclear. […] Brucella can modify immune response in host cells; it has an affinity to the cells of specific tissues, e.g. placental trophoblast in fetal lung, pregnant females or reproductive system.
  • #9 Brucellosis: Review on the Recent Trends in Pathogenicity and Laboratory Diagnosis – Journal of Laboratory Physicians
    https://jlabphy.org/brucellosis-review-on-the-recent-trends-in-pathogenicity-and-laboratory-diagnosis/
    A type IV secretion system (Vir B) selectively transports proteins and macromolecules through the membranes and is essential for intracellular survival, in case of Brucella. […] A large number of attenuated mutants, with structural defects in their Lipopolysaccharide, confirm the importance of this molecule in Brucella virulence. […] Hsp60 seems to play a part in cell adherence by binding to a cellular prion molecule called PrPr. […] This acidification is thought to induce Vir B expression.
  • #10
    https://pmc.ncbi.nlm.nih.gov/articles/PMC7256693/
    Brucella strains penetrate the host cells through a zipper-like mechanism. […] The Brucella strains survive and multiply within both phagocytic and non-phagocytic cells. […] The interaction with early endocytic network last about 10 minutes. […] Brucella type IV secretion (T4SS encoded by virB operon) is responsible for regulation of intracellular trafficking from autophagosome to endoplasmatic reticulum (ER). […] The final step of Brucella intercellular trafficking is an acquisition of the markers characteristic of the endoplasmic reticulum: calnexin, calreticulin and Sec61, although in this step BCV lose the LAMP-1. […] The mechanism of BCV-ER connection remains unclear. […] Brucella can modify immune response in host cells; it has an affinity to the cells of specific tissues, e.g. placental trophoblast in fetal lung, pregnant females or reproductive system.
  • #11 The Mechanism of Facultative Intracellular Parasitism of Brucella
    https://www.mdpi.com/1422-0067/22/7/3673
    After Brucella invades the host cells, it mainly causes chronic infection by avoiding the host immune-reaction system, but the molecular mechanism of Brucella facultative intracellular parasitism has not been clear. […] Brucella interacts with the cell membrane of macrophages through lipid rafts and enters the host cells to form Brucella-containing vacuoles (BCV) surrounded by phagocytic vesicles. […] The BCV escaping Lys degradation will reach the ER and fuse with the ER in a Sar1 and Rab2 dependent manner. […] Brucella can survive and propagate in the host cell mainly by the action of LPS, OMP, T4SS, two-component regulatory system and other virulence factors. […] The interaction between host and LPS may play an important role in Brucella’s cell viability. […] Brucella can not only escape from immune surveillance, but also adapt to the internal environment of phagocytes and nonphagocytes and survive in the cell.
  • #12 Brucella – Virulence Factors, Pathogenesis and Treatment
    https://sciendo.com/article/10.21307/pjm-2018-029
    Brucellae are Gram-negative, small rods infecting mammals and capable of causing disease called brucellosis. […] The most important feature of Brucella is the ability to survive and multiply within both phagocytic and non-phagocytic cells. […] Major virulence factors are: lipopolysaccharide (LPS), T4SS secretion system and BvrR/BvrS system, which allow interaction with host cell surface, formation of an early, late BCV (Brucella Containing Vacuole) and interaction with endoplasmic reticulum (ER) when the bacteria multiply.
  • #13
    https://pmc.ncbi.nlm.nih.gov/articles/PMC7256693/
    Brucella strains penetrate the host cells through a zipper-like mechanism. […] The Brucella strains survive and multiply within both phagocytic and non-phagocytic cells. […] The interaction with early endocytic network last about 10 minutes. […] Brucella type IV secretion (T4SS encoded by virB operon) is responsible for regulation of intracellular trafficking from autophagosome to endoplasmatic reticulum (ER). […] The final step of Brucella intercellular trafficking is an acquisition of the markers characteristic of the endoplasmic reticulum: calnexin, calreticulin and Sec61, although in this step BCV lose the LAMP-1. […] The mechanism of BCV-ER connection remains unclear. […] Brucella can modify immune response in host cells; it has an affinity to the cells of specific tissues, e.g. placental trophoblast in fetal lung, pregnant females or reproductive system.
  • #14
    https://pmc.ncbi.nlm.nih.gov/articles/PMC7256693/
    Brucellae are Gram-negative, small rods infecting mammals and capable of causing disease called brucellosis. […] The most important feature of Brucella is the ability to survive and multiply within both phagocytic and non-phagocytic cells. […] Major virulence factors are: lipopolysaccharide (LPS), T4SS secretion system and BvrR/BvrS system, which allow interaction with host cell surface, formation of an early, late BCV (Brucella Containing Vacuole) and interaction with endoplasmic reticulum (ER) when the bacteria multiply. […] Pathogenicity of Brucella is dependent on their ability to multiply and survive within macrophages. […] Brucella is an intracellular pathogen, during an infection it survives and multiplies in macrophages; the bacteria adapt to the acidic pH, low levels of oxygen, and low levels of nutrients.
  • #15 Brucella – Virulence Factors, Pathogenesis and Treatment
    https://sciendo.com/article/10.21307/pjm-2018-029
    Brucellae are Gram-negative, small rods infecting mammals and capable of causing disease called brucellosis. […] The most important feature of Brucella is the ability to survive and multiply within both phagocytic and non-phagocytic cells. […] Major virulence factors are: lipopolysaccharide (LPS), T4SS secretion system and BvrR/BvrS system, which allow interaction with host cell surface, formation of an early, late BCV (Brucella Containing Vacuole) and interaction with endoplasmic reticulum (ER) when the bacteria multiply.
  • #16
    https://pmc.ncbi.nlm.nih.gov/articles/PMC7256693/
    The appearance of elongated fatty acid on the lipid A leads to poor activation of TLR4 (Tool-like receptor 4). […] The other feature of Brucella spp. LPS is core oligosaccharide glycosylation pattern that prevents a connection of the bacteria with TLR4. […] Brucella TIR domain-containing protein mimics properties of the toll-like receptor adaptor protein TIRAP. […] TcpB promotes a degradation of TIRAP and disrupts TLR4 signalling that result in inhibition of proinflammatory cytokines production and dendritic cell maturation. […] Brucella can be recognized by TLRs, but owing to modifications its interaction with TLRs is 10-fold lesser than for Enterobacteria. […] The process of infection is a complex one, and there are many unexplained issues associated with it.
