Leptospiroza (choroba weila)
Patofizjologia i mechanizm

Leptospiroza, wywoływana przez krętki z rodzaju Leptospira, jest zoonozą o przebiegu dwufazowym: faza ostra (septyczna) trwająca około tygodnia charakteryzuje się bakteriemią i objawami grypopodobnymi, a faza immunologiczna wiąże się z produkcją przeciwciał i eliminacją bakterii z krwi, choć mogą one utrzymywać się w nerkach, oczach i mózgu. Ciężka postać choroby, zespół Weila, występuje u 5-10% pacjentów i objawia się uszkodzeniem wielonarządowym, głównie nerek, wątroby i płuc. Patogeneza obejmuje bezpośrednie uszkodzenie komórek przez proteazy leptospir, zapalenie naczyń włosowatych z obrzękiem śródbłonka i martwicą, a także nadmierną odpowiedź immunologiczną, w tym „burzę cytokinową” z udziałem IL-6, IL-1β, TNF-α i IL-8, co prowadzi do masowego stanu zapalnego i uszkodzenia tkanek. Genetyczna zmienność gospodarza, zwłaszcza w loci HLA-A, B oraz genach IL12RB1, IL1 i CISH, wpływa na podatność na zakażenie.

  1. Patofizjologia leptospirozy (choroba Weila)
    1. Droga zakażenia i fazy choroby
    2. Mechanizmy patogenetyczne
  2. Odpowiedź immunologiczna i burza cytokinowa
    1. Rola cytokin w uszkodzeniu tkanek
    2. Genetyczna podatność na zakażenie
  3. Patofizjologia uszkodzenia narządów
    1. Uszkodzenie nerek
    2. Uszkodzenie wątroby
    3. Uszkodzenie płuc
    4. Uszkodzenie układu naczyniowego
  4. Rola endotoksyn i innych czynników wirulencji
    1. Glikolipoproteina (GLP)
    2. Lipopolisacharyd (LPS)
    3. Inne czynniki wirulencji
  5. Rola mikrobioty jelitowej
  6. Podsumowanie mechanizmu patogenezy
    1. Kolejne rozdziały

Patofizjologia leptospirozy (choroba Weila)

Leptospiroza (choroba Weila) to ostra bakteryjna choroba zakaźna wywoływana przez krętki z rodzaju Leptospira, która wpływa na ludzi i zwierzęta na całym świecie. Jest to zoonoza o szerokim spektrum objawów klinicznych – od łagodnej postaci grypopodobnej do ciężkiego zespołu wielonarządowego uszkodzenia, znanego jako zespół Weila. Zrozumienie patofizjologii tej choroby jest kluczowe dla właściwego leczenia i zapobiegania poważnym powikłaniom.12

Droga zakażenia i fazy choroby

Leptospiry wnikają do organizmu człowieka przez uszkodzoną skórę, błony śluzowe lub spojówki oczu. Po wniknięciu, bakterie szybko przedostają się do krwiobiegu i rozprzestrzeniają się drogą krwionośną do wszystkich narządów, szczególnie wątroby i nerek.34 Choroba ma zazwyczaj przebieg dwufazowy:

  1. Faza ostra (septyczna/leptospiremiczna) – trwa około tygodnia, charakteryzuje się bakteriemią, gorączką i objawami grypopodobnymi. W tej fazie leptospiry można wyizolować z krwi i płynu mózgowo-rdzeniowego.
  2. Faza immunologiczna – występuje po fazie ostrej, związana jest z produkcją przeciwciał i eliminacją leptospir z krwiobiegu. W tej fazie bakterie mogą utrzymywać się w niektórych tkankach, zwłaszcza w nerkach, oczach i mózgu.56

Ciężka postać leptospirozy, zespół Weila, występuje u około 5-10% zakażonych pacjentów i może rozwinąć się pod koniec pierwszej fazy lub podczas drugiej fazy choroby.78

Mechanizmy patogenetyczne

Patogeneza leptospirozy jest złożona i wciąż nie w pełni poznana. Wyróżnia się kilka kluczowych mechanizmów uszkodzenia tkanek:910

  • Bezpośrednie uszkodzenie komórek – leptospiry mogą bezpośrednio uszkadzać komórki poprzez wydzielanie proteaz i innych produktów degradujących błony komórkowe.11
  • Zapalenie naczyń – najspójniejszym patologicznym odkryciem w leptospirozie jest zapalenie naczyń włosowatych, charakteryzujące się obrzękiem śródbłonka, martwicą i naciekiem limfocytarnym.1213
  • Reakcje immunologiczne – nadmierna odpowiedź immunologiczna, w tym „burza cytokinowa”, może przyczyniać się do uszkodzenia tkanek.1415
  • Adhezja do komórek gospodarza – leptospiry przyczepiają się do śródbłonka naczyń krwionośnych i macierzy pozakomórkowej, a następnie wykorzystują swoją ruchliwość do przemieszczania się między warstwami komórek.16

Odpowiedź immunologiczna i burza cytokinowa

W patogenezie leptospirozy kluczową rolę odgrywa odpowiedź immunologiczna gospodarza. Układ odpornościowy wrodzony stanowi pierwszą linię obrony i jest niezbędny do wczesnego rozpoznania i eliminacji leptospir. Jednak nadmierna lub nieprawidłowo regulowana odpowiedź immunologiczna może prowadzić do uszkodzenia tkanek.1718

Rola cytokin w uszkodzeniu tkanek

W ciężkiej leptospirozie obserwuje się nadmierne uwalnianie cytokin prozapalnych, w tym:

Ten masywny i przedłużony wzrost poziomu cytokin prozapalnych, zwany „burzą cytokinową”, może prowadzić do utrzymującego się stanu zapalnego, a następnie do masowej i ogólnoustrojowej produkcji cytokin przeciwzapalnych. Objawy kliniczne ciężkiej leptospirozy mogą przypominać wstrząs septyczny, z niewydolnością wielonarządową, hipotensją i śmiercią, co sugeruje, że rozwój ciężkiej leptospirozy może być związany z nieprawidłowo regulowanym procesem zapalnym.2122

Badania wskazują, że dla eliminacji bakterii cytokiny zapalne powinny być indukowane szybko. Opóźniona ekspresja może umożliwić kolonizację i namnażanie się bakterii. Jednak produkcja cytokin zapalnych powinna być odpowiednio regulowana – przedłużona produkcja może sprzyjać dalszemu uszkodzeniu tkanek.23

Genetyczna podatność na zakażenie

Zmienność genetyczna gospodarza może wpływać na podatność na leptospirozę. Badania wykazały, że podatność na zakażenie leptospirami była znacząco związana z allelami w loci HLA-A i B oraz różnymi haplotypami HLA. Inne badania odkryły, że zakażenie leptospirozą było podatne na różnorodność genetyczną w genach IL12RB1, IL1 i CISH.24

Patofizjologia uszkodzenia narządów

W ciężkiej leptospirozie dochodzi do uszkodzenia wielu narządów, przy czym „triadę” narządów docelowych stanowią nerki, wątroba i płuca.25

Uszkodzenie nerek

Nerki są głównym narządem docelowym w patologii ludzkiej leptospirozy. Uszkodzenie nerek w leptospirozie związane jest z masywną aktywacją inflamasomów i cytokin prozapalnych we wczesnych fazach, powodujących zapalenie nerek i następnie ich uszkodzenie.26

Patologicznie wszystkie struktury nerkowe są zaangażowane, ale podstawową zmianą w leptospirozie jest śródmiąższowe zapalenie nerek. Zaburzenia czynności kanalików poprzedzają spadek wskaźnika filtracji kłębuszkowej. Ostra niewydolność nerek może manifestować się w postaci skąpomoczu lub wielomoczu, z zaburzeniami elektrolitowymi odzwierciedlającymi dysfunkcję kanalików nerkowych proksymalnych.27

Charakterystyczną cechą laboratoryjną ostrej niewydolności nerek w przebiegu leptospirozy jest hipokaliemia, która wynika ze znacznego zajęcia kanalikowych-śródmiąższowych struktur nerek, niezależnie od hiperkatabolizmu, rabdomiolizy, kwasicy czy skąpomoczu.28

Interesującym mechanizmem jest możliwość adherencji leptospir do komórek nabłonka kanalików nerkowych. Bakterie te mogą tworzyć biofilmy w kanalikach nerkowych, co przyczynia się do ich przetrwania mimo odpowiedzi immunologicznej i antybiotykoterapii.29

Uszkodzenie wątroby

Patogenne leptospiry wnikają do przestrzeni międzykomórkowych hepatocytów, przyczyniając się do zaburzenia połączeń międzykomórkowych. Zaburzenie architektoniki płytek komórek wątrobowych (tzw. „liver cell plate disarray”) jest głównym histopatologicznym odkryciem w ludzkiej leptospirozie.3031

W leptospirozie ekspresja E-kadheryny w komórkach wątroby jest zmniejszona i/lub nieobecna w obszarach zrazika, co przyczynia się do braku stabilnej adhezji międzykomórkowej. Wiązanie patogennych leptospir z komórkami gospodarza poprzez receptory, takie jak kadheryny, nie jest następstwem definitywnej inwazji wewnątrzkomórkowej. Jednak dane eksperymentalne i z autopsji sugerują zmienioną przepuszczalność błony komórkowej z obecnością pozostałości leptospir i/lub antygenów w cytoplazmie, a nawet w jądrach komórek śródbłonka i ludzkich komórek wątrobowych.32

