In vivo apoptosis of hepatocytes in guinea pigs infected with<i>Leptospira interrogans</i>serovar icterohaemorrhagiae

Mérien, Fabrice; Truccolo, Johann; Rougier, Y.; Baranton, Guy; Perolat, P.

doi:10.1111/j.1574-6968.1998.tb13304.x

Cited by 54 publications

(16 citation statements)

References 16 publications

(14 reference statements)

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“…Our finding that L. interrogans attaches better to cadherins than does the L. biflexa is consistent with previous data showing that pathogenic strains of Leptospira bind epithelial and endothelial cells more efficiently than saprophytic strains [2], [5], [6], [9], [11]. Several studies also demonstrated that L. biflexa adheres well to inert surfaces such as glass and plastic [8], [10], [67].…”

Section: Discussionsupporting

confidence: 92%

Leptospira interrogans Binds to Cadherins

et al. 2014

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Leptospirosis, caused by pathogenic species of Leptospira, is the most widespread zoonosis and has emerged as a major public health problem worldwide. The adhesion of pathogenic Leptospira to host cells, and to extracellular matrix (ECM) components, is likely to be necessary for the ability of leptospires to penetrate, disseminate and persist in mammalian host tissues. Previous work demonstrated that pathogenic L. interrogans binds to host cells more efficiently than to ECM. Using two independent screening methods, mass spectrometry and protein arrays, members of the cadherin family were identified as potential L. interrogans receptors on mammalian host surfaces. We focused our investigation on vascular endothelial (VE)-cadherin, which is widely expressed on endothelia and is primarily responsible for endothelial cell-cell adhesion. Monolayers of EA.hy926 and HMEC-1 endothelial cells produce VE-cadherin, bind L. interrogans in vitro, and are disrupted upon incubation with the bacteria, which may reflect the endothelial damage seen in vivo. Dose-dependent and saturable binding of L. interrogans to the purified VE-cadherin receptor was demonstrated and pretreatment of purified receptor or endothelial cells with function-blocking antibody against VE-cadherin significantly inhibited bacterial attachment. The contribution of VE-cadherin to leptospiral adherence to host endothelial cell surfaces is biologically significant because VE-cadherin plays an important role in maintaining the barrier properties of the vasculature. Attachment of L. interrogans to the vasculature via VE-cadherin may result in vascular damage, facilitating the escape of the pathogen from the bloodstream into different tissues during disseminated infection, and may contribute to the hemorrhagic manifestations of leptospirosis. This work is first to describe a mammalian cell surface protein as a receptor for L. interrogans.

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Section: Discussionsupporting

confidence: 92%

Leptospira interrogans Binds to Cadherins

et al. 2014

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“…Using the virulent Leptospira interrogans Icterohaemorragiae strain Verdun [45],[46], we determined the dose of 10 8 live leptospires injected via the intra-peritoneal route as leading to ca. 50% mortality.…”

Section: Discussionmentioning

confidence: 99%

Differential Cytokine Gene Expression According to Outcome in a Hamster Model of Leptospirosis

Vernel-Pauillac

Goarant²

2010

PLoS Negl Trop Dis

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BackgroundParameters predicting the evolution of leptospirosis would be useful for clinicians, as well as to better understand severe leptospirosis, but are scarce and rarely validated. Because severe leptospirosis includes septic shock, similarities with predictors evidenced for sepsis and septic shock were studied in a hamster model.Methodology/Principal FindingsUsing an LD50 model of leptospirosis in hamsters, we first determined that 3 days post-infection was a time-point that allowed studying the regulation of immune gene expression and represented the onset of the clinical signs of the disease. In the absence of tools to assess serum concentrations of immune effectors in hamsters, we determined mRNA levels of various immune genes, especially cytokines, together with leptospiraemia at this particular time-point. We found differential expression of both pro- and anti-inflammatory mediators, with significantly higher expression levels of tumor necrosis factor α, interleukin 1α, cyclo-oxygenase 2 and interleukin 10 genes in nonsurvivors compared to survivors. Higher leptospiraemia was also observed in nonsurvivors. Lastly, we demonstrated the relevance of these results by comparing their respective expression levels using a LD100 model or an isogenic high-passage nonvirulent variant.Conclusions/SignificanceUp-regulated gene expression of both pro- and anti-inflammatory immune effectors in hamsters with fatal outcome in an LD50 model of leptospirosis, together with a higher Leptospira burden, suggest that these gene expression levels could be predictors of adverse outcome in leptospirosis.

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“…Much interest has developed recently concerning the role of apoptosis in the pathogenesis of bacterial disease, although to date there have been no reports to demonstrate evasion of host cell apoptosis by bacterial organisms (28,29). Several bacterial agents have been shown to exert a proapoptotic influence on host cells (28,30,31), and it can only be speculated whether the capacity to induce host cell apoptosis evolved as a cellular host defense strategy or whether it provided the bacterial organism with a selective advantage. Members of the genus Rickettsia, are unique among bacterial organisms in that they are strict obligate intracellular parasites requiring a viable host cell for survival and replication.…”

Section: Discussionmentioning

confidence: 99%

NF-κB-dependent inhibition of apoptosis is essential for host cell survival during Rickettsia rickettsii infection

Clifton

Goss

Sahni

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

214

200

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The possibility that bacteria may have evolved strategies to overcome host cell apoptosis was explored by using Rickettsia rickettsii, an obligate intracellular Gram-negative bacteria that is the etiologic agent of Rocky Mountain spotted fever. The vascular endothelial cell, the primary target cell during in vivo infection, exhibits no evidence of apoptosis during natural infection and is maintained for a sufficient time to allow replication and cell-to-cell spread prior to eventual death due to necrotic damage. Prior work in our laboratory demonstrated that R. rickettsii infection activates the transcription factor NF-B and alters expression of several genes under its control. However, when R. rickettsiiinduced activation of NF-B was inhibited, apoptosis of infected but not uninfected endothelial cells rapidly ensued. In addition, human embryonic fibroblasts stably transfected with a superrepressor mutant inhibitory subunit IB that rendered NF-B inactivatable also underwent apoptosis when infected, whereas infected wild-type human embryonic fibroblasts survived. R. rickettsii, therefore, appeared to inhibit host cell apoptosis via a mechanism dependent on NF-B activation. Apoptotic nuclear changes correlated with presence of intracellular organisms and thus this previously unrecognized proapoptotic signal, masked by concomitant NF-B activation, likely required intracellular infection. Our studies demonstrate that a bacterial organism can exert an antiapoptotic effect, thus modulating the host cell's apoptotic response to its own advantage by potentially allowing the host cell to remain as a site of infection.

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In vivo apoptosis of hepatocytes in guinea pigs infected withLeptospira interrogansserovar icterohaemorrhagiae

Cited by 54 publications

References 16 publications

Leptospira interrogans Binds to Cadherins

Leptospira interrogans Binds to Cadherins

Differential Cytokine Gene Expression According to Outcome in a Hamster Model of Leptospirosis

NF-κB-dependent inhibition of apoptosis is essential for host cell survival during Rickettsia rickettsii infection

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