  • #17 A Review of Brucellosis: A Recent Major Outbreak in Lebanon
    http://www.fortunejournals.com/articles/a-review-of-brucellosis-a-recent-major-outbreak-in-lebanon.html
    Brucella infection remains the world’s most common bacterial zoonosis, with over half a million new cases annually, which brought renewed attention of this neglected disease. […] Here comes the necessity of this review to shed light on the complexity of neglected brucellosis. It discusses the etiology, taxonomy, pathogenesis, epidemiology, sources, transmission, clinical manifestations, diagnosis, treatment and prevention of this disease. […] Several studies point at the outer membrane being the main component for virulence factor of Brucella, this membrane contains Lipopolysaccharides (LPS). It possesses a peculiar non-classical LPS as compared to the classical LPS from Enterobacteria, such as Escherichia coli. Generally, smooth LPS has a role in cell entry and immune evasion of the infected cell. It also alters the capacity of the infected cell to present foreign antigens, hence, prevents the immune system attack for the infected cell.
  • #18 Brucellosis: Review on the Recent Trends in Pathogenicity and Laboratory Diagnosis – Journal of Laboratory Physicians
    https://jlabphy.org/brucellosis-review-on-the-recent-trends-in-pathogenicity-and-laboratory-diagnosis/
    A type IV secretion system (Vir B) selectively transports proteins and macromolecules through the membranes and is essential for intracellular survival, in case of Brucella. […] A large number of attenuated mutants, with structural defects in their Lipopolysaccharide, confirm the importance of this molecule in Brucella virulence. […] Hsp60 seems to play a part in cell adherence by binding to a cellular prion molecule called PrPr. […] This acidification is thought to induce Vir B expression.
  • #19
    https://pmc.ncbi.nlm.nih.gov/articles/PMC7256693/
    The strains with S-LPS are able to restrain host cell apoptosis by the interaction of the O-chain with TNF- (tumor necrosis factor). Thus, dead cells do not release specific factors, therefore they do not activate the immune system and Brucellae are able to avoid host immune surveillance. […] BvrR/BvrS are the best characterized components of the virulence system; mutants are incapable of invasion, prevention phagosome-lysosome fusion and intracellular replication. […] The influence of Omp3a and Omp3b on virulence remains unexplained in details. […] The analysis of Brucella genomic library has confirmed an occurrence of two open reading frames: bvrR and bvrS. […] The bvrR encodes BvrR proteins and bvrS encodes BvrS. […] BvrR activates transcription of omp3a, omp3b and other genes responsible for lipid A structure and perhaps core of LPS.
  • #20 Brucellosis pathophysiology – wikidoc
    https://www.wikidoc.org/index.php/Brucellosis_pathophysiology
    Brucellosis is a zoonotic disease, humans could be infected by eating undercook meat or raw dairy products, inhalation of the bacteria and direct contact of bacteria with skin wounds or mucous membranes. Following transmission, white blood cells phagocyte the pathogen and transports it via hematologic or lymphatic route to different organs specially to those of the reticuloendothelial system. […] The pathogenesis of brucellosis is complex and not fully understood. By avoiding innate immunity, brucella survive with in monocytic cells. Endotoxic lipopolysaccharide (LPS), plays a key role in survival of bacteria inside monocytic cell. LPS helps in survival of the bacteria inside the monocytic cell, by suppressing phagosomelysosome fusion, internalizing bacteria into endoplasmic reticulum and inhibiting apoptosis of infected cell. Type IV secretion system (VirB) and type III secretion system, that regulates intracellular survival and trafficking has been identified, although type 3 not yet confirmed. Secretion system plays an important role in intracellular transport of the bacteria acid-stable proteins produced by brucella, facilitates the survival in phagosomes. Cu-Zn superoxide dismutase, produced by brucellae, gives them resistance from reactive oxygen intermediates. Two component BvrS/BvrR system, codes for histidine kinase sensor. Histidine kinase sensor plays an important role in controlling the expression of molecular determinants which are necessary for cell invasion. Hemolysins help the bacteria to be released from a cell and induce cell necrosis.
  • #21
    https://ajbms.knu.edu.af/index.php/ajbms/article/view/3
    Brucella genus is Gram-negative coccobacilli that cause a zoonotic disease called brucellosis in humans and animals. […] Due to having virulence factors such as type IV secretion system (T4SS), superoxide dismutase enzyme, BvrS/BvrR two-component system, LPS with O chain, and cyclic beta-glucan, Brucella can survive and replicate intracellularly and cause disease.
  • #22 Pathogenesis of Brucella
    https://bibliotecadigital.ipb.pt/handle/10198/20905?locale=en
    The goal of this chapter is to describe the pathogenesis of Brucella reporting, the host-pathogen and the cell/macrophage Brucella interactions, and the major virulence factors of this bacteria genus. […] The mechanisms by which Brucella enters the cells and evades the host immune system remains poorly understood. However, in the past decade, the mechanisms of Brucella pathogenesis and host immunity have been extensively investigated. Brucella has the ability to survive and replicate intracellularly in mononuclear phagocytes and to control host immune responses. This pathogen developed several strategies to evade the host s immune defense mechanisms preventing inflammatory responses at the site of entrance in the host and maintain the infection. […] Unlike other bacteria, Brucella lacks classical bacterial virulence factors such as exotoxins, capsules, secreted proteases, fimbriae, flagella, virulence plasmids, resistant strains and phage-encoded toxins. Other virulence factors have been implicated in the pathogenesis as the type IV secretion system, the BvrR/BvrS two component regulatory system, the Brucella intact lipopolysaccharide O-antigen in smooth strains, and cyclic -1,2-glucans.