Mechanizm powstawania żółtaczki zaproponowany przez Miyharę i wsp. jest poparty znaleziskiem w mikroskopii elektronowej leptospir i/lub ich pozostałości w przestrzeniach międzykomórkowych hepatocytów u ludzi. Leptospiry zakłócają integralność połączeń międzykomórkowych, co prowadzi do wycieku żółci z kanalików żółciowych do zatok, co wyjaśnia bardzo wysokie poziomy bilirubiny bezpośredniej, bez większych zmian w aktywności ALP lub GGT. Ponadto, ze względu na brak martwicy hepatokomórkowej, poziomy transaminaz nie są podwyższone.3334

Obecność żółtaczki implikuje złe rokowanie, ze wskaźnikiem śmiertelności na poziomie 19,1%.35

Uszkodzenie płuc

Zajęcie płuc występuje u 20-70% pacjentów z leptospirozą i czasem jest objawem prezentacyjnym. Jego ciężkość waha się od nieproduktywnego kaszlu do niewydolności oddechowej z powodu rozległego krwotoku płucnego i tworzenia się błon szklistych.36

Główną przyczyną śmierci u pacjentów z leptospirozą jest zespół krwotoczny płuc w leptospirozie (LPHS). Wskaźniki śmiertelności związane z LPHS przekraczają 50%. Chociaż konkretne toksyny są nadal nieznane, genomy patogennych Leptospira kodują szereg przewidywanych proteaz i hemolizyn, które mogą być zaangażowane w uszkodzenie płuc.37

Charakterystycznymi radiologicznymi objawami zajęcia płuc w leptospirozie w tomografii komputerowej są obustronne zacienienia typu „ground-glass” głównie w obwodowych i dolnych strefach płuc.38

Uszkodzenie układu naczyniowego

Krwawienie jest częstym objawem ciężkiej leptospirozy. Uszkodzenie komórek śródbłonka i zapalenie naczyń są ogólnie przyjętymi jako główne cechy patologiczne leptospirozy. Zdolność do przyłączania się do kadheryn, rodziny zależnych od wapnia przezbłonowych białek adhezyjnych, które funkcjonują w celu utrzymania integralności komórka-komórka i służą jako receptory dla Leptospira interrogans, jest jednym z mechanizmów adhezji do komórek gospodarza.39

Leptospira wiąże się z kadheryną śródbłonka naczyniowego, która znajduje się w połączeniach międzykomórkowych, a także z kadheryną neuronalną, która znajduje się głównie na powierzchni komórki. Dlatego komórka śródbłonka jest uszkodzona w leptospirozie, a obejmuje to nie tylko najważniejszą zmianę w połączeniu adhezyjnym, ale także zmiany błony komórkowej, prowadzące do zmienionej przepuszczalności.4041

Ogólny wzorzec zmienionej adhezji komórkowej z częściowym lub całkowitym zanikiem kadheryn występuje również w naczyniach mikrokrążenia. Uszkodzenie układu naczyniowego jako całości może prowadzić do wycieku z naczyń włosowatych, hipowolemii i wstrząsu.4243

Rola endotoksyn i innych czynników wirulencji

Patogenność leptospir wynika z ich zdolności do przenikania przez błony śluzowe lub uszkodzoną skórę oraz do rozprzestrzeniania się drogą krwionośną. Chociaż bezpośrednia inwazja tkanek może powodować pewne efekty patologiczne, badacze zauważają, że wyraźny stopień wielonarządowego uszkodzenia tkanek wydaje się niezgodny z liczbą leptospir znalezionych podczas mikroskopowego badania tkanek. Inne mediatory indukowane przez leptospiry są podejrzewane o powodowanie różnych manifestacji choroby.44

Glikolipoproteina (GLP)

GLP jest endotoksyną znajdującą się w ścianie komórkowej Leptospira, która odgrywa ważną rolę w patogenezie choroby. Wykrycie GLP w tkankach świadczy o znaczeniu tej endotoksyny w wirulencji i patogenezie Leptospira. Zakażenie aktywuje system obronny gospodarza i generuje lizę bakteryjną, eksponując endotoksynę GLP. Zależność molowa między biodostępnością GLP a stężeniem białek obecnych w tkankach, szczególnie albuminy, determinuje lokalny potencjał cytotoksyczny endotoksyny GLP.45

Lipotoksyczność GLP obejmuje hamowanie aktywności Na/K-ATPazy, co jest mechanizmem wystarczającym do wywołania wielu różnorodnych manifestacji klinicznych w różnych narządach i tkankach. Hamowanie enzymatyczne manifestuje się klinicznie w zależności od zaangażowanych komórek:

  • W spolaryzowanych komórkach nabłonkowych dochodzi do rozproszenia gradientu przeznabłonkowego, co zaburza liczne funkcje wydzielania i reabsorpcji zależne od gradientu sodowego.
  • W neuronach i komórkach pobudliwych zaburza generowanie i przewodzenie impulsów nerwowych.
  • W komórkach ogólnie GLP może aktywować wewnątrzkomórkową sygnalizację prozapalną za pośrednictwem signalosomu Na/K-ATPazy.46

Lipopolisacharyd (LPS)

Niezwykły skład fragmentu lipidu A leptospiralnego LPS może być strategią, którą patogenne Leptospira może wykorzystywać do uniknięcia aktywacji komórek immunologicznych, przyczyniając się do zapoczątkowania choroby u ludzi. Asocjacja PAMP/PRR wyzwala kaskadę zapalną poprzez aktywację wielu wewnątrzkomórkowych szlaków sygnałowych, w tym czynników transkrypcyjnych NF-κB i aktywatora białka 1 (AP-1), które z kolei regulują ekspresję cytokin, prostaglandyn (PG) i tlenku azotu (NO).47

Rola LPS pochodzącego z jelit jako kofaktora w ostrym uszkodzeniu wątroby została wykazana w modelach ostrego uszkodzenia wątroby wywołanego przez różne czynniki hepatotoksyczne. To wskazuje na potencjalne znaczenie mikrobioty jelitowej w patogenezie leptospirozy.48

Inne czynniki wirulencji

Czynniki bakteryjne wpływające na patogenność obejmują lipopolisacharyd (LPS), hemolizyny, regulatory komplementu, czynniki adhezji i enzymy. Po wniknięciu do organizmu gospodarza, krętki szybko przedostają się do krwiobiegu. Uwalniane toksyny prowadzą do uszkodzenia ścian naczyń i wycieku płynu.49

Leptospira wykorzystuje również swoją ruchliwość dzięki flagellom, co umożliwia jej przemieszczanie się przez tkanki. Jest zdolna do wiązania się z komórkami takimi jak fibroblasty, makrofagi, komórki śródbłonka i komórki nabłonka nerek. Wiąże się również z kilkoma białkami ludzkimi, takimi jak białka dopełniacza, trombina, fibrynogen i plazminogen, wykorzystując powierzchniowe białka podobne do immunoglobulin leptospir (Lig), takie jak LigB i LipL32, których geny znajdują się we wszystkich patogennych gatunkach.50

Rola mikrobioty jelitowej

Istnieją coraz liczniejsze dowody na istnienie krytycznego połączenia między mikrobiomem jelitowym a innymi narządami najbardziej dotkniętymi leptospirozą, takimi jak wątroba, płuca i nerki. Mikrobiota jelitowa może odgrywać kluczową rolę w kierowaniu odpowiedziami immunologicznymi poza lokalnym środowiskiem, w tym w płucach, nerkach i wątrobie. Może to być osiągnięte przez ogólnoustrojowe rozprzestrzenianie się metabolitów, jak wykazano w przypadku krótkołańcuchowych kwasów tłuszczowych (SCFA).5152

Dysbioza jelitowa jest jednym z potencjalnych czynników, które mogą wpływać na przebieg kliniczny leptospirozy. Zaburzenie mikrobioty, takie jak leczenie antybiotykami, może zwiększyć podatność na zakażenie L. interrogans. Modulacja mikrobioty jelitowej przez probiotyki i/lub przeszczep mikrobioty kałowej w leptospirozie może stać się ważnym obszarem badań naukowych.5354

Podsumowanie mechanizmu patogenezy

Podsumowując, pierwotną zmianą w leptospirozie wydaje się być uszkodzenie błony komórkowej mediowane przez nieznane czynniki, prawdopodobnie białka leptospiralne i/lub toksyczne składniki komórkowe. Ta zmiana prowadzi do kaskady wydarzeń, które mogą powodować uszkodzenie wielonarządowe.5556

Patogeneza leptospirozy obejmuje złożone interakcje między czynnikami patogenu a odpowiedzią immunologiczną gospodarza. Zarówno czynniki gospodarza, jak i patogeny mogą odgrywać istotną rolę w patogenezie leptospirozy. Indukcja odpowiedzi zapalnej przez patogen może inicjować destrukcyjne mechanizmy immunologiczne prowadzące do uszkodzenia tkanek gospodarza, sepsy i śmierci.57

Zrozumienie mechanizmów molekularnych zaangażowanych w patogenezę i patologię leptospirozy ma ogromne znaczenie dla zastosowań prognostycznych i terapeutycznych, w tym dla opracowania skutecznych szczepionek i nowych strategii leczenia ciężkich przypadków leptospirozy.58

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  1. 15.04.2026
  2. www.leksykon.com.pl

