Tissue apoptosis in mice infected with Leptospira interrogans serovar Icterohaemorrhagiae

Marinho, Márcia; Táparo, Cilene Vidovix; Oliveira-Júnior, Itamar Souza; Perri, Sílvia Helena Venturoli; Cardoso, Tereza Cristina

doi:10.1186/s40409-015-0022-y

Cited by 6 publications

(6 citation statements)

References 25 publications

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“…Understanding the fate of those immune cells in spleen can further lead to understanding persistent inflammation in the host during leptospirosis. Induction of apoptosis in macrophages and fibroblasts by pathogenic Leptospira was evident from earlier studies in mice and suggested that persistent infection can lead to cellular necrosis depending on virulence of the Leptospira strains ( 1 , 18 , 19 ). The goal of the current study was to analyze the cell death processes involved in splenic inflammation of C3H-HeJ mice infected with pathogenic and non-pathogenic Leptospira in the first three days of infection.…”

Section: Introductionmentioning

confidence: 91%

Necroptosis Contributes to Persistent Inflammation During Acute Leptospirosis

2022

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Leptospirosis is an emerging infectious disease. Recently, canine and human leptospirosis outbreaks were reported in California and New York, respectively. In this study we evaluated the role that cell death processes play in the inflammatory response to Leptospira. Groups of male C3H/HeJ mice were infected with pathogenic L. interrogans and non-pathogenic L. biflexa for 24 and 72 hours; inflammatory processes were characterized for apoptosis and necroptosis by flowcytometry of spleen cells and were further assessed for expression of biomarkers of necroptosis by western blot. We found that pathogenic L. interrogans promotes apoptosis in myeloid neutrophils and monocytes at 24h and 72h post-infection, whereas L. biflexa promotes apoptosis of myeloid monocytes only at 24h post-infection. It is interesting that the immune cells undergoing the common programmed cell death pathway (apoptosis) are the cell types which were not increased in frequency in spleen of mice infected with L. interrogans (neutrophils) and L. biflexa (monocytes) in our previous study. The same trend was observed with pathogenic L. interrogans inducing necroptosis of myeloid neutrophils in addition to monocytes and macrophages at 24h and/or 72h post-infection, whereas L. biflexa promoted this pro-inflammatory cell death process in monocytes and macrophages only at 24h post-infection. Thus, early apoptosis and necroptosis of these cell types may explain its absence in frequency in spleen. Furthermore, at 24h and 72h, expression of the necroptosis molecular biomarkers p-MLKL, p-RIP1 and p-RIP3 was increased post infection with pathogenic L. interrogans. These data suggest that the underlying cell death processes involved in immune responses to pathogenic Leptospira contribute directly to persistent inflammation during the early stages of leptospirosis.

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Section: Introductionmentioning

confidence: 91%

Necroptosis Contributes to Persistent Inflammation During Acute Leptospirosis

2022

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“…Although TNF-α was the first cytokine to be associated with leptospirosis severity (Estavoyer et al, 1991 ; Tajiki and Salomão, 1996 ), its precise role in the disease pathophysiology is still under debate. Macrophage apoptosis induced by L. interrogans in vitro is triggered via caspase-8 and caspase-3-dependant pathways (Jin et al, 2009 ), and Leptospira were suggested to induce apoptosis in organs though the caspase-3-dependent pathway in infected mice (Marinho et al, 2015 ). Thus, TNF-α might play a role in Leptospira -induced apoptosis as it can activate caspase-3- and caspase-8-associated apoptosis (Zhao et al, 2001 ; Wang et al, 2008 ).…”

Section: Role Of Cytokines In the Pathophysiology Of Severe Leptospirmentioning

confidence: 99%

Leptospirosis Pathophysiology: Into the Storm of Cytokines

Cagliero

Villanueva

Matsui

2018

Front. Cell. Infect. Microbiol.