  • #23
    https://pmc.ncbi.nlm.nih.gov/articles/PMC7256693/
    Brucella strains penetrate the host cells through a zipper-like mechanism. […] The Brucella strains survive and multiply within both phagocytic and non-phagocytic cells. […] The interaction with early endocytic network last about 10 minutes. […] Brucella type IV secretion (T4SS encoded by virB operon) is responsible for regulation of intracellular trafficking from autophagosome to endoplasmatic reticulum (ER). […] The final step of Brucella intercellular trafficking is an acquisition of the markers characteristic of the endoplasmic reticulum: calnexin, calreticulin and Sec61, although in this step BCV lose the LAMP-1. […] The mechanism of BCV-ER connection remains unclear. […] Brucella can modify immune response in host cells; it has an affinity to the cells of specific tissues, e.g. placental trophoblast in fetal lung, pregnant females or reproductive system.
  • #24
    https://pmc.ncbi.nlm.nih.gov/articles/PMC7256693/
    The strains with S-LPS are able to restrain host cell apoptosis by the interaction of the O-chain with TNF- (tumor necrosis factor). Thus, dead cells do not release specific factors, therefore they do not activate the immune system and Brucellae are able to avoid host immune surveillance. […] BvrR/BvrS are the best characterized components of the virulence system; mutants are incapable of invasion, prevention phagosome-lysosome fusion and intracellular replication. […] The influence of Omp3a and Omp3b on virulence remains unexplained in details. […] The analysis of Brucella genomic library has confirmed an occurrence of two open reading frames: bvrR and bvrS. […] The bvrR encodes BvrR proteins and bvrS encodes BvrS. […] BvrR activates transcription of omp3a, omp3b and other genes responsible for lipid A structure and perhaps core of LPS.
  • #25 Brucellosis of the nervous system | MedLink Neurology
    https://www.medlink.com/articles/brucellosis-of-the-nervous-system
    By virtue of its virulence factors, brucella evades the immune response inside the phagocytes and spreads through the lymph nodes to multiple organs of the body. One mechanism of immune evasion includes the inhibition of Toll-like receptor 4 (TLR4) by the lipid A of the brucellas lipopolysaccharide. TLR4 is a transmembrane protein that induces the innate immune response. Another mechanism is the inhibition of host cell apoptosis thanks to the interaction between the brucellas O-polysaccharide and tumor necrosis factor (TNF)-alpha. Inside the host cells, brucella pathogens also express a type IV secretion system on their cell membrane, enabling them to secrete molecules that are necessary for intracellular survival. Brucella also produces a protein called outer membrane protein 25 (Omp25) that regulates the secretion of TNF-alpha, thus, suppressing the maturation of dendritic cells, antigen presentation, and naive T-cell activation.
  • #26
    https://pmc.ncbi.nlm.nih.gov/articles/PMC7256693/
    The appearance of elongated fatty acid on the lipid A leads to poor activation of TLR4 (Tool-like receptor 4). […] The other feature of Brucella spp. LPS is core oligosaccharide glycosylation pattern that prevents a connection of the bacteria with TLR4. […] Brucella TIR domain-containing protein mimics properties of the toll-like receptor adaptor protein TIRAP. […] TcpB promotes a degradation of TIRAP and disrupts TLR4 signalling that result in inhibition of proinflammatory cytokines production and dendritic cell maturation. […] Brucella can be recognized by TLRs, but owing to modifications its interaction with TLRs is 10-fold lesser than for Enterobacteria. […] The process of infection is a complex one, and there are many unexplained issues associated with it.
  • #27
    https://pmc.ncbi.nlm.nih.gov/articles/PMC7256693/
    The appearance of elongated fatty acid on the lipid A leads to poor activation of TLR4 (Tool-like receptor 4). […] The other feature of Brucella spp. LPS is core oligosaccharide glycosylation pattern that prevents a connection of the bacteria with TLR4. […] Brucella TIR domain-containing protein mimics properties of the toll-like receptor adaptor protein TIRAP. […] TcpB promotes a degradation of TIRAP and disrupts TLR4 signalling that result in inhibition of proinflammatory cytokines production and dendritic cell maturation. […] Brucella can be recognized by TLRs, but owing to modifications its interaction with TLRs is 10-fold lesser than for Enterobacteria. […] The process of infection is a complex one, and there are many unexplained issues associated with it.
  • #28
    https://pmc.ncbi.nlm.nih.gov/articles/PMC7256693/
    Brucella strains penetrate the host cells through a zipper-like mechanism. […] The Brucella strains survive and multiply within both phagocytic and non-phagocytic cells. […] The interaction with early endocytic network last about 10 minutes. […] Brucella type IV secretion (T4SS encoded by virB operon) is responsible for regulation of intracellular trafficking from autophagosome to endoplasmatic reticulum (ER). […] The final step of Brucella intercellular trafficking is an acquisition of the markers characteristic of the endoplasmic reticulum: calnexin, calreticulin and Sec61, although in this step BCV lose the LAMP-1. […] The mechanism of BCV-ER connection remains unclear. […] Brucella can modify immune response in host cells; it has an affinity to the cells of specific tissues, e.g. placental trophoblast in fetal lung, pregnant females or reproductive system.
  • #29 Pathogenesis and pathobiology of brucellosis in wildlife. – Abstract – Europe PMCEurope PMC
    https://europepmc.org/article/med/23837371
    Natural infections by Brucella spp. have been observed in wild populations. Owing to the similarity of lesions and the course of disease across host and pathogen species, the pathogenesis of brucellosis in wildlife is considered similar to that in domestic animals, which has been studied extensively. […] Similarities include tropism for reproductive and mammary tissues, trophoblast colonisation by the organism, and similar histopathological findings in organs, especially in the reproductive tract. […] Differences in the disease course exist and are likely to be attributable to immunological and behavioural differences among species. Further study of the pathogenesis and pathobiology of brucellosis in wildlife is expected to yield unique knowledge with application to disease management in both wild and domestic species.