Materiały źródłowe

  • #1
    https://pmc.ncbi.nlm.nih.gov/articles/PMC5975557/
    Leptospirosis is an acute bacterial septicemic febrile disease caused by pathogenic leptospires, which affect humans and animals in all parts of the world. […] Leptospires enter the body by penetrating mucous membranes or skin abrasions and disseminate through the hematogenic route. […] The severe forms of the disease may be life threatening with multisystem damage including renal failure, hepatic dysfunction, vascular damage, pulmonary hemorrhage and muscle lesions. […] In this review, we present and discuss the pathogenesis of the human disease and the mechanisms of cell membrane injuries, which occur mainly due to the presence of leptospires and/or their antigen/s in the host tissues. […] The most severe form of the disease, with multisystem damage, including vascular, hepatic, renal, pulmonary and skeletal muscles injury, is known as the Weil syndrome.
  • #2 Weil’s Disease—Immunopathogenesis, Multiple Organ Failure, and Potential Role of Gut Microbiota
    https://pmc.ncbi.nlm.nih.gov/articles/PMC9775223/
    Leptospirosis is an important zoonotic disease, causing about 60,000 deaths annually. […] In this review, we have described in detail the immunopathogenesis of leptospirosis, the influence of cytokines, genetic susceptibility on the course of the disease, and the evasion of the immune response. […] These data are combined with information about immunological and pathomorphological changes in the kidneys, liver, and lungs, which are most affected by Weils disease. […] The review also suggests a possible role of the gut microbiota in the clinical course of leptospirosis, the main mechanisms of the influence of gut dysbiosis on damage in the liver, kidneys, and lungs through several axes, i.e., gut-liver, gut-kidney, and gut-lungs. […] Both host factors and pathogens may play an important role in the pathogenesis of leptospirosis.
  • #3 Leptospirosis: Practice Essentials, Background, Pathophysiology
    https://emedicine.medscape.com/article/220563-overview
    Virulent organisms in a susceptible host gain rapid access to the bloodstream through the lymphatics, resulting in leptospiremia and spread to all organs, but particularly the liver and kidney. […] The damage to the vascular system as a whole can result in capillary leakage, hypovolemia, and shock. […] The organism affects at least 160 mammalian species and has been recovered from rats, swine, dogs, cats, raccoons, cattle, mongooses, and bandicoots. […] Leptospires may persist for long periods in the renal tubules of animals by establishing a symbiotic relationship with little or no evidence of disease or pathological changes in the kidney. […] Leptospires are thin, coiled, gram-negative, aerobic organisms 6-20 m in length. They are motile, with hooked ends and paired axial flagella (one on each end), enabling them to burrow into tissue. […] The organism typically is transmitted via exposure of mucous membranes or abraded skin to the body fluid of an acutely infected animal or by exposure to soil or fresh water contaminated with the urine of a chronic carrier.
  • #4 Leptospirosis – Wikipedia
    https://en.wikipedia.org/wiki/Leptospirosis
    When animals ingest the bacteria, they circulate in the bloodstream, then lodge themselves into the kidneys through the glomerular or peritubular capillaries. The bacteria then pass into the lumens of the renal tubules and colonise the brush border and proximal convoluted tubule. This causes the continuous shedding of bacteria in the urine without the animal experiencing significant ill effects. This relationship between the animal and the bacteria is known as a commensal relationship, and the animal is known as a reservoir host. […] The pathogenesis of leptospirosis remains poorly understood despite research efforts. The bacteria enter the human body through a breach in the skin or the mucous membrane, then into the bloodstream. The bacteria later attach to the endothelial cells of the blood vessels and extracellular matrix (a complex network of proteins and carbohydrates present between cells). The bacteria use their flagella to move between cell layers. They bind to cells such as fibroblasts, macrophages, endothelial cells, and kidney epithelial cells. They also bind to several human proteins such as complement proteins, thrombin, fibrinogen, and plasminogen using surface leptospiral immunoglobulin-like (Lig) proteins such as LigB and LipL32, whose genes are found in all pathogenic species.
  • #5 Leptospirosis: Causes, Symptoms, Diagnosis & Treatment
    https://my.clevelandclinic.org/health/diseases/24021-leptospirosis
    Leptospirosis is an illness caused by the bacteria Leptospira. […] Leptospirosis can cause flu-like symptoms that can worsen into Weils syndrome, a life-threatening illness, in a small number of people. […] Leptospirosis consists of two phases: the leptospiremic (acute) phase and the immune (delayed) phase. […] During the leptospirosis phase (also called the septicemic phase) you may experience a sudden onset of flu-like symptoms. […] In this phase, bacteria are in your bloodstream and moving to your organs. […] In the immune phase, Leptospira bacteria has moved from your blood to your organs. […] A small number of people will get very sick with Weils syndrome in this phase. Weils syndrome causes internal bleeding, kidney damage and severe yellowing of your skin and eyes (jaundice).
  • #6 Leptospira weil’s disease | PPT
    https://www.slideshare.net/slideshow/leptospira-weils-disease/249804382
    Leptospirosis is transmitted through contact with urine from infected animals. […] The pathogenesis of leptospirosis is incompletely understood. Leptospires enter the host through abrasions in the skin or through intact mucous membranes, especially the conjunctiva and the lining of the oro- and nasopharynx. […] After entry of the organisms, leptospiremia develops, with subsequent spread to all organs. Multiplication takes place in blood and in tissues, and leptospires can be isolated from blood and cerebrospinal fluid (CSF) during the first 4-10 days of illness. […] The most important known pathogenic properties of leptospires are adhesion to cell surfaces and cellular toxicity. […] Vasculitis is responsible for the most important manifestations of the disease. Leptospires mainly infect the kidneys and liver but other organs may be affected.
  • #7 Fulminant Leptospirosis (Weil’s disease) in an urban setting as an overlooked cause of multiorgan failure: a case report | Journal of Medical Case Reports | Full Text
    https://jmedicalcasereports.biomedcentral.com/articles/10.1186/1752-1947-5-7
    Leptospirosis is a zoonosis of worldwide distribution caused by infection with Leptospira interrogans, a pathogenic spirochete. The majority of patients manifest a mild, anicteric febrile illness, but a minority of patients develop a severe form with multiorgan involvement, called Weil’s disease. Weil’s disease is characterized by multisystem dysfunction and can present with high fever, significant jaundice, renal failure, hepatic necrosis, pulmonary involvement, cardiovascular collapse, neurologic changes and hemorrhagic diathesis. […] Weil’s disease is the most severe form of leptospirosis. Patients can present with high fever (40C), significant jaundice, renal failure, hepatic necrosis, pulmonary involvement, cardiovascular collapse, neurologic changes and hemorrhagic diathesis, with a variable clinical course. Weil’s disease can occur at the end of the first stage and peaks during the second stage but can occur at any time during acute leptospirosis as a single, progressive illness.
  • #8 Leptospirosis: Epidemiology, microbiology, clinical manifestations, and diagnosis – UpToDate
    https://www.uptodate.com/contents/leptospirosis-epidemiology-microbiology-clinical-manifestations-and-diagnosis
    Leptospirosis is a zoonosis with protean clinical manifestations caused by pathogenic spirochetes of the genus Leptospira. […] Whole-genome sequencing of strains of the pathogenic species L. interrogans and L. borgpetersenii, and of the saprophytic species L. biflexa, has identified a series of genes possibly related to adhesion, invasion, and hematologic findings in hosts. […] Transmission of the organism to humans occurs via portals of entry, including cuts or abraded skin, mucous membranes, or conjunctivae. […] During the immune phase, leptospires are absent from the blood, and antibodies to the organism are present. […] Icteric leptospirosis occurs in approximately 5 to 10 percent of symptomatic leptospirosis cases and is a rapidly progressive multisystem illness associated with mortality rates of 5 to 15 percent. […] Severe pulmonary disease, characterized by pulmonary hemorrhage, is a serious complication of Weil’s disease. […] Cardiovascular abnormalities, including myocarditis with heart failure or cardiogenic shock, have been reported.
  • #9 SciELO Brazil – Pathology and pathogenesis of human leptospirosis: a commented review Pathology and pathogenesis of human leptospirosis: a commented review
    https://www.scielo.br/j/rimtsp/a/MhPBFRmcXR6RsCrxM5HjyPJ/
    Leptospirosis is an acute bacterial septicemic febrile disease caused by pathogenic leptospires, which affect humans and animals in all parts of the world. […] In this review, we present and discuss the pathogenesis of the human disease and the mechanisms of cell membrane injuries, which occur mainly due to the presence of leptospires and/or their antigen/s in the host tissues. […] The most severe form of the disease, with multisystem damage, including vascular, hepatic, renal, pulmonary and skeletal muscles injury, is known as the Weil syndrome. […] However, morphological lesions, such as the disappearance of the PAS (periodic acid-Schiff reaction) and alkaline phosphatase histochemical reactions, are present in this segment of the nephron during the infection, suggesting that the presence of the microorganism can damage the host during active disease.
  • #10 Azthena logo with the word Azthena
    https://www.news-medical.net/health/Leptospirosis-Bacterial-Disease.aspx
