Pathogenic, but Not Nonpathogenic,
            <i>Rickettsia</i>
            spp. Evade Inflammasome-Dependent IL-1 Responses To Establish an Intracytosolic Replication Niche

Voß, Oliver; Cobb, Jennifer; Gaytan, Hodalis; Díaz, Nora; Sanchez, Rigoberto; DeTolla, Louis J.; Rahman, M. Sayeedur; Azad, Abdu F.

doi:10.1128/mbio.02918-21

Cited by 11 publications

(57 citation statements)

References 43 publications

(81 reference statements)

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“…Collectively, our data are in agreement with previous reports (21,22,29,31), indicating that, unlike non-pathogenic R. montanensis spp, both pathogenic R. typhi , and R. rickettsii spp, induce autophagy, but evade autophagolysosomal destruction, and reduce anti-rickettsial inflammasome-dependent IL-1 cytokine responses to establish an intracytosolic replication niche in macrophages.…”

Section: Resultssupporting

confidence: 93%

“…Based on recent findings from other laboratories and ours (21–24,29,31–34,39), it has become evident that Rickettsia spp exhibit variable pathogenicity, indicating species-specific strategies to respond to mechanism of host defense surveillance, including autophagy and inflammasome responses. In our efforts to address the role of autophagy in modulating the intracellular survival of Rickettsia spp, we first determined the colocalization status of R. montanensis, R. typhi , and R. rickettsii with LC3B during infection of ATG5 fl/fl or ATG5 fl/fl -LysM-Cre BMDMΦ by IFA.…”

Section: Resultsmentioning

confidence: 62%

“…Preceding findings suggest that intracellular pathogens, like Rickettsia , not only encounter inflammasome-dependent defense mechanisms but are also confronted by another cytosolic defense pathway, autophagy (21–24,29,31–34). Both responses not only are key to mount the appropriate host defense responses, but are also functionally interconnected (15,16).…”

Section: Resultsmentioning

confidence: 99%

“…Our recent findings identified a previously unappreciated mechanism by which highly pathogenic Rickettsia spp ( R. typhi , and R. rickettsii ), unlike non-pathogenic rickettsiae, benefitted from a reduced IL-1 signaling response, specifically IL-1α, to support their replication within the host (31). Intriguingly, R. australis benefited from ATG5-dependent autophagy induction and reduction of pro-inflammatory cytokine responses (21,22), however, a successful host colonization of R. parkeri involved the evasion of autophagy and inflammasome-mediated host cell death (23,24), leaving the precise mechanism inconclusive.…”

Section: Resultsmentioning

confidence: 99%

“…Such strategies entail reprogramming host phosphoinositide (PI) metabolism, which can facilitate uptake into host cells, modify phagosomes, undermine apoptosis, and interfere with other cellular defense mechanisms, such as inflammasomes and autophagy. However, in the case of Rickettsia the mechanisms by which these pathogens modulate both inflammasome and autophagy responses to facilitate their replication in endothelial cells and immune cells, like macrophages, is only now emerging (21,22,40,23,24,29,31–34,39). In fact, recent findings from others and our laboratory have provided some insight on how highly pathogenic Rickettsia spp modulate inflammasome-mediated immune responses to establish an intracellular niche.…”

Section: Discussionmentioning

confidence: 99%

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Pathogenic Rickettsia species evade autophagosomal maturation and reduce anti-microbicidal pro-inflammatory IL-1 responses to support their intracellular survival

Voß

Gaytan

Rahman

et al. 2022

Preprint

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Species of genus Rickettsia are obligate intracellular bacterial parasites of a wide range of arthropod and vertebrate hosts. Some Rickettsia species are responsible for several serious human diseases. One fascinating feature of these stealthy group of pathogens is their ability to exploit host cytosolic defense responses to their benefits. However, the precise mechanism by which pathogenic Rickettsia elude host immune defense responses remains to be determined. Here, we observed that pathogenic R. typhi and R. rickettsii, but not non-pathogenic R. montanensis become ubiquitinated and induce autophagy upon entry into bone-marrow-derived macrophages.Moreover, unlike R. montanensis, R. typhi, and R. rickettsii colocalized with LC3B but not with Lamp2 upon host cell entry. Finally, we observed that pathogenic but not non-pathogenic Rickettsia reduce pro-inflammatory IL-1 responses. In sum, we identified a previously unappreciated pathway by which pathogenic, but not non-pathogenic, Rickettsia become ubiquitinated and induced autophagy, but avoided autophagolysosomal destruction as well as inflammasome-mediated anti-microbicidal IL-1 cytokine responses to establish an intracytosolic niche in macrophages.