  • #30 Brucellosis: Background, Pathophysiology, Etiology
    https://emedicine.medscape.com/article/213430-overview
    Brucellae that survive are transported into the lymphatic system and may replicate there locally; they also may replicate in the kidney, liver, spleen, breast tissue, or joints, causing both localized and systemic infection. Any organ system can be involved (eg, central nervous system [CNS], heart, joints, genitourinary system, pulmonary system, and skin); localization of the process may cause focal symptoms or findings. After replication in the endoplasmic reticulum, the brucellae are released with the help of hemolysins and induced cell necrosis. […] Development of cell-mediated immunity is the principal mechanism of recovery. The host response to infection with B abortus is characterized by the development of tissue granulomas indistinguishable from those of sarcoidosis. In contrast, infection with the more virulent species (B melitensis and B suis) more commonly results in visceral microabscesses.
  • #31 Pigs, pooches and pasteurisation: The changing face of brucellosis in Australia
    https://www1.racgp.org.au/ajgp/2018/march/brucellosis
    Brucellosis is a disease caused by the intracellular, Gram-negative bacteria, Brucella species. […] An infectious dose of 10-100 organisms is sufficient to cause systemic infection. After entry of the organism, three main phases can be distinguished: incubation phase, acute phase and chronic phase. The incubation period of brucellosis can be variable and difficult to ascertain, but is generally two to four weeks, with a range of five days to five months. The acute phase is characterised by the onset of signs and symptoms such as fever, sweats, fatigue, hepatomegaly and splenomegaly. Because of several virulence factors, Brucella is able to survive in host cells and evade host immune responses to establish chronic foci of infection. […] Overall, the case fatality rate is 2%. Early diagnosis and treatment are important for limiting duration and preventing complications. The disease may last months to years if untreated. Despite appropriate antibiotics, relapse occurs in up to 10% of all patients, and this usually occurs within the first year after infection.
  • #32 Brucellosis ppt | PPT
    https://www.slideshare.net/slideshow/brucellosis-ppt/243633491
    Brucellosis: Phase of diseases Incubation phase: before clinical symptoms are evident. Acute phase: during which time the pathogen invades and disseminates in host tissue Chronic phase: ability of the organism to persist in the cells of the host in which brucellae are distributed by way of the lymphoreticular system to eventually cause cardiovascular, hepatic, lymphoreticular, neurologic, and osteoarticular disease can eventually result in severe organ damage and death of the host organism […] With the development of cell mediated immunity body is better able to contain and eliminate Brucella organism.
  • #33 The Mechanism of Facultative Intracellular Parasitism of Brucella
    https://www.mdpi.com/1422-0067/22/7/3673
    The propagation of Brucella in cells includes two stages: the stable stage and the exponential stage. […] Brucella can inhibit the apoptosis of the macrophage by inhibiting the secretion of TNF-α so that it can survive in the cell and multiply in large numbers, weaken the phagocytic function of macrophage, lose the killing effect and antigenic presenting function of macrophage, and finally escape the immune surveillance of host. […] Brucella regulates the immune response by inducing regulatory cytokines (such as IL-10), which indicates that the IL-10 pathway plays an important role in the chronic infection caused by Brucella.
  • #34 The Mechanism of Facultative Intracellular Parasitism of Brucella
    https://www.mdpi.com/1422-0067/22/7/3673
    After Brucella invades the host cells, it mainly causes chronic infection by avoiding the host immune-reaction system, but the molecular mechanism of Brucella facultative intracellular parasitism has not been clear. […] Brucella interacts with the cell membrane of macrophages through lipid rafts and enters the host cells to form Brucella-containing vacuoles (BCV) surrounded by phagocytic vesicles. […] The BCV escaping Lys degradation will reach the ER and fuse with the ER in a Sar1 and Rab2 dependent manner. […] Brucella can survive and propagate in the host cell mainly by the action of LPS, OMP, T4SS, two-component regulatory system and other virulence factors. […] The interaction between host and LPS may play an important role in Brucella’s cell viability. […] Brucella can not only escape from immune surveillance, but also adapt to the internal environment of phagocytes and nonphagocytes and survive in the cell.
  • #35 Overview of Brucellosis – Creative Diagnostics
    https://www.creative-diagnostics.com/blog/index.php/overview-of-brucellosis/
    The long-term residence of pathogens in host phagocytes may be due to their adaptation to this harsh pH environment, nutrient deprivation, aerobic and nitrogen-mediated reactions, and lysosome lysis in the phagosome through their own genetic changes. […] The internalization process of Brucella abortus can change the transport pathway of Brucella in host cells, change the normal maturation process of phagosomes in host cells and interfere with the adhesion of phagolysosomes to Brucella. […] Brucella has virulence factors (such as exotoxins, cytolysins, endotoxins, lipopolysaccharides, and apoptosis inducers) that are not typical, but these virulence factors play a role in bacterial invasion of host cells, intracellular parasitism, and arrival of cells.
  • #36 Brucellosis: an Overview – Volume 3, Number 2—June 1997 – Emerging Infectious Diseases journal – CDC
    https://wwwnc.cdc.gov/eid/article/3/2/97-0219_article
    Brucella organisms can infect both nonphagocytic and phagocytic cells. The mechanism of invasion of nonphagocytic cells is not clearly established. […] Within nonphagocytic cells, brucellae tend to localize in the rough endoplasmic reticulum. In polymorphonuclear or mononuclear phagocytic cells, they use a number of mechanisms for avoiding or suppressing bactericidal responses. The S-LPS probably plays a substantial role in intracellular survival, as smooth organisms survive much more effectively than nonsmooth ones. Compared with enterobacterial LPS, S-LPS has many unusual properties: a relatively low toxicity for endotoxin-sensitive mice, rabbits, and chick embryos; low toxicity for macrophages; low pyrogenicity; and low hypoferremia-inducing activity. […] An important determinant of virulence is the production of adenine and guanine monophosphate, which inhibit phagolysosome fusion; degranulation and activation of the myelo-peroxidase-halide system; and production of tumor necrosis factor. […] The mechanisms of pathogenesis of Brucella infection in its natural host species and in humans are still not completely understood, and further studies are needed.