    The pathogenic bacterial spirochetes of the Leptospiragenus are responsible for the infectious disease called leptospirosis. […] The pathogenesis of leptospirosis is not entirely clear. However, a number of suggestions have been put forward to elucidate the virulent factors involved. The production of endotoxins has been observed in many serotypes. Virulent leptospires have been demonstrated to attach to epithelial cells in in vitro studies. They have also been shown to cause LPS-mediated adherence of neutrophils to platelets and endothelial cells. This leads to aggregation and suggests a possible link to the development of thrombocytopenia in affected patients. LPS and other outer membrane proteins are very immunogenic and determine the specificity of the serotype. […] Studies propose the severity of the symptoms may be immune-mediated, because the levels of circulating immune complexes correlate with symptom-related disease severity. Leptospirosis immunity is for the most part humoral (i.e., antibody-mediated). There are some reports of cell-mediated immune responses to the disease, but this is not a significant component.
  • #11
    https://pmc.ncbi.nlm.nih.gov/articles/PMC5975557/
    It should be expected that the presence of the microorganism in the reservoir host might be accompanied, at least in certain cases, by discrete pathophysiological manifestations. […] However, morphological lesions, such as the disappearance of the PAS (periodic acid-Schiff reaction) and alkaline phosphatase histochemical reactions, are present in this segment of the nephron during the infection, suggesting that the presence of the microorganism can damage the host during active disease. […] Liver cell plate disarray is a major histopathologic finding in human autopsies of leptospirosis, receiving attention since the early pathologic studies of the disease during the first World War. […] It was speculated at the time that the damage to cell membranes could be the result of hypothetical toxins produced by pathogenic leptospires, since it has been shown that leptospires have genes encoding for proteases and other products that can cause host cell membrane degradation.
  • #12 Leptospirosis: Practice Essentials, Background, Pathophysiology
    https://emedicine.medscape.com/article/220563-overview
    Leptospirosis is an infectious disease of humans and animals that is caused by pathogenic spirochetes of the genus Leptospira. […] Leptospirosis typically is a biphasic pattern of early flu-like, septicemic illness followed by an inflammatory second phase. The latter may be characterized by systemic inflammatory response syndrome (SIRS) or cytokine storm. […] The most consistent pathologic finding in leptospirosis is vasculitis of capillaries, manifested by endothelial edema, necrosis, and lymphocytic infiltration. […] Although direct invasion of tissue may cause some pathologic effects, researchers note that the marked degree of multiorgan tissue injury appears inconsistent with the number of leptospires found on microscopic examination of tissue. Other mediators induced by the leptospire are the suspected causes of the disease’s various manifestations.
  • #13 Acute renal failure in Weil’s disease | Diálisis y Trasplante
    https://www.elsevier.es/en-revista-dialisis-trasplante-275-articulo-acute-renal-failure-in-weil39s-S1886284512001373
    Leptospirosis is an emerging worldwide zoonotic disease. Renal involvement is common; it may vary from sub-clinical course with mild proteinuria and urinary sediment changes to severe renal failure. […] The most severe form of Leptospirosis, characterized by jaundice, acute kidney injury and haemorrhagic diathesis, is referred as Weil’s disease. […] Leptospirosis is an infectious vasculitis. Its pathogenesis is related both to the ability of the leptospira to damage the small blood vessels wall and to systemic immune response. […] Haemodynamic alterations, bacterial invasion, inflammatory process and direct toxicity of bacterial products are thought to be responsible for nephropathy development. […] Renal impairment is a frequent complication in patients with severe form of leptospirosis, mainly characterized by an association of interstitial and tubular damage.
  • #14 Weil’s Disease—Immunopathogenesis, Multiple Organ Failure, and Potential Role of Gut Microbiota
    https://pmc.ncbi.nlm.nih.gov/articles/PMC9775223/
    Induction of an inflammatory response by a pathogen can initiate destructive immune mechanisms leading to host tissue damage, sepsis, and death. […] The extensive release of cytokines, including interleukin 6 (IL-6), interleukin 1 beta (IL-1), and tumor necrosis factor-alpha (TNF-), is known as a cytokine storm. […] There is growing evidence that there is a critical link between the gut microbiome and other organs most affected by leptospirosis, such as the liver, lungs, and kidneys. […] The kidneys are the target organs in human leptospirosis pathology. […] Leptospirosis is associated with an overwhelming activation of inflammasomes and proinflammatory cytokines in the early phases, causing kidney inflammation and subsequent damage. […] The pathogenic leptospires invade the intercellular junctions of host hepatocytes, and this invasion contributes to the disruption of the junction.
  • #15 Weil’s Disease—Immunopathogenesis, Multiple Organ Failure, and Potential Role of Gut Microbiota
    https://www.mdpi.com/2218-273X/12/12/1830
    Leptospirosis is an important zoonotic disease, causing about 60,000 deaths annually. In this review, we have described in detail the immunopathogenesis of leptospirosis, the influence of cytokines, genetic susceptibility on the course of the disease, and the evasion of the immune response. […] The review also suggests a possible role of the gut microbiota in the clinical course of leptospirosis, the main mechanisms of the influence of gut dysbiosis on damage in the liver, kidneys, and lungs through several axes, i.e., gut-liver, gut-kidney, and gut-lungs. Modulation of gut microbiota by probiotics and/or fecal microbiota transplantation in leptospirosis may become an important area of scientific research. […] Both host factors and pathogens may play an important role in the pathogenesis of leptospirosis. Induction of an inflammatory response by a pathogen can initiate destructive immune mechanisms leading to host tissue damage, sepsis, and death.
  • #16 Leptospirosis – Wikipedia
    https://en.wikipedia.org/wiki/Leptospirosis
    When animals ingest the bacteria, they circulate in the bloodstream, then lodge themselves into the kidneys through the glomerular or peritubular capillaries. The bacteria then pass into the lumens of the renal tubules and colonise the brush border and proximal convoluted tubule. This causes the continuous shedding of bacteria in the urine without the animal experiencing significant ill effects. This relationship between the animal and the bacteria is known as a commensal relationship, and the animal is known as a reservoir host. […] The pathogenesis of leptospirosis remains poorly understood despite research efforts. The bacteria enter the human body through a breach in the skin or the mucous membrane, then into the bloodstream. The bacteria later attach to the endothelial cells of the blood vessels and extracellular matrix (a complex network of proteins and carbohydrates present between cells). The bacteria use their flagella to move between cell layers. They bind to cells such as fibroblasts, macrophages, endothelial cells, and kidney epithelial cells. They also bind to several human proteins such as complement proteins, thrombin, fibrinogen, and plasminogen using surface leptospiral immunoglobulin-like (Lig) proteins such as LigB and LipL32, whose genes are found in all pathogenic species.
  • #17 Weil’s Disease—Immunopathogenesis, Multiple Organ Failure, and Potential Role of Gut Microbiota
    https://www.mdpi.com/2218-273X/12/12/1830
    The extensive release of cytokines, including interleukin 6 (IL-6), interleukin 1 beta (IL-1β), and tumor necrosis factor-alpha (TNF-α), is known as a cytokine storm. Several studies have shown how cytokines contribute to pathogenesis and clinical manifestations of leptospirosis. […] Gut dysbiosis is one of the potential factors that can affect the clinical course of leptospirosis. […] The innate immune system is the first line of host defense and is essential in the early recognition and elimination of leptospires. […] The PAMPs/PRR association triggers an inflammatory cascade by activating multiple intracellular signaling pathways, including the NF-κB and activator protein 1 (AP-1) transcription factors, which in turn regulates the expression of cytokines, prostaglandins (PGs), and nitric oxide (NO).
  • #18 Weil’s Disease | Encyclopedia MDPI
    https://encyclopedia.pub/entry/39015
    Leptospirosis is one of the most widespread and dangerous zoonoses in the world. The main cause of death in leptospirosis is the development of a severe form of leptospirosis—Weil’s disease, which affects the kidneys, lungs, and liver, which are a “triad” of target organs in leptospirosis. […] Both host factors and pathogens may play an important role in the pathogenesis of leptospirosis. Induction of an inflammatory response by a pathogen can initiate destructive immune mechanisms leading to host tissue damage, sepsis, and death. […] Several studies have shown how cytokines contribute to pathogenesis and clinical manifestations of leptospirosis. […] Gut dysbiosis is one of the potential factors that can affect the clinical course of leptospirosis. […] There is growing evidence that there is a critical link between the gut microbiome and other organs most affected by leptospirosis, such as the liver, lungs, and kidneys.
  • #19 Weil’s Disease—Immunopathogenesis, Multiple Organ Failure, and Potential Role of Gut Microbiota
    https://www.mdpi.com/2218-273X/12/12/1830
    The extensive release of cytokines, including interleukin 6 (IL-6), interleukin 1 beta (IL-1β), and tumor necrosis factor-alpha (TNF-α), is known as a cytokine storm. Several studies have shown how cytokines contribute to pathogenesis and clinical manifestations of leptospirosis. […] Gut dysbiosis is one of the potential factors that can affect the clinical course of leptospirosis. […] The innate immune system is the first line of host defense and is essential in the early recognition and elimination of leptospires. […] The PAMPs/PRR association triggers an inflammatory cascade by activating multiple intracellular signaling pathways, including the NF-κB and activator protein 1 (AP-1) transcription factors, which in turn regulates the expression of cytokines, prostaglandins (PGs), and nitric oxide (NO).
  • #20 Weil’s Disease | Encyclopedia MDPI
    https://encyclopedia.pub/entry/39015
