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Abstract Number: 942

Role of the Pyrin Inflammasome in Resistance to Yersinia Pestis: A Possible Selective Advantage for Carriers of MEFV Mutations

Yong Hwan Park1, Wonyong Lee1, Lawton Chung2, James Bliska2, Daniel L. Kastner1 and Jae Jin Chae3, 1Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 2Department of Molecular Genetics and Microbiology, School of Medicine, Stony Brook University, Stony Brook, NY, 3Inflammatory disease section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: Autoinflammatory Disease, Familial Mediterranean fever, infection and inflammasome activation

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Session Information

Date: Sunday, November 5, 2017

Title: Pediatric Rheumatology – Pathogenesis and Genetics

Session Type: ACR Concurrent Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose: Mutations in MEFV, encoding pyrin, cause the prototypic autoinflammatory disease, familial Mediterranean fever (FMF). The carrier frequency of FMF-associated MEFV mutations is extraordinarily high in Mediterranean and Middle Eastern populations, suggesting that heterozygous FMF mutations may confer a selective advantage against some pathogenic microbes. Inactivation of the RhoA GTPase is a common bacterial virulence mechanism, because RhoA activation is required for actin polymerization and leukocyte migration, phagocytosis, and degranulation. The pyrin inflammasome senses RhoA inactivation and activates IL-1β as part of the host defense against these bacteria. Pathogenic Yersinia, including Y. pestis, the agent of plague in humans, deliver virulence effectors, termed Yersinia outer proteins (Yops), into host cells; some of these Yops are known to inactivate RhoA. In the current study, we utilized pyrin knockin (KI) and knockout (KO) mice to examine the role of pyrin in host defense against Yersinia infection.

Methods: Pyrin-KO and FMF-KI mice harboring the FMF-associated M680I or V726A mutations were examined for susceptibility to Y. pestis by infection studies. We measured IL-1β production by ELISA in immune cells from wild type and from FMF-KI mouse strains, in response to wild type (WT) Y. pseudotuberculosis or Y. pestis, or to mutant Yersinia strains with deletions of specific Yops. Protein interactions were studied by immunoprecipitation.

Results: In Yersinia-infected macrophages, the pyrin inflammasome was activated by the RhoA-inactivating enzymatic activities of YopE and YopT. On the other hand, YopM specifically inhibited pyrin to promote virulence by activating the host protein kinases (PKN1 and PKN2) that phosphorylate pyrin to block pyrin inflammasome activation. Pyrin-KO mice were highly susceptible to Yersinia yopM mutant infection, while WT mice were not susceptible. However, bone marrow-derived macrophages (BMDMs) from both homozygous and heterozygous FMF-KI mice released significantly higher levels of IL-1β in comparison with WT BMDMs in response to Yersinia infection. These results suggest that the FMF-associated mutant pyrin is not suppressed by YopM, thereby providing survival advantage of FMF-KI mice against Yersinia infection. Indeed, FMF-KI mice, both homozygotes and heterozygotes, showed significant resistance to Y. pestis infection in comparison with WT mice.

Conclusion: These findings, taken together with the historical record of high-mortality epidemics throughout human history, suggest that Yersinia pestis played an important role in selecting for the high frequency of FMF-associated MEFV mutations in Mediterranean and Middle Eastern populations.


Disclosure: Y. H. Park, None; W. Lee, None; L. Chung, None; J. Bliska, None; D. L. Kastner, None; J. J. Chae, None.

To cite this abstract in AMA style:

Park YH, Lee W, Chung L, Bliska J, Kastner DL, Chae JJ. Role of the Pyrin Inflammasome in Resistance to Yersinia Pestis: A Possible Selective Advantage for Carriers of MEFV Mutations [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/role-of-the-pyrin-inflammasome-in-resistance-to-yersinia-pestis-a-possible-selective-advantage-for-carriers-of-mefv-mutations/. Accessed .
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