  • #37
    https://pmc.ncbi.nlm.nih.gov/articles/PMC7256693/
    Brucellae are Gram-negative, small rods infecting mammals and capable of causing disease called brucellosis. […] The most important feature of Brucella is the ability to survive and multiply within both phagocytic and non-phagocytic cells. […] Major virulence factors are: lipopolysaccharide (LPS), T4SS secretion system and BvrR/BvrS system, which allow interaction with host cell surface, formation of an early, late BCV (Brucella Containing Vacuole) and interaction with endoplasmic reticulum (ER) when the bacteria multiply. […] Pathogenicity of Brucella is dependent on their ability to multiply and survive within macrophages. […] Brucella is an intracellular pathogen, during an infection it survives and multiplies in macrophages; the bacteria adapt to the acidic pH, low levels of oxygen, and low levels of nutrients.
  • #38 Brucellosis pathophysiology – wikidoc
    https://www.wikidoc.org/index.php/Brucellosis_pathophysiology
    Brucellosis is a zoonotic disease, humans could be infected by eating undercook meat or raw dairy products, inhalation of the bacteria and direct contact of bacteria with skin wounds or mucous membranes. Following transmission, white blood cells phagocyte the pathogen and transports it via hematologic or lymphatic route to different organs specially to those of the reticuloendothelial system. […] The pathogenesis of brucellosis is complex and not fully understood. By avoiding innate immunity, brucella survive with in monocytic cells. Endotoxic lipopolysaccharide (LPS), plays a key role in survival of bacteria inside monocytic cell. LPS helps in survival of the bacteria inside the monocytic cell, by suppressing phagosomelysosome fusion, internalizing bacteria into endoplasmic reticulum and inhibiting apoptosis of infected cell. Type IV secretion system (VirB) and type III secretion system, that regulates intracellular survival and trafficking has been identified, although type 3 not yet confirmed. Secretion system plays an important role in intracellular transport of the bacteria acid-stable proteins produced by brucella, facilitates the survival in phagosomes. Cu-Zn superoxide dismutase, produced by brucellae, gives them resistance from reactive oxygen intermediates. Two component BvrS/BvrR system, codes for histidine kinase sensor. Histidine kinase sensor plays an important role in controlling the expression of molecular determinants which are necessary for cell invasion. Hemolysins help the bacteria to be released from a cell and induce cell necrosis.
  • #39 Overview of Brucellosis – Creative Diagnostics
    https://www.creative-diagnostics.com/blog/index.php/overview-of-brucellosis/
    The long-term residence of pathogens in host phagocytes may be due to their adaptation to this harsh pH environment, nutrient deprivation, aerobic and nitrogen-mediated reactions, and lysosome lysis in the phagosome through their own genetic changes. […] The internalization process of Brucella abortus can change the transport pathway of Brucella in host cells, change the normal maturation process of phagosomes in host cells and interfere with the adhesion of phagolysosomes to Brucella. […] Brucella has virulence factors (such as exotoxins, cytolysins, endotoxins, lipopolysaccharides, and apoptosis inducers) that are not typical, but these virulence factors play a role in bacterial invasion of host cells, intracellular parasitism, and arrival of cells.
  • #40 Brucellosis: Background, Pathophysiology, Etiology
    https://emedicine.medscape.com/article/213430-overview
    Brucellae that survive are transported into the lymphatic system and may replicate there locally; they also may replicate in the kidney, liver, spleen, breast tissue, or joints, causing both localized and systemic infection. Any organ system can be involved (eg, central nervous system [CNS], heart, joints, genitourinary system, pulmonary system, and skin); localization of the process may cause focal symptoms or findings. After replication in the endoplasmic reticulum, the brucellae are released with the help of hemolysins and induced cell necrosis. […] Development of cell-mediated immunity is the principal mechanism of recovery. The host response to infection with B abortus is characterized by the development of tissue granulomas indistinguishable from those of sarcoidosis. In contrast, infection with the more virulent species (B melitensis and B suis) more commonly results in visceral microabscesses.
  • #41 Brucellosis: Background, Pathophysiology, Etiology
    https://emedicine.medscape.com/article/213430-overview
    Brucellae that survive are transported into the lymphatic system and may replicate there locally; they also may replicate in the kidney, liver, spleen, breast tissue, or joints, causing both localized and systemic infection. Any organ system can be involved (eg, central nervous system [CNS], heart, joints, genitourinary system, pulmonary system, and skin); localization of the process may cause focal symptoms or findings. After replication in the endoplasmic reticulum, the brucellae are released with the help of hemolysins and induced cell necrosis. […] Development of cell-mediated immunity is the principal mechanism of recovery. The host response to infection with B abortus is characterized by the development of tissue granulomas indistinguishable from those of sarcoidosis. In contrast, infection with the more virulent species (B melitensis and B suis) more commonly results in visceral microabscesses.
  • #42 Brucellosis: Background, Pathophysiology, Etiology
    https://emedicine.medscape.com/article/213430-overview
    Although Brucella infection is primarily controlled through cell-mediated immunity rather than antibody activity, some immunity to reinfection is provided by serum immunoglobulin (Ig). Initially, IgM levels rise, followed by IgG titers. IgM may remain in the serum in low levels for several months, whereas IgG eventually declines. Persistently elevated IgG titers or second rises in IgG usually indicate chronic or relapsed infection. IgA antibodies are elaborated late and also may persist for very long intervals.
  • #43 Brucellosis: Background, Pathophysiology, Etiology
    https://emedicine.medscape.com/article/213430-overview
    Although Brucella infection is primarily controlled through cell-mediated immunity rather than antibody activity, some immunity to reinfection is provided by serum immunoglobulin (Ig). Initially, IgM levels rise, followed by IgG titers. IgM may remain in the serum in low levels for several months, whereas IgG eventually declines. Persistently elevated IgG titers or second rises in IgG usually indicate chronic or relapsed infection. IgA antibodies are elaborated late and also may persist for very long intervals.