    This different recognition is attributed to the unusual composition of the leptospiral Lipid A moiety and could be a strategy that pathogenic Leptospira may use to avoid activation of immune cells, contributing to the initiation of the disease in humans. […] The PAMPs/PRR association triggers an inflammatory cascade by activating multiple intracellular signaling pathways, including the NF-κB and activator protein 1 (AP-1) transcription factors, which in turn regulates the expression of cytokines, prostaglandins (PGs), and nitric oxide (NO). […] Pro-inflammatory cytokines include interleukins (IL)-1β, IL-6, IL-12, interferons (IFNs), and tumor necrosis factors (TNFs), as well as chemokines, which act as chemoattractants to recruit leucocytes to the site of tissue damage and infection. […] Severe infectious diseases are often associated with a prolonged increase in pro-inflammatory IL-1β, TNF-α, IL-6 expression, or “cytokine storm”, causing persistent inflammation and followed by a massive and systemic production of anti-inflammatory cytokines.
  • #21 Weil’s Disease—Immunopathogenesis, Multiple Organ Failure, and Potential Role of Gut Microbiota
    https://www.mdpi.com/2218-273X/12/12/1830
    Inflammatory cytokines and cytokine regulators participate in pathogen clearance without excessive inflammation-induced organ damage. Severe infectious diseases are often associated with a prolonged increase in pro-inflammatory IL-1β, TNF-α, IL-6 expression, or “cytokine storm”, causing persistent inflammation and followed by a massive and systemic production of anti-inflammatory cytokines. […] The kidneys are the target organs in human leptospirosis pathology. Leptospirosis is associated with an overwhelming activation of inflammasomes and proinflammatory cytokines in the early phases, causing kidney inflammation and subsequent damage. […] The pathogenic leptospires invade the intercellular junctions of host hepatocytes, and this invasion contributes to the disruption of the junction.
  • #22 Weil’s Disease | Encyclopedia MDPI
    https://encyclopedia.pub/entry/39015
    Interestingly, the clinical hallmarks of severe leptospirosis can resemble septic shock, with multi-organ failure, hypotension, and death, which suggest that the development of severe leptospirosis could be associated with dysregulated inflammation. […] The very first research of cytokines in human leptospirosis showed a significant increase in TNF-α levels from patient sera. […] Inflammatory response is restricted by regulatory cytokines, such as IL-4 or IL-13, promoting T helper (Th) lymphocyte differentiation toward Th2, suppressing tissue-damaging effects of sustained inflammation. […] High levels of chemokines are found in susceptible hamsters, and are associated with organ damage and poor outcome. […] Notably, patients with severe clinical signs had higher levels of CXCL8/IL-8 expression, and these patients had a higher mortality rate.
  • #23 Immune responses to Leptospira infection: roles as biomarkers for disease severity | The Brazilian Journal of Infectious Diseases
    https://www.bjid.org.br/en-immune-responses-leptospira-infection-roles-articulo-S141386701300264X
    These data suggest that for bacterial eradication, inflammatory cytokines should be induced rapidly. Delayed expression may allow for bacterial colonization and multiplication. However, production of inflammatory cytokines should be properly regulated. Prolonged production could promote further tissue damage. Leptospira toxins could directly induce tissue damage which is further promoted by inflammatory response. […] High IL-10/TNF- ratio was shown to be associated with less disease severity in one study. However, in another study, high IL-10/TNF- ratio was associated with fatal outcome of leptospirosis patients. […] Chemokine involvement has been widely investigated in leptospirosis. Induction of IL-8 was delayed and sustained in C3H/HeJ mice infected with leptospires than in the resistant mice.
  • #24 Weil’s Disease | Encyclopedia MDPI
    https://encyclopedia.pub/entry/39015
    In leptospirosis patients, increasing serum levels of PTX-3 were associated with mortality and disease severity. […] Variations in the genetic makeup of the host may result in changes in susceptibility to leptospirosis. […] According to the researchers, susceptibility to leptospiral infection was significantly associated with alleles in the HLA-A and B loci and various HLA haplotypes. […] Other researchers, on the other hand, discovered that leptospirosis infection was responsive to genetic diversity in the IL12RB1, IL1, and CISH genes. […] Neutrophils are key cells that act against extracellular pathogens through three major mechanisms, i.e., phagocytosis, degranulation, and the release of extracellular traps. […] According to a recent study, most pathogenic leptospires were found on the neutrophil surface and were not phagocytized. […] Although leptospiral serum resistance to host complement was described many decades ago, the mechanisms underlying this resistance have only recently begun to be unraveled.
  • #25 Weil’s Disease | Encyclopedia MDPI
    https://encyclopedia.pub/entry/39015
    Leptospirosis is one of the most widespread and dangerous zoonoses in the world. The main cause of death in leptospirosis is the development of a severe form of leptospirosis—Weil’s disease, which affects the kidneys, lungs, and liver, which are a “triad” of target organs in leptospirosis. […] Both host factors and pathogens may play an important role in the pathogenesis of leptospirosis. Induction of an inflammatory response by a pathogen can initiate destructive immune mechanisms leading to host tissue damage, sepsis, and death. […] Several studies have shown how cytokines contribute to pathogenesis and clinical manifestations of leptospirosis. […] Gut dysbiosis is one of the potential factors that can affect the clinical course of leptospirosis. […] There is growing evidence that there is a critical link between the gut microbiome and other organs most affected by leptospirosis, such as the liver, lungs, and kidneys.
  • #26 Weil’s Disease—Immunopathogenesis, Multiple Organ Failure, and Potential Role of Gut Microbiota
    https://pmc.ncbi.nlm.nih.gov/articles/PMC9775223/
    Induction of an inflammatory response by a pathogen can initiate destructive immune mechanisms leading to host tissue damage, sepsis, and death. […] The extensive release of cytokines, including interleukin 6 (IL-6), interleukin 1 beta (IL-1), and tumor necrosis factor-alpha (TNF-), is known as a cytokine storm. […] There is growing evidence that there is a critical link between the gut microbiome and other organs most affected by leptospirosis, such as the liver, lungs, and kidneys. […] The kidneys are the target organs in human leptospirosis pathology. […] Leptospirosis is associated with an overwhelming activation of inflammasomes and proinflammatory cytokines in the early phases, causing kidney inflammation and subsequent damage. […] The pathogenic leptospires invade the intercellular junctions of host hepatocytes, and this invasion contributes to the disruption of the junction.
  • #27 Acute renal failure in Weil’s disease | Diálisis y Trasplante
    https://www.elsevier.es/en-revista-dialisis-trasplante-275-articulo-acute-renal-failure-in-weil39s-S1886284512001373
    Pathologically all renal structures are involved but interstitial nephritis is the basic lesion of leptospirosis. […] Tubular function abnormalities precede a decline in the glomerular filtration rate. […] AKI can manifest after several days of illness in oliguric or non-oliguric form, with serum electrolyte abnormalities reflecting proximal renal tubular dysfunction. […] Hypokalaemia is the most characteristic laboratory finding of leptospirosis-AKI. […] The considerable tubulo-interstitial involvement explains hypokalaemia such as constant and relevant characteristic of leptospirosis-AKI at the time of diagnosis, regardless of hypercatabolism, rhabdomyolysis, acidosis or oliguria. […] The most severe form of leptospirosis is Weil’s disease, characterized by jaundice, AKI, hypotension, pulmonary oedema and haemorrhage, most commonly involving the lungs but also potentially affecting the gastrointestinal tract, retroperitoneum, pericardium and brain. […] Prognosis of leptospirosis-AKI is usually favourable unless complicated by multiple organ involvement.
  • #28 Acute renal failure in Weil’s disease | Diálisis y Trasplante
    https://www.elsevier.es/en-revista-dialisis-trasplante-275-articulo-acute-renal-failure-in-weil39s-S1886284512001373
    Pathologically all renal structures are involved but interstitial nephritis is the basic lesion of leptospirosis. […] Tubular function abnormalities precede a decline in the glomerular filtration rate. […] AKI can manifest after several days of illness in oliguric or non-oliguric form, with serum electrolyte abnormalities reflecting proximal renal tubular dysfunction. […] Hypokalaemia is the most characteristic laboratory finding of leptospirosis-AKI. […] The considerable tubulo-interstitial involvement explains hypokalaemia such as constant and relevant characteristic of leptospirosis-AKI at the time of diagnosis, regardless of hypercatabolism, rhabdomyolysis, acidosis or oliguria. […] The most severe form of leptospirosis is Weil’s disease, characterized by jaundice, AKI, hypotension, pulmonary oedema and haemorrhage, most commonly involving the lungs but also potentially affecting the gastrointestinal tract, retroperitoneum, pericardium and brain. […] Prognosis of leptospirosis-AKI is usually favourable unless complicated by multiple organ involvement.
  • #29 A global one health perspective on leptospirosis in humans and animals in: Journal of the American Veterinary Medical Association Volume 260 Issue 13 (2022)
    https://avmajournals.avma.org/view/journals/javma/260/13/javma.22.06.0258.xml
    Pathogen factors, reservoir host animals, and environmental factors play critical roles in the maintenance of transmission. After burrowing through tissues at the site of inoculation, spirochetes rapidly multiply in the bloodstream. Organism virulence factors and an individual host’s immune response to the pathogen impact outcome of infection. […] The organism forms biofilms within the renal tubules that may contribute to its persistence in the face of the immune response and antimicrobial therapy. […] Although it was thought that pathogenic leptospires could only replicate in infected hosts and not in the environment, a 2022 study found that the organism could replicate in waterlogged soil, but not in soil or water alone. This could ultimately explain why outbreaks of leptospirosis follow flooding after a lag time, typically 1 to 3 months.