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Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 62%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Pathogenic Rickettsia species evade autophagosomal maturation and reduce anti-microbicidal pro-inflammatory IL-1 responses to support their intracellular survival

Voß

Gaytan

Rahman

et al. 2022

Preprint

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Japanese spotted fever in an area endemic to SFTS virus: Case report and review of the literature

Liu,

2024

Medicine

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Rationale: The geographic spread of Japanese spotted fever (JSF) in China is gradually expanding, particularly in regions where severe fever with thrombocytopenia syndrome (SFTS) is highly prevalent, with both diseases sharing similarities in epidemiology and clinical presentation. The microbiological diagnosis of JSF is challenging, compounded by low awareness among healthcare professionals in newly affected areas. Moreover, primary healthcare facilities without polymerase chain reaction (PCR) testing capabilities for SFTS often misdiagnose JSF as SFTS. Patient concerns: All 3 patients had a history of working in the fields, with cold like symptoms in the early fever stages, but the fever did not improve after a few days. The accompanying symptoms were also very different. Physical examination revealed enlarged lymph nodes, different forms of rash, with or without eschar. Laboratory tests showed thrombocytopenia, eosinophilia, elevated lactate dehydrogenase, and transaminase, with 1 patient experiencing renal damage. It is worth noting that these 3 patients reside in an area where SFTS is endemic, and there have been no prior reports of JSF. They exhibited clinical symptoms and laboratory test results closely resembling those of SFTS. Therefore, they were initially misdiagnosed with SFTS in their local hospitals. Diagnoses: The 3 patients who arrived at our hospital 7 days after symptom onset and were subsequently diagnosed with JSF by metagenomic next-generation sequencing (mNGS). Interventions: Doxycycline treatment for 1 week. Outcomes: The patients’ symptoms quickly improved with no side effects, and the results of laboratory tests went back to normal. Lessons: By comparing the clinical characteristics of JSF patients and SFTS patients comprehensively, we found that APTT and procalcitonin levels may be valuable in assisting in the identification of SFTS and JSF. In all areas where tick-borne diseases are endemic, include SFTS-epidemic areas, we recommend using the Weil–Felix test to screen for potential rickettsiosis in patients presenting with fever and thrombocytopenia with or without rash in primary healthcare settings, as well as simultaneous testing for the SFTS virus and spotted fever group rickettsioses sequence. Additionally, mNGS sequencing should be used to confirm the diagnosis and provide information for epidemiological investigations in patients who are suspected of having spotted fever group rickettsiosis.

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Pathogenic rickettsiae utilize the phosphatidylserine binding receptor CD300f on macrophages for host invasion and pathogenesis

Voss,

Moin,

Gaytan

et al. 2024

Preprint

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Some arthropod-borne obligate intracellular rickettsiae are among the most virulent human pathogens. Upon entry, Rickettsia species modulate immune (e.g., macrophages; MΦ) and non-immune cell (e.g., endothelial cells) responses to create a habitable environment for host colonization. In particular, MΦ play a crucial role in either terminating an infection at an early stage or succumbing to bacterial replication and colonization. However, our understanding on how Rickettsia species modulate crucial cellular processes within MΦ, including phagocytosis, and host cell defenses, to establish an intracytosolic replication niche, remain poorly defined. In this study, we describe a previously unappreciated mechanism, in which pathogenic rickettsiae infection is mediated by the phosphatidylserine (PS)-binding receptor, CD300f. We found that CD300f-/- mice but not wild-type (WT) C57BL/6J mice were protected against R. typhi- or R. rickettsii [Shelia Smith]-induced fatal rickettsiosis. Adoptative transfer studies further revealed that CD300f-expressing bone marrow-derived macrophages (BMDMΦ) are important mediators to control rickettsiosis in WT mice. Mechanistical analysis, using WT or CD300f-/- BMDMΦ, showed that CD300f facilitates the engulfment of both pathogenic R. typhi and R. rickettsii species, likely via a PS-mediated mechanism. Furthermore, CD300f was involved in the intracytosolic replication of both pathogenic rickettsiae by differentially modulating the anti-inflammatory Interleukin (IL)-10 and anti-rickettsial IL-1alpha and IL-1beta cytokine responses. Collectively, our findings describe a previously unappreciated role for the efferocytic receptor, CD300f, to facilitate engulfment and the intracellular survival of pathogenic rickettsiae within the host.

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Pathogenic, but Not Nonpathogenic, Rickettsia spp. Evade Inflammasome-Dependent IL-1 Responses To Establish an Intracytosolic Replication Niche

Cited by 11 publications

References 43 publications

Pathogenic Rickettsia species evade autophagosomal maturation and reduce anti-microbicidal pro-inflammatory IL-1 responses to support their intracellular survival

Pathogenic Rickettsia species evade autophagosomal maturation and reduce anti-microbicidal pro-inflammatory IL-1 responses to support their intracellular survival

Japanese spotted fever in an area endemic to SFTS virus: Case report and review of the literature

Pathogenic rickettsiae utilize the phosphatidylserine binding receptor CD300f on macrophages for host invasion and pathogenesis

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