  • #44 A Review of Brucellosis: A Recent Major Outbreak in Lebanon
    http://www.fortunejournals.com/articles/a-review-of-brucellosis-a-recent-major-outbreak-in-lebanon.html
    The lipopolysaccharide coat being smooth in B. melitensis, abortus, suis and rough in B. canis can inhibit phagosomal fusion and oxidative burst activity. Phagocytes can readily kill B. abortus resulting in development of tissue granulomas and rarely ingest B. melitensis resulting in visceral micro-abscesses; thus explaining the differences in pathogenicity and clinical manifestations in human cases of brucellosis. […] This leaves about 15 to 30% of Brucella alive which is transported into the lymphatic system and may cause systemic infection. After replication in the endoplasmic reticulum, the Brucella are released with the help of hemolysins and induced cell necrosis. Development of cell-mediated immunity controls Brucella infection and helps in the recovery. Some immunity to reinfection is provided by serum immunoglobulin (Ig): IgM antibodies may remain in the serum in low levels for several months, IgG declines but persistent elevation indicate chronic or relapsed infection, and IgA may persist for very long intervals.
  • #45 The Mechanism of Facultative Intracellular Parasitism of Brucella
    https://www.mdpi.com/1422-0067/22/7/3673
    The propagation of Brucella in cells includes two stages: the stable stage and the exponential stage. […] Brucella can inhibit the apoptosis of the macrophage by inhibiting the secretion of TNF-α so that it can survive in the cell and multiply in large numbers, weaken the phagocytic function of macrophage, lose the killing effect and antigenic presenting function of macrophage, and finally escape the immune surveillance of host. […] Brucella regulates the immune response by inducing regulatory cytokines (such as IL-10), which indicates that the IL-10 pathway plays an important role in the chronic infection caused by Brucella.
  • #46 The Mechanism of Facultative Intracellular Parasitism of Brucella
    https://www.mdpi.com/1422-0067/22/7/3673
    The propagation of Brucella in cells includes two stages: the stable stage and the exponential stage. […] Brucella can inhibit the apoptosis of the macrophage by inhibiting the secretion of TNF-α so that it can survive in the cell and multiply in large numbers, weaken the phagocytic function of macrophage, lose the killing effect and antigenic presenting function of macrophage, and finally escape the immune surveillance of host. […] Brucella regulates the immune response by inducing regulatory cytokines (such as IL-10), which indicates that the IL-10 pathway plays an important role in the chronic infection caused by Brucella.
  • #47 Brucellosis
    https://www.atsu.edu/faculty/chamberlain/website/lectures/lecture/brucell.htm
    Brucella organisms penetrate the skin or mucous membranes, are engulfed by polymorphonuclear leukocytes, and then enter the lymphatics and the bloodstream. […] Brucella multiplies within the polymorphonuclear leukocytes and lyses them (facultative intracellular parasite). […] Brucella can also multiply within the macrophages of the reticuloendothelial system inducing small granulomas and abscesses. […] Periodic release of Brucella into the blood induces recurrent chills and fever. […] Antigen-specific activated macrophages are able to kill Brucella with T lymphocytes. […] B melitensis infections are usually the most severe. […] B abortus is associated with less frequent infection and a greater proportion of subclinical cases. […] The virulence of B suis strains for humans varies but is generally intermediate in severity.
  • #48 A Review of Brucellosis: A Recent Major Outbreak in Lebanon
    http://www.fortunejournals.com/articles/a-review-of-brucellosis-a-recent-major-outbreak-in-lebanon.html
    The lipopolysaccharide coat being smooth in B. melitensis, abortus, suis and rough in B. canis can inhibit phagosomal fusion and oxidative burst activity. Phagocytes can readily kill B. abortus resulting in development of tissue granulomas and rarely ingest B. melitensis resulting in visceral micro-abscesses; thus explaining the differences in pathogenicity and clinical manifestations in human cases of brucellosis. […] This leaves about 15 to 30% of Brucella alive which is transported into the lymphatic system and may cause systemic infection. After replication in the endoplasmic reticulum, the Brucella are released with the help of hemolysins and induced cell necrosis. Development of cell-mediated immunity controls Brucella infection and helps in the recovery. Some immunity to reinfection is provided by serum immunoglobulin (Ig): IgM antibodies may remain in the serum in low levels for several months, IgG declines but persistent elevation indicate chronic or relapsed infection, and IgA may persist for very long intervals.
  • #49 Pathogenesis and pathobiology of brucellosis in wildlife. – Abstract – Europe PMCEurope PMC
    https://europepmc.org/article/med/23837371
    Natural infections by Brucella spp. have been observed in wild populations. Owing to the similarity of lesions and the course of disease across host and pathogen species, the pathogenesis of brucellosis in wildlife is considered similar to that in domestic animals, which has been studied extensively. […] Similarities include tropism for reproductive and mammary tissues, trophoblast colonisation by the organism, and similar histopathological findings in organs, especially in the reproductive tract. […] Differences in the disease course exist and are likely to be attributable to immunological and behavioural differences among species. Further study of the pathogenesis and pathobiology of brucellosis in wildlife is expected to yield unique knowledge with application to disease management in both wild and domestic species.
  • #50 Pathogenesis and pathobiology of brucellosis in wildlife. – Abstract – Europe PMCEurope PMC
    https://europepmc.org/article/med/23837371
    Natural infections by Brucella spp. have been observed in wild populations. Owing to the similarity of lesions and the course of disease across host and pathogen species, the pathogenesis of brucellosis in wildlife is considered similar to that in domestic animals, which has been studied extensively. […] Similarities include tropism for reproductive and mammary tissues, trophoblast colonisation by the organism, and similar histopathological findings in organs, especially in the reproductive tract. […] Differences in the disease course exist and are likely to be attributable to immunological and behavioural differences among species. Further study of the pathogenesis and pathobiology of brucellosis in wildlife is expected to yield unique knowledge with application to disease management in both wild and domestic species.
  • #51 A one-health review on brucellosis in the United States in: Journal of the American Veterinary Medical Association Volume 261 Issue 4 (2023)
    https://avmajournals.avma.org/view/journals/javma/261/4/javma.23.01.0033.xml
    The mode of transmission and clinical signs of B suis are similar to those of other Brucella spp. Nonreproductive clinical signs in pigs include arthritis, discospondylitis, lameness, and posterior paralysis. […] Clinical manifestations of B abortus in cattle mimic Brucella spp infection in other species. Infected bulls are often asymptomatic but rarely develop systemic signs of fever, inappetence, and depression.