  • #30 Weil’s Disease—Immunopathogenesis, Multiple Organ Failure, and Potential Role of Gut Microbiota
    https://pmc.ncbi.nlm.nih.gov/articles/PMC9775223/
    Induction of an inflammatory response by a pathogen can initiate destructive immune mechanisms leading to host tissue damage, sepsis, and death. […] The extensive release of cytokines, including interleukin 6 (IL-6), interleukin 1 beta (IL-1), and tumor necrosis factor-alpha (TNF-), is known as a cytokine storm. […] There is growing evidence that there is a critical link between the gut microbiome and other organs most affected by leptospirosis, such as the liver, lungs, and kidneys. […] The kidneys are the target organs in human leptospirosis pathology. […] Leptospirosis is associated with an overwhelming activation of inflammasomes and proinflammatory cytokines in the early phases, causing kidney inflammation and subsequent damage. […] The pathogenic leptospires invade the intercellular junctions of host hepatocytes, and this invasion contributes to the disruption of the junction.
  • #31 SciELO Brazil – Pathology and pathogenesis of human leptospirosis: a commented review Pathology and pathogenesis of human leptospirosis: a commented review
    https://www.scielo.br/j/rimtsp/a/MhPBFRmcXR6RsCrxM5HjyPJ/
    Liver cell plate disarray is a major histopathologic finding in human autopsies of leptospirosis, receiving attention since the early pathologic studies of the disease during the first World War. […] It was speculated at the time that the damage to cell membranes could be the result of hypothetical toxins produced by pathogenic leptospires, since it has been shown that leptospires have genes encoding for proteases and other products that can cause host cell membrane degradation. […] In leptospirosis, the expression of E-cadherin in liver cells is diminished and/or absent in areas of the lobule, thus contributing to the lack of a stable intercellular adhesion. […] The binding of pathogenic leptospires to host cells through receptors, such as cadherins, is not followed by a definite intracellular invasion. However, experimental and autopsy data suggest an altered cell membrane permeability with the presence of leptospira remnants and/or antigens in the cytoplasm and even in the nuclei of endothelial and human hepatic cells.
  • #32 SciELO Brazil – Pathology and pathogenesis of human leptospirosis: a commented review Pathology and pathogenesis of human leptospirosis: a commented review
    https://www.scielo.br/j/rimtsp/a/MhPBFRmcXR6RsCrxM5HjyPJ/
    Liver cell plate disarray is a major histopathologic finding in human autopsies of leptospirosis, receiving attention since the early pathologic studies of the disease during the first World War. […] It was speculated at the time that the damage to cell membranes could be the result of hypothetical toxins produced by pathogenic leptospires, since it has been shown that leptospires have genes encoding for proteases and other products that can cause host cell membrane degradation. […] In leptospirosis, the expression of E-cadherin in liver cells is diminished and/or absent in areas of the lobule, thus contributing to the lack of a stable intercellular adhesion. […] The binding of pathogenic leptospires to host cells through receptors, such as cadherins, is not followed by a definite intracellular invasion. However, experimental and autopsy data suggest an altered cell membrane permeability with the presence of leptospira remnants and/or antigens in the cytoplasm and even in the nuclei of endothelial and human hepatic cells.
  • #33 Weil’s Disease—Immunopathogenesis, Multiple Organ Failure, and Potential Role of Gut Microbiota
    https://www.mdpi.com/2218-273X/12/12/1830
    The mechanism of jaundice proposed by Miyhara et al. is supported by the electron microscopy finding for leptospires and/or their remnants in the intercellular spaces of hepatocytes in humans, particularly in guinea pigs experimental disease. […] The main cause of death in patients with leptospirosis is LPHS. The LPHS-related fatality rates are greater than 50%. […] Although specific toxins are still unknown, a wide range of predicted proteases and hemolysins that may be involved in lung damage are encoded in the genomes of pathogenic Leptospira. […] The role of gut-derived LPS as a cofactor in acute liver injury has been shown in models of acute liver injury induced by various hepatotoxic agents. […] The gut microbiota can play a crucial role in directing immune responses outside the local environment, including the lungs, kidneys, and liver. This may be achieved by the systemic dissemination of metabolites, as has been shown for SCFAs. […] Disturbance of the microbiota, such as antibiotic treatment, could increase susceptibility to L. interrogans infection.
  • #34 Weil’s disease as a differential diagnosis of jaundice: A case report | Revista de Gastroenterología de México
    https://www.revistagastroenterologiamexico.org/en-weils-disease-as-differential-diagnosis-avance-S2255534X22000895
    The most characteristic severe form is Weils disease. It can appear after the acute phase and is characterized by altered liver function, and pulmonary and renal involvement. The mortality rate in patients with untreated severe disease reaches 40%. […] Leptospira spirochetes infiltrate the space of Disse and damage the hepatocytes, altering their intercellular binding and causing bile leakage from the bile canaliculi into the sinusoids, which explains the very high levels of direct bilirubin, with no major alterations in ALP or GGT. In addition, due to the fact that there is no hepatocellular necrosis, transaminase levels are not elevated. […] The mechanism of pancreatitis is not clearly defined but it has been postulated that the vasculitis and associated ischemic injury cause the activation of proteolytic enzymes and autodigestion.
  • #35 Weil’s Disease—Immunopathogenesis, Multiple Organ Failure, and Potential Role of Gut Microbiota
    https://pmc.ncbi.nlm.nih.gov/articles/PMC9775223/
    The presence of jaundice implies a poor prognosis with a mortality rate of 19.1%. […] The mechanism of jaundice proposed by Miyhara et al. is supported by the electron microscopy finding for leptospires and/or their remnants in the intercellular spaces of hepatocytes in humans. […] Bleeding is a common symptom of severe leptospirosis. […] Endothelial cell injury and vasculitis are generally accepted as major pathological characteristics of leptospirosis. […] The ability to attach to cadherins, a family of calcium-dependent transmembrane adhesion proteins that function to maintain cell-cell integrity and serve as receptors for Leptospira interrogans, is one of the mechanisms of adhesion to host cells. […] Leptospira binds to vascular endothelial cadherin, which is found at intercellular junctions, as well as neural cadherin, which is found largely on the cell surface.
  • #36 Pulmonary haemorrhage in Weil’s disease | BMJ Case Reports
    https://casereports.bmj.com/content/13/1/e227570
    Pulmonary involvement occurs in 20%70% of patients with leptospirosis and sometimes is the presenting symptom. Its severity ranges from a non-productive cough to respiratory failure due to extensive pulmonary haemorrhage and the formation of hyaline membranes. […] The haemorrhagic form has a mortality rate of up to 60%. […] Characteristic radiological findings of pulmonary involvement in leptospirosis on CT are bilateral ground-glass opacities mainly in the peripheral and lower long zones. […] Pulmonary involvement is one of the predictors associated with worse outcome. Therefore, it is very important to recognise this involvement as potentially presenting symptom of Weils disease. […] In summary, this case illustrates a severe case of Weils disease including pulmonary haemorrhage with full recovery after initiation of treatment in early state of disease.
  • #37 Weil’s Disease—Immunopathogenesis, Multiple Organ Failure, and Potential Role of Gut Microbiota
    https://www.mdpi.com/2218-273X/12/12/1830
    The mechanism of jaundice proposed by Miyhara et al. is supported by the electron microscopy finding for leptospires and/or their remnants in the intercellular spaces of hepatocytes in humans, particularly in guinea pigs experimental disease. […] The main cause of death in patients with leptospirosis is LPHS. The LPHS-related fatality rates are greater than 50%. […] Although specific toxins are still unknown, a wide range of predicted proteases and hemolysins that may be involved in lung damage are encoded in the genomes of pathogenic Leptospira. […] The role of gut-derived LPS as a cofactor in acute liver injury has been shown in models of acute liver injury induced by various hepatotoxic agents. […] The gut microbiota can play a crucial role in directing immune responses outside the local environment, including the lungs, kidneys, and liver. This may be achieved by the systemic dissemination of metabolites, as has been shown for SCFAs. […] Disturbance of the microbiota, such as antibiotic treatment, could increase susceptibility to L. interrogans infection.
  • #38 Pulmonary haemorrhage in Weil’s disease | BMJ Case Reports
    https://casereports.bmj.com/content/13/1/e227570
    Pulmonary involvement occurs in 20%70% of patients with leptospirosis and sometimes is the presenting symptom. Its severity ranges from a non-productive cough to respiratory failure due to extensive pulmonary haemorrhage and the formation of hyaline membranes. […] The haemorrhagic form has a mortality rate of up to 60%. […] Characteristic radiological findings of pulmonary involvement in leptospirosis on CT are bilateral ground-glass opacities mainly in the peripheral and lower long zones. […] Pulmonary involvement is one of the predictors associated with worse outcome. Therefore, it is very important to recognise this involvement as potentially presenting symptom of Weils disease. […] In summary, this case illustrates a severe case of Weils disease including pulmonary haemorrhage with full recovery after initiation of treatment in early state of disease.
  • #39 Weil’s Disease—Immunopathogenesis, Multiple Organ Failure, and Potential Role of Gut Microbiota
    https://pmc.ncbi.nlm.nih.gov/articles/PMC9775223/
