Evasion of autophagy mediated by Rickettsia surface protein OmpB is critical for virulence

Engström, Patrik; Burke, Thomas; Mitchell, Gabriel; Ingabire, Nadia; Mark, Kevin G.; Golovkine, Guillaume; Iavarone, Anthony T.; Rapé, Michael; Cox, Jeffery S.; Welch, Matthew

doi:10.1038/s41564-019-0583-6

Cited by 62 publications

(145 citation statements)

References 75 publications

(73 reference statements)

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“…Additionally, the Iowa strain is also defective in processing of another important outer membrane protein, rOmpB [37,40]. rOmpB has also been associated with rickettsial virulence [41].…”

Section: Discussionmentioning

confidence: 99%

Comparative Analysis of Infection by Rickettsia rickettsii Sheila Smith and Taiaçu Strains in a Murine Model

et al. 2020

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Rocky Mountain spotted fever (RMSF) is a life-threatening tick-borne disease caused by Rickettsia rickettsii, which is widely distributed throughout the Americas. Over 4000 cases of RMSF are recorded annually in the United States, while only around 100 cases are reported in Brazil. Conversely, while case fatality rates in the United States oscillate around 5%, in Brazil they can surpass 70%, suggesting that differences in tick vectoring capacity, population sensitivity, and/or variability in virulence of the rickettsial strains may exist. In this study, we compared the susceptibility of C3H/HeN mice to two highly virulent strains of R. rickettsii, one from the United States (Sheila Smith) and the other from Brazil (Taiaçu). Animals inoculated with the Taiaçu strain succumbed to infection earlier and exhibited severe histological lesions in both liver and spleen sooner than mice infected with the Sheila Smith strain. These differences in survival and signs of the disease are not related to a greater proliferation of the Taiaçu strain, as there were no significant differences in the rickettsial load in mice tissues inoculated with either strain. The present study is the first step to experimentally assess differences in fatality rates of RMSF in two different regions of the American continent.

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“…Additionally, the Iowa strain is also defective in processing of another important outer membrane protein, rOmpB [37,40]. rOmpB has also been associated with rickettsial virulence [41].…”

Section: Discussionmentioning

confidence: 99%

Comparative Analysis of Infection by Rickettsia rickettsii Sheila Smith and Taiaçu Strains in a Murine Model

et al. 2020

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“…Our findings that Ifnar −/− Ifngr −/− mice rapidly succumb to infection are of strong practical importance, as they suggest that the Ifnar −/− Ifngr −/− mouse may serve as an animal model to identify and characterize bacterial virulence genes. As a proof of concept, we infected Ifnar −/− Ifngr −/− mice with an R. parkeri mutant lacking outer membrane protein B (OmpB) 41 . In contrast with WT bacteria, infection with the ompB mutant caused no lethality in Ifnar −/− Ifngr −/− mice ( Fig.…”

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confidence: 99%

Inflammasome-mediated antagonism of type I interferon enhances Rickettsia pathogenesis

et al. 2020

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Summary The innate immune system fights infection with inflammasomes and interferons. Facultative bacterial pathogens that inhabit the host cytosol avoid inflammasomes 1 – 6 and are often insensitive to type I interferons (IFN-I), but are restricted by IFN-γ 7 – 11 . However, it remains unclear how obligate cytosolic bacterial pathogens, including Rickettsia species, interact with innate immunity. Here, we report that the human pathogen Rickettsia parkeri is sensitive to IFN-I and benefits from inflammasome-mediated host cell death that antagonizes IFN-I. R. parkeri -induced cell death requires the cytosolic lipopolysaccharide (LPS) receptor caspase-11 and antagonizes IFN-I production mediated by the DNA sensor cGAS. The restrictive effects of IFN-I require the interferon regulatory factor IRF5, which upregulates genes encoding guanylate binding proteins (GBPs) and inducible nitric oxide synthase (iNOS), which we found to inhibit R. parkeri . Mice lacking both IFN-I and IFN-γ receptors succumb to R. parkeri , revealing critical and overlapping roles for these cytokines in vivo . The interactions of R. parkeri with inflammasomes and interferons are similar to those of viruses, which can exploit the inflammasome to avoid IFN-I 12 , are restricted by IFN-I via IRF5 13 , 14 , and are controlled by IFN-I and IFN-γ in vivo 15 – 17 . Our results suggest that the innate immune response to an obligate cytosolic pathogen lies at the intersection of anti-bacterial and anti-viral responses.

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“…90 % of OmpB -R.p. were positive for M1, K63 or K48-linked ubiquitin chains 30 and interestingly M1 and K63 are ubiquitin chains are also known to activate NF-κΒ [48][49][50] . Taken together, it is possible that unlike L.m., WT R.p.…”

Section: Discussionmentioning

confidence: 97%

“…infected cells show NF-κΒ activation at these late times pI. OmpB outer membrane protein blocks poly-ubiquitylation of the bacterial surface proteins but is dispensable for cell growth in endothelial cells but not in macrophages 30 . Given previous studies, it appears that there is a link between poly-ubiquitinylation and NF-κΒ activation [48][49][50] .…”

Section: Discussionmentioning

confidence: 98%

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Mechanical competition triggered by innate immune signaling drives the collective extrusion of bacterially-infected epithelial cells

Bastounis

Alcade

Radhakrishnan

et al. 2020

Preprint

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Intracellular bacterial pathogens often reprogram their mammalian host cells, including cell mechanical properties, to promote their own replication and spread. However, it is unclear whether mammalian host cells may modulate their biomechanics in response to infection in a way that would benefit the host by limiting bacterial infection. Inspired by this question, we monitored epithelial cell monolayers infected with low levels of Listeria monocytogenes. We found that, as the bacteria replicate and spread from cell to cell over several days, the infected host cells within the infection focus get progressively compressed by surrounding uninfected cells. Surrounding uninfected cells become highly polarized and move directionally towards the infection focus, squeezing the infected cells that eventually get extruded from the monolayer.Extruded cells continue adhering to the cellular monolayer, giving rise to a 3-dimensional (3D) mound of infected cells. We hypothesized that 3D mounding was driven by changes in the biomechanics of uninfected cells surrounding the mounds (surrounders) as well as the infected cells that eventually compose the mound (mounders). Indeed, we found that infected mounders, but not surrounders, become softer during infection and adhere more weakly on deformable matrices mimicking their natural environment. Through a combination of transcriptomics, pharmacological and genetic perturbations, we find that differentially upregulated innate immunity signaling, and downregulated cell-cell and cell-matrix adhesion pathways synergistically can drive the observed cellular competition between infected mounders and surrounders. Most importantly we find that activation of NF-κB is critical for mound formation, and show evidence that our findings extend to bacterial pathogens other than L. monocytogenes. Overall, our findings highlight the dynamic remodeling capability of epithelial tissue, and propose a novel biomechanical mechanism employed by host epithelial cells to eliminate bacterial infection.

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Evasion of autophagy mediated by Rickettsia surface protein OmpB is critical for virulence

Cited by 62 publications

References 75 publications

Comparative Analysis of Infection by Rickettsia rickettsii Sheila Smith and Taiaçu Strains in a Murine Model

Comparative Analysis of Infection by Rickettsia rickettsii Sheila Smith and Taiaçu Strains in a Murine Model

Inflammasome-mediated antagonism of type I interferon enhances Rickettsia pathogenesis

Mechanical competition triggered by innate immune signaling drives the collective extrusion of bacterially-infected epithelial cells

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