  • #52 Brucellosis (Swine Brucellosis) | Iowa State University
    https://vetmed.iastate.edu/vdpam/about/focus-areas/swine/swine-disease-manual/index-diseases/brucellosis
    Penetration of mucous membranes by B. suis results in colonization of regional lymph nodes, either in lymph or within macrophages. Colonization in regional lymph nodes is followed by long, continuous or intermittent periods of bacteremia. The bacteria then infect and persist in many other organs, including lymph nodes, placenta, mammary gland, joint fluids, bone and in the testicles or accessory genital organs of boars. […] A large percentage of swine, especially the females, recover after several months. The recovery rate in boars is low, perhaps never more than 50%. Enough animals remain infected in a herd to perpetuate the disease. Surprisingly, most piglets in infected herds are free of infection at the time of weaning.
  • #53 Brucellosis: epidemiology, pathogenesis, diagnosis and treatment–a comprehensive review
    https://pmc.ncbi.nlm.nih.gov/articles/PMC10769134/
    Brucella spp. exploit host immune defences to establish chronic infections, leading to a spectrum of clinical manifestations ranging from fever, fatigue and joint pain to more severe complications, such as endocarditis and neurological disorders. […] The pathogenesis of brucellosis is intricate and involves bacterial invasion of host cells, immune evasion and chronic infections. Brucella uniquely penetrates and persists within host cells, such as macrophages, and uses strategies to bypass host immune defences, leading to prolonged infection. Symptoms in humans include fatigue, fever, generalised discomfort, and more severe manifestations, such as arthritis, osteomyelitis, endocarditis and meningoencephalitis. […] Brucella is an adept intracellular pathogen that can survive and replicate within the host cells, evading the immune system. They inhibit phagocytosis, reduce bactericidal activity, diminish endotoxic reactions and impede antigen presentation.
  • #54 Brucellosis – Bacterial Diseases – Infectious Diseases – Diseases – McMaster Textbook of Internal Medicine
    https://empendium.com/mcmtextbook/chapter/B31.II.18.96.2.
    2. Pathogenesis: Bacterial entry is followed by granulocyte activation and accumulation at the inoculation site. Then, the bacteria undergo opsonization and are phagocyted by granulocytes and monocytes. As facultative intracellular pathogens, they survive and proliferate inside granulocytes. Brucella bacilli likely initially proliferate inside the cells of lymph nodes located near the portal of entry. From there they are transported via blood to various organs, which they colonize. They have a particular affinity to tissues rich in reticuloendothelial cells, such as the liver, spleen, or bone marrow, as well as to musculoskeletal and genitourinary tissues. Abscesses and granulomas with or without necrosis are formed in tissues, and the tissues undergo caseation. The main antigen present in bacterial walls and virulence factor is a smooth lipopolysaccharide (S-LPS) molecule. Some of its components are responsible for cross-reactions with Vibrio cholerae O1 and Yersinia enterocolitica O9 antigens.
  • #55 Brucellosis – Bacterial Diseases – Infectious Diseases – Diseases – McMaster Textbook of Internal Medicine
    https://empendium.com/mcmtextbook/chapter/B31.II.18.96.2.
    2. Pathogenesis: Bacterial entry is followed by granulocyte activation and accumulation at the inoculation site. Then, the bacteria undergo opsonization and are phagocyted by granulocytes and monocytes. As facultative intracellular pathogens, they survive and proliferate inside granulocytes. Brucella bacilli likely initially proliferate inside the cells of lymph nodes located near the portal of entry. From there they are transported via blood to various organs, which they colonize. They have a particular affinity to tissues rich in reticuloendothelial cells, such as the liver, spleen, or bone marrow, as well as to musculoskeletal and genitourinary tissues. Abscesses and granulomas with or without necrosis are formed in tissues, and the tissues undergo caseation. The main antigen present in bacterial walls and virulence factor is a smooth lipopolysaccharide (S-LPS) molecule. Some of its components are responsible for cross-reactions with Vibrio cholerae O1 and Yersinia enterocolitica O9 antigens.
  • #56 Brucellosis – Wikipedia
    https://en.wikipedia.org/wiki/Brucellosis
    The bacteria causing this disease, Brucella, are small, Gram-negative, nonmotile, nonspore-forming, rod-shaped (coccobacilli) bacteria. They function as facultative intracellular parasites, causing chronic disease, which usually persists for life. […] The consequences of Brucella infection are highly variable and may include arthritis, spondylitis, thrombocytopenia, meningitis, uveitis, optic neuritis, endocarditis, and various neurological disorders collectively known as neurobrucellosis. […] Brucellosis induces inconstant fevers, miscarriage, sweating, weakness, anemia, headaches, depression, and muscular and bodily pain. […] The two main causes for spontaneous abortion in animals are erythritol, which can promote infections in the fetus and placenta, and the lack of anti-Brucella activity in the amniotic fluid.
  • #57 Brucellosis – Wikipedia
    https://en.wikipedia.org/wiki/Brucellosis
    The bacteria causing this disease, Brucella, are small, Gram-negative, nonmotile, nonspore-forming, rod-shaped (coccobacilli) bacteria. They function as facultative intracellular parasites, causing chronic disease, which usually persists for life. […] The consequences of Brucella infection are highly variable and may include arthritis, spondylitis, thrombocytopenia, meningitis, uveitis, optic neuritis, endocarditis, and various neurological disorders collectively known as neurobrucellosis. […] Brucellosis induces inconstant fevers, miscarriage, sweating, weakness, anemia, headaches, depression, and muscular and bodily pain. […] The two main causes for spontaneous abortion in animals are erythritol, which can promote infections in the fetus and placenta, and the lack of anti-Brucella activity in the amniotic fluid.