    The presence of jaundice implies a poor prognosis with a mortality rate of 19.1%. […] The mechanism of jaundice proposed by Miyhara et al. is supported by the electron microscopy finding for leptospires and/or their remnants in the intercellular spaces of hepatocytes in humans. […] Bleeding is a common symptom of severe leptospirosis. […] Endothelial cell injury and vasculitis are generally accepted as major pathological characteristics of leptospirosis. […] The ability to attach to cadherins, a family of calcium-dependent transmembrane adhesion proteins that function to maintain cell-cell integrity and serve as receptors for Leptospira interrogans, is one of the mechanisms of adhesion to host cells. […] Leptospira binds to vascular endothelial cadherin, which is found at intercellular junctions, as well as neural cadherin, which is found largely on the cell surface.
  • #40 Weil’s Disease—Immunopathogenesis, Multiple Organ Failure, and Potential Role of Gut Microbiota
    https://pmc.ncbi.nlm.nih.gov/articles/PMC9775223/
    The presence of jaundice implies a poor prognosis with a mortality rate of 19.1%. […] The mechanism of jaundice proposed by Miyhara et al. is supported by the electron microscopy finding for leptospires and/or their remnants in the intercellular spaces of hepatocytes in humans. […] Bleeding is a common symptom of severe leptospirosis. […] Endothelial cell injury and vasculitis are generally accepted as major pathological characteristics of leptospirosis. […] The ability to attach to cadherins, a family of calcium-dependent transmembrane adhesion proteins that function to maintain cell-cell integrity and serve as receptors for Leptospira interrogans, is one of the mechanisms of adhesion to host cells. […] Leptospira binds to vascular endothelial cadherin, which is found at intercellular junctions, as well as neural cadherin, which is found largely on the cell surface.
  • #41 SciELO Brazil – Pathology and pathogenesis of human leptospirosis: a commented review Pathology and pathogenesis of human leptospirosis: a commented review
    https://www.scielo.br/j/rimtsp/a/MhPBFRmcXR6RsCrxM5HjyPJ/
    Therefore, the endothelial cell is injured in leptospirosis, and this includes not only the main important lesion at the adherens junction but also alterations of the cell membrane, leading to altered permeability. […] The general pattern of altered cell adhesion with partial or total disappearance of cadherins is also present in microcirculatory vessels. […] In summary, the primary lesion in leptospirosis seems to be the cell membrane damage mediated by unknown factors, possibly leptospiral proteins and/or toxic cellular components. […] Understanding the molecular mechanisms involved in the pathogenesis and pathology of leptospirosis is of utmost importance for prognostic and therapeutic applications.
  • #42 SciELO Brazil – Pathology and pathogenesis of human leptospirosis: a commented review Pathology and pathogenesis of human leptospirosis: a commented review
    https://www.scielo.br/j/rimtsp/a/MhPBFRmcXR6RsCrxM5HjyPJ/
    Therefore, the endothelial cell is injured in leptospirosis, and this includes not only the main important lesion at the adherens junction but also alterations of the cell membrane, leading to altered permeability. […] The general pattern of altered cell adhesion with partial or total disappearance of cadherins is also present in microcirculatory vessels. […] In summary, the primary lesion in leptospirosis seems to be the cell membrane damage mediated by unknown factors, possibly leptospiral proteins and/or toxic cellular components. […] Understanding the molecular mechanisms involved in the pathogenesis and pathology of leptospirosis is of utmost importance for prognostic and therapeutic applications.
  • #43 Leptospirosis: Practice Essentials, Background, Pathophysiology
    https://emedicine.medscape.com/article/220563-overview
    Virulent organisms in a susceptible host gain rapid access to the bloodstream through the lymphatics, resulting in leptospiremia and spread to all organs, but particularly the liver and kidney. […] The damage to the vascular system as a whole can result in capillary leakage, hypovolemia, and shock. […] The organism affects at least 160 mammalian species and has been recovered from rats, swine, dogs, cats, raccoons, cattle, mongooses, and bandicoots. […] Leptospires may persist for long periods in the renal tubules of animals by establishing a symbiotic relationship with little or no evidence of disease or pathological changes in the kidney. […] Leptospires are thin, coiled, gram-negative, aerobic organisms 6-20 m in length. They are motile, with hooked ends and paired axial flagella (one on each end), enabling them to burrow into tissue. […] The organism typically is transmitted via exposure of mucous membranes or abraded skin to the body fluid of an acutely infected animal or by exposure to soil or fresh water contaminated with the urine of a chronic carrier.
  • #44 Leptospirosis: Practice Essentials, Background, Pathophysiology
    https://emedicine.medscape.com/article/220563-overview
    Leptospirosis is an infectious disease of humans and animals that is caused by pathogenic spirochetes of the genus Leptospira. […] Leptospirosis typically is a biphasic pattern of early flu-like, septicemic illness followed by an inflammatory second phase. The latter may be characterized by systemic inflammatory response syndrome (SIRS) or cytokine storm. […] The most consistent pathologic finding in leptospirosis is vasculitis of capillaries, manifested by endothelial edema, necrosis, and lymphocytic infiltration. […] Although direct invasion of tissue may cause some pathologic effects, researchers note that the marked degree of multiorgan tissue injury appears inconsistent with the number of leptospires found on microscopic examination of tissue. Other mediators induced by the leptospire are the suspected causes of the disease’s various manifestations.
  • #45 Cellular Pathophysiology of Leptospirosis: Role of Na/K-ATPase
    https://www.mdpi.com/2076-2607/11/7/1695
    Leptospira penetrates the host and effortlessly reaches the bloodstream, promoting bacteremia. The bacteria reach organs and tissues through circulation, colonizing the spleen, liver, lungs, and kidneys, where they multiply and spread. The highest load of leptospira in the blood can be detected on the fifth day after infection. […] The detection of GLP in tissues evidences the importance of this endotoxin in the virulence and pathogenesis of Leptospira. […] The infection activates the host’s defense system and generates bacterial lysis, exposing the endotoxin GLP, which integrates the cell wall of the Leptospira. The molar relationship between the bioavailability of GLP and the concentration of proteins present in the tissues, notably albumin, results in the local cytotoxicity potential of the GLP endotoxin.
  • #46 Cellular Pathophysiology of Leptospirosis: Role of Na/K-ATPase
    https://www.mdpi.com/2076-2607/11/7/1695
    The GLP lipotoxicity involves inhibiting Na/K-ATPase activity, a mechanism sufficient to cause many varied clinical manifestations in different organs and tissues. Enzymatic inhibition is clinically manifested according to the cells involved. In polarized epithelial cells, there is a dissipation of the transepithelial gradient, compromising the multiple functions of secretion and reabsorption dependent on the sodium gradient. In neurons and excitable cells, it compromises the generation and conduction of nerve impulses. In cells in general, GLP can activate intracellular pro-inflammatory signaling via the Na/K-ATPase signalosome. Activations of intracellular pathways promote the expression of pro-apoptotic genes, culminating in cell death. In addition to inflammatory status induced during leptospirosis, metabolic alterations occur with increased levels of NEFA-inducing lipotoxicity. Thus, GLP has the potential to induce inflammatory and metabolic alterations through Na/K-ATPase inhibition or triggering the signalosome, which might explain their cellular and clinical conditions. Future studies may help to unveil the role of Na/K-ATPase in Leptospirosis pathogenesis and as a potential therapeutic target for critically ill patients with Weil’s Syndrome.
  • #47 Weil’s Disease | Encyclopedia MDPI
    https://encyclopedia.pub/entry/39015
    This different recognition is attributed to the unusual composition of the leptospiral Lipid A moiety and could be a strategy that pathogenic Leptospira may use to avoid activation of immune cells, contributing to the initiation of the disease in humans. […] The PAMPs/PRR association triggers an inflammatory cascade by activating multiple intracellular signaling pathways, including the NF-κB and activator protein 1 (AP-1) transcription factors, which in turn regulates the expression of cytokines, prostaglandins (PGs), and nitric oxide (NO). […] Pro-inflammatory cytokines include interleukins (IL)-1β, IL-6, IL-12, interferons (IFNs), and tumor necrosis factors (TNFs), as well as chemokines, which act as chemoattractants to recruit leucocytes to the site of tissue damage and infection. […] Severe infectious diseases are often associated with a prolonged increase in pro-inflammatory IL-1β, TNF-α, IL-6 expression, or “cytokine storm”, causing persistent inflammation and followed by a massive and systemic production of anti-inflammatory cytokines.
  • #48 Weil’s Disease—Immunopathogenesis, Multiple Organ Failure, and Potential Role of Gut Microbiota
    https://www.mdpi.com/2218-273X/12/12/1830
    The mechanism of jaundice proposed by Miyhara et al. is supported by the electron microscopy finding for leptospires and/or their remnants in the intercellular spaces of hepatocytes in humans, particularly in guinea pigs experimental disease. […] The main cause of death in patients with leptospirosis is LPHS. The LPHS-related fatality rates are greater than 50%. […] Although specific toxins are still unknown, a wide range of predicted proteases and hemolysins that may be involved in lung damage are encoded in the genomes of pathogenic Leptospira. […] The role of gut-derived LPS as a cofactor in acute liver injury has been shown in models of acute liver injury induced by various hepatotoxic agents. […] The gut microbiota can play a crucial role in directing immune responses outside the local environment, including the lungs, kidneys, and liver. This may be achieved by the systemic dissemination of metabolites, as has been shown for SCFAs. […] Disturbance of the microbiota, such as antibiotic treatment, could increase susceptibility to L. interrogans infection.