112

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Leptospirosis is a neglected tropical zoonosis caused by pathogenic spirochetes of the genus Leptospira. Infected reservoir animals, typically mice and rats, are asymptomatic, carry the pathogen in their renal tubules, and shed pathogenic spirochetes in their urine, contaminating the environment. Humans are accidental hosts of pathogenic Leptospira. Most human infections are mild or asymptomatic. However, 10% of human leptospirosis cases develop into severe forms, including high leptospiremia, multi-organ injuries, and a dramatically increased mortality rate, which can relate to a sepsis-like phenotype. During infection, the triggering of the inflammatory response, especially through the production of cytokines, is essential for the early elimination of pathogens. However, uncontrolled cytokine production can result in a cytokine storm process, followed by a state of immunoparalysis, which can lead to sepsis and associated organ failures. In this review, the involvement of cytokine storm and subsequent immunoparalysis in the development of severe leptospirosis in susceptible hosts will be discussed. The potential contribution of major pro-inflammatory cytokines in the development of tissue lesions and systemic inflammatory response, as well as the role of anti-inflammatory cytokines in contributing to the onset of a deleterious immunosuppressive cascade will also be examined. Data from studies comparing susceptible and resistant mouse models will be included. Lastly, a concise discussion on the use of cytokines for therapeutic purposes or as biomarkers of leptospirosis severity will be provided.

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“…The most striking feature was the decrease in the circumferential F‐actin belt and the appearance of F‐actin‐lined vacuoles, which did not colocalise with bacteria (Figure 5d ). Marinho et al reported by using an animal model that L. interrogans induces cell death of renal epithelial cells in later phases of infection (Marinho, Táparo, Oliveira‐Júnior, Perri, & Cardoso, 2015 ). To investigate if F‐actin disruption and AJC disassembly reflects a consequence of cell death, cell viability, and DNA fragmentation were evaluated in infected RPTECs using cisplatin as a positive control of cell death‐inducer of RPTECs (Sallustio et al, 2013 ).…”

Section: Resultsmentioning

confidence: 99%

Disassembly of the apical junctional complex during the transmigration of Leptospira interrogans across polarized renal proximal tubule epithelial cells

Sebastián

Okura

Humbel

et al. 2021

Cellular Microbiology

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Bacterial pathogens have evolved multiple strategies to disassemble epithelial cell apical junctional complexes (AJCs) and infect epithelial cells. Leptospirosis is a widespread zoonotic infection, mainly caused by Leptospira interrogans, and its dissemination across host cell barriers is essential for its pathogenesis. However, the mechanism of bacterial dissemination across epithelial cell barriers remains poorly characterised. In this study, we analysed the interaction of L. interrogans with renal proximal tubule epithelial cells (RPTECs) and found that at 24 hr post‐infection, L. interrogans remain in close contact with the plasma membrane of the RPTEC by extracellularly adhering or crawling. Leptospira interrogans cleaved E‐cadherin and induced its endocytosis with release of the soluble N‐terminal fragment into the extracellular medium. Concomitantly, a gradual decrease in transepithelial electrical resistance (TEER), mislocalisation of AJC proteins (occludin, claudin‐10, ZO‐1, and cingulin) and cytoskeletal rearrangement were observed. Inhibition of clathrin‐mediated E‐cadherin endocytosis prevented the decrease in TEER. We showed that disassembly of AJCs in epithelial cells and transmigration of bacteria through the paracellular route are important for the dissemination of L. interrogans in the host.

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Tissue apoptosis in mice infected with Leptospira interrogans serovar Icterohaemorrhagiae

Cited by 6 publications

References 25 publications

Necroptosis Contributes to Persistent Inflammation During Acute Leptospirosis

Necroptosis Contributes to Persistent Inflammation During Acute Leptospirosis

Leptospirosis Pathophysiology: Into the Storm of Cytokines

Disassembly of the apical junctional complex during the transmigration of Leptospira interrogans across polarized renal proximal tubule epithelial cells

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