  • #58 Brucellosis – Wikipedia
    https://en.wikipedia.org/wiki/Brucellosis
    The bacteria causing this disease, Brucella, are small, Gram-negative, nonmotile, nonspore-forming, rod-shaped (coccobacilli) bacteria. They function as facultative intracellular parasites, causing chronic disease, which usually persists for life. […] The consequences of Brucella infection are highly variable and may include arthritis, spondylitis, thrombocytopenia, meningitis, uveitis, optic neuritis, endocarditis, and various neurological disorders collectively known as neurobrucellosis. […] Brucellosis induces inconstant fevers, miscarriage, sweating, weakness, anemia, headaches, depression, and muscular and bodily pain. […] The two main causes for spontaneous abortion in animals are erythritol, which can promote infections in the fetus and placenta, and the lack of anti-Brucella activity in the amniotic fluid.
  • #59 Pigs, pooches and pasteurisation: The changing face of brucellosis in Australia
    https://www1.racgp.org.au/ajgp/2018/march/brucellosis
    Brucellosis is a disease caused by the intracellular, Gram-negative bacteria, Brucella species. […] An infectious dose of 10-100 organisms is sufficient to cause systemic infection. After entry of the organism, three main phases can be distinguished: incubation phase, acute phase and chronic phase. The incubation period of brucellosis can be variable and difficult to ascertain, but is generally two to four weeks, with a range of five days to five months. The acute phase is characterised by the onset of signs and symptoms such as fever, sweats, fatigue, hepatomegaly and splenomegaly. Because of several virulence factors, Brucella is able to survive in host cells and evade host immune responses to establish chronic foci of infection. […] Overall, the case fatality rate is 2%. Early diagnosis and treatment are important for limiting duration and preventing complications. The disease may last months to years if untreated. Despite appropriate antibiotics, relapse occurs in up to 10% of all patients, and this usually occurs within the first year after infection.
  • #60 Brucellosis of the nervous system | MedLink Neurology
    https://www.medlink.com/articles/brucellosis-of-the-nervous-system
    It is generally accepted in the literature that the neurologic symptoms of neurobrucellosis are attributed to an inflammatory process within the CNS, leading to neuronal damage. Research is still ongoing on how brucella penetrates the CNS. One proposed mechanism is that brucella replicates in macrophages residing in the CNS, namely the microglia. Another possible mechanism is endothelial cell invasion, which facilitates the passage of inflammatory cells through the blood-brain barrier. It has been shown that the presence of brucella abortus within the CNS leads to reactive microgliosis and astrogliosis, which are hallmarks of the inflammatory response in neurobrucellosis. Astrocytes and microglia, activated by the presence of B abortus, secrete a variety of cytokines that lead to inflammation and damage of the neuronal tissue: TNF-alpha, interleukin (IL)-1beta and IL-6, and chemokines and monocyte chemoattractant protein-1 (MCP-1). Brucella virulence factors Omp19 and Pam3Cys were implicated in the secretion of these cytokines.
  • #61 Brucellosis of the nervous system | MedLink Neurology
    https://www.medlink.com/articles/brucellosis-of-the-nervous-system
    It is generally accepted in the literature that the neurologic symptoms of neurobrucellosis are attributed to an inflammatory process within the CNS, leading to neuronal damage. Research is still ongoing on how brucella penetrates the CNS. One proposed mechanism is that brucella replicates in macrophages residing in the CNS, namely the microglia. Another possible mechanism is endothelial cell invasion, which facilitates the passage of inflammatory cells through the blood-brain barrier. It has been shown that the presence of brucella abortus within the CNS leads to reactive microgliosis and astrogliosis, which are hallmarks of the inflammatory response in neurobrucellosis. Astrocytes and microglia, activated by the presence of B abortus, secrete a variety of cytokines that lead to inflammation and damage of the neuronal tissue: TNF-alpha, interleukin (IL)-1beta and IL-6, and chemokines and monocyte chemoattractant protein-1 (MCP-1). Brucella virulence factors Omp19 and Pam3Cys were implicated in the secretion of these cytokines.
  • #62
    https://grantome.com/grant/NIH/R21-AI135160-01
    Brucella infections can cause debilitating disease with relapses of an undulating fever and lifelong complications, including arthritis, endocarditis, and possible neurological complications, even with antibiotic treatment. […] However, mechanisms underlying Brucella’s ability to cause chronic infection remain largely unknown. The overall goal of this project is to better understand the role of B cells in the pathogenesis of chronic brucellosis. […] In our preliminary data, we found that B cells contained 90% of viable, recoverable, intracellular Brucella from infected wild-type mouse spleens. […] In the proposed studies, we will investigate the role of B cells as a reservoir of chronic Brucella infection and determine what genes Brucella requires to chronically infect B cells in vivo.
  • #63
    https://grantome.com/grant/NIH/R21-AI135160-01
    The role of specific B cell subsets (B1a and marginal zone B cells) in the pathogenesis of chronic brucellosis will also be assessed. […] Collectively, our results will enhance our knowledge of the pathogenesis of chronic brucellosis and should also have implications for future rational design of Brucella vaccines.
  • #64 Brucellosis program | Research, Innovation & Impact
    https://research.missouri.edu/laboratory-for-infectious-disease-research/brucellosis-program
    Brucellosis is an infectious disease caused by bacterial pathogen Brucella. […] Currently little is known about the pathogenesis of articular brucellosis. Researchers at MU are investigating the immunologic basis for Brucella-induced osteoarticular pathology. The goal of these studies at LIDR is to identify pathogenic immune responses that can be targeted as a means to augment antibiotic resolution of joint inflammation in osteoarticular brucellosis.
  • #65 Host Immune Responses and Pathogenesis to Brucella spp. Infection | MDPI Books
    https://www.mdpi.com/books/reprint/4567-host-immune-responses-and-pathogenesis-to-brucella-spp-infection
    Brucellosis, caused by the facultative intracellular bacteria Brucella species, is one the most prevalent zoonosis worldwide. […] The findings described here will help to advance in the comprehension of bacterial pathogenesis and contribute to the future development of drugs or vaccines to control brucellosis.
  • #66 Pathogenesis of Brucella
    https://bibliotecadigital.ipb.pt/handle/10198/20905?locale=en
    Future perspectives include new genomics and omics technologies and software tools to analyze virulent genes associated with a Brucella infection. This information will provide a better knowledge of infection and Brucella-host relations that are necessary for vaccine production and strategies to prevent and control brucellosis in small ruminants.

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