  • #49 Leptospira/Leptospirosis | Concise Medical Knowledge
    https://www.lecturio.com/concepts/leptospira-leptospirosis/
    Bacterial factors affecting pathogenicity include lipopolysaccharide (LPS), hemolysins, complement regulators, adherence factors, and enzymes. Once in the host, the spirochetes enter the bloodstream. Toxins released lead to breakdown of the vessel walls and fluid leakage. At this time, organisms have escaped from the bloodstream to the tissues. Leptospires are absent in the blood, but are found in the urine. Immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies directed against the Leptospira LPS are generated by the host. These antibodies are opsonins that enhance phagocytosis. […] Initially, Leptospira in the bloodstream cause flu-like symptoms. From the bloodstream, bacteria establish in other areas, particularly parenchymatous organs. Renal effects include renal failure and hypokalemia. Hepatic effects involve vascular injury in hepatic capillaries and jaundice. Pulmonary effects include capillary damage and alveolar hemorrhage, leading to acute respiratory distress syndrome. Hematologic effects include hemolysis and thrombocytopenia. […] The pathogenic capacity of an organism is determined by its virulence factors.
  • #50 Leptospirosis – Wikipedia
    https://en.wikipedia.org/wiki/Leptospirosis
    When animals ingest the bacteria, they circulate in the bloodstream, then lodge themselves into the kidneys through the glomerular or peritubular capillaries. The bacteria then pass into the lumens of the renal tubules and colonise the brush border and proximal convoluted tubule. This causes the continuous shedding of bacteria in the urine without the animal experiencing significant ill effects. This relationship between the animal and the bacteria is known as a commensal relationship, and the animal is known as a reservoir host. […] The pathogenesis of leptospirosis remains poorly understood despite research efforts. The bacteria enter the human body through a breach in the skin or the mucous membrane, then into the bloodstream. The bacteria later attach to the endothelial cells of the blood vessels and extracellular matrix (a complex network of proteins and carbohydrates present between cells). The bacteria use their flagella to move between cell layers. They bind to cells such as fibroblasts, macrophages, endothelial cells, and kidney epithelial cells. They also bind to several human proteins such as complement proteins, thrombin, fibrinogen, and plasminogen using surface leptospiral immunoglobulin-like (Lig) proteins such as LigB and LipL32, whose genes are found in all pathogenic species.
  • #51 Weil’s Disease—Immunopathogenesis, Multiple Organ Failure, and Potential Role of Gut Microbiota
    https://pmc.ncbi.nlm.nih.gov/articles/PMC9775223/
    The gut microbiota can play a crucial role in directing immune responses outside the local environment, including the lungs, kidneys, and liver. […] Therefore, the cross-connection of the gut microbiota with many internal organs of the body plays an important role in the clinical course of many diseases, including leptospirosis.
  • #52 Weil’s Disease—Immunopathogenesis, Multiple Organ Failure, and Potential Role of Gut Microbiota
    https://www.mdpi.com/2218-273X/12/12/1830
    The mechanism of jaundice proposed by Miyhara et al. is supported by the electron microscopy finding for leptospires and/or their remnants in the intercellular spaces of hepatocytes in humans, particularly in guinea pigs experimental disease. […] The main cause of death in patients with leptospirosis is LPHS. The LPHS-related fatality rates are greater than 50%. […] Although specific toxins are still unknown, a wide range of predicted proteases and hemolysins that may be involved in lung damage are encoded in the genomes of pathogenic Leptospira. […] The role of gut-derived LPS as a cofactor in acute liver injury has been shown in models of acute liver injury induced by various hepatotoxic agents. […] The gut microbiota can play a crucial role in directing immune responses outside the local environment, including the lungs, kidneys, and liver. This may be achieved by the systemic dissemination of metabolites, as has been shown for SCFAs. […] Disturbance of the microbiota, such as antibiotic treatment, could increase susceptibility to L. interrogans infection.
  • #53 Weil’s Disease—Immunopathogenesis, Multiple Organ Failure, and Potential Role of Gut Microbiota
    https://www.mdpi.com/2218-273X/12/12/1830
    The extensive release of cytokines, including interleukin 6 (IL-6), interleukin 1 beta (IL-1β), and tumor necrosis factor-alpha (TNF-α), is known as a cytokine storm. Several studies have shown how cytokines contribute to pathogenesis and clinical manifestations of leptospirosis. […] Gut dysbiosis is one of the potential factors that can affect the clinical course of leptospirosis. […] The innate immune system is the first line of host defense and is essential in the early recognition and elimination of leptospires. […] The PAMPs/PRR association triggers an inflammatory cascade by activating multiple intracellular signaling pathways, including the NF-κB and activator protein 1 (AP-1) transcription factors, which in turn regulates the expression of cytokines, prostaglandins (PGs), and nitric oxide (NO).
  • #54 Weil’s Disease—Immunopathogenesis, Multiple Organ Failure, and Potential Role of Gut Microbiota
    https://www.mdpi.com/2218-273X/12/12/1830
    Leptospirosis is an important zoonotic disease, causing about 60,000 deaths annually. In this review, we have described in detail the immunopathogenesis of leptospirosis, the influence of cytokines, genetic susceptibility on the course of the disease, and the evasion of the immune response. […] The review also suggests a possible role of the gut microbiota in the clinical course of leptospirosis, the main mechanisms of the influence of gut dysbiosis on damage in the liver, kidneys, and lungs through several axes, i.e., gut-liver, gut-kidney, and gut-lungs. Modulation of gut microbiota by probiotics and/or fecal microbiota transplantation in leptospirosis may become an important area of scientific research. […] Both host factors and pathogens may play an important role in the pathogenesis of leptospirosis. Induction of an inflammatory response by a pathogen can initiate destructive immune mechanisms leading to host tissue damage, sepsis, and death.
  • #55
    https://pmc.ncbi.nlm.nih.gov/articles/PMC5975557/
    Therefore, we suggest that the endothelial cell is injured in leptospirosis, and this includes not only the main important lesion at the adherens junction but also alterations of the cell membrane, leading to altered permeability. […] In summary, the primary lesion in leptospirosis seems to be the cell membrane damage mediated by unknown factors, possibly leptospiral proteins and/or toxic cellular components.
  • #56 SciELO Brazil – Pathology and pathogenesis of human leptospirosis: a commented review Pathology and pathogenesis of human leptospirosis: a commented review
    https://www.scielo.br/j/rimtsp/a/MhPBFRmcXR6RsCrxM5HjyPJ/
    Therefore, the endothelial cell is injured in leptospirosis, and this includes not only the main important lesion at the adherens junction but also alterations of the cell membrane, leading to altered permeability. […] The general pattern of altered cell adhesion with partial or total disappearance of cadherins is also present in microcirculatory vessels. […] In summary, the primary lesion in leptospirosis seems to be the cell membrane damage mediated by unknown factors, possibly leptospiral proteins and/or toxic cellular components. […] Understanding the molecular mechanisms involved in the pathogenesis and pathology of leptospirosis is of utmost importance for prognostic and therapeutic applications.
  • #57 Weil’s Disease—Immunopathogenesis, Multiple Organ Failure, and Potential Role of Gut Microbiota
    https://www.mdpi.com/2218-273X/12/12/1830
    Leptospirosis is an important zoonotic disease, causing about 60,000 deaths annually. In this review, we have described in detail the immunopathogenesis of leptospirosis, the influence of cytokines, genetic susceptibility on the course of the disease, and the evasion of the immune response. […] The review also suggests a possible role of the gut microbiota in the clinical course of leptospirosis, the main mechanisms of the influence of gut dysbiosis on damage in the liver, kidneys, and lungs through several axes, i.e., gut-liver, gut-kidney, and gut-lungs. Modulation of gut microbiota by probiotics and/or fecal microbiota transplantation in leptospirosis may become an important area of scientific research. […] Both host factors and pathogens may play an important role in the pathogenesis of leptospirosis. Induction of an inflammatory response by a pathogen can initiate destructive immune mechanisms leading to host tissue damage, sepsis, and death.
  • #58 SciELO Brazil – Pathology and pathogenesis of human leptospirosis: a commented review Pathology and pathogenesis of human leptospirosis: a commented review
    https://www.scielo.br/j/rimtsp/a/MhPBFRmcXR6RsCrxM5HjyPJ/
    Therefore, the endothelial cell is injured in leptospirosis, and this includes not only the main important lesion at the adherens junction but also alterations of the cell membrane, leading to altered permeability. […] The general pattern of altered cell adhesion with partial or total disappearance of cadherins is also present in microcirculatory vessels. […] In summary, the primary lesion in leptospirosis seems to be the cell membrane damage mediated by unknown factors, possibly leptospiral proteins and/or toxic cellular components. […] Understanding the molecular mechanisms involved in the pathogenesis and pathology of leptospirosis is of utmost importance for prognostic and therapeutic applications.

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faza immunologiczna rabdomioliza zespół Weila mikrobiota jelitowa hipokaliemia niewydolność wielonarządowa śródmiąższowe zapalenie nerek hipotensja żółtaczka interleukina-6 zoonoza lipopolisacharyd krętki Leptospira niewydolność oddechowa bakteriemia leptospiroza wstrząs septyczny płyn mózgowo-rdzeniowy zapalenie naczyń włosowatych dysbioza jelitowa burza cytokinowa ostra niewydolność nerek czynnik martwicy nowotworów alfa choroba Weila interleukina-1β zespół krwotoczny płuc uszkodzenie śródbłonka