NAIP-NLRC4-deficient Mice Are Susceptible to Shigellosis

Overview

Journal Elife

Specialty Biology

Date 2020 Oct 19

PMID 33074100

Citations 40

Authors

Patrick S Mitchell

Justin L Roncaioli

Elizabeth A Turcotte

Lisa Goers

Roberto A Chavez

Angus Y Lee

Cammie F Lesser

Isabella Rauch

Russell E Vance

Affiliations

Soon will be listed here.

Abstract

Bacteria of the genus cause shigellosis, a severe gastrointestinal disease that is a major cause of diarrhea-associated mortality in humans. Mice are highly resistant to and the lack of a tractable physiological model of shigellosis has impeded our understanding of this important human disease. Here, we propose that the differential susceptibility of mice and humans to is due to mouse-specific activation of the NAIP-NLRC4 inflammasome. We find that NAIP-NLRC4-deficient mice are highly susceptible to oral infection and recapitulate the clinical features of human shigellosis. Although inflammasomes are generally thought to promote pathogenesis, we instead demonstrate that intestinal epithelial cell (IEC)-specific NAIP-NLRC4 activity is sufficient to protect mice from shigellosis. In addition to describing a new mouse model of shigellosis, our results suggest that the lack of an inflammasome response in IECs may help explain the susceptibility of humans to shigellosis.

Citing Articles

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OspF blocks rapid p38-dependent priming of the NAIP-NLRC4 inflammasome.

Turcotte E, Kim K, Eislmayr K, Goers L, Mitchell P, Lesser C bioRxiv. 2025; .

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A newly developed oral infection mouse model of shigellosis for immunogenicity and protective efficacy studies of a candidate vaccine.

Haldar R, Halder P, Koley H, Miyoshi S, Das S Infect Immun. 2024; 93(1):e0034624.

PMID: 39692481 PMC: 11784180. DOI: 10.1128/iai.00346-24.

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Scott T, Baker K, Trotter C, Jenkins C, Mostowy S, Hawkey J Nat Rev Microbiol. 2024; .

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TLR priming licenses NAIP inflammasome activation by immunoevasive ligands.

Grayczyk J, Liu L, Egan M, Aunins E, Wynosky-Dolfi M, Canna S Proc Natl Acad Sci U S A. 2024; 121(48):e2412700121.

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References

Sansonetti P, Phalipon A, Arondel J, Thirumalai K, Banerjee S, Akira S . Caspase-1 activation of IL-1beta and IL-18 are essential for Shigella flexneri-induced inflammation. Immunity. 2000; 12(5):581-90. DOI: 10.1016/s1074-7613(00)80209-5. View

Ashida H, Kim M, Sasakawa C . Manipulation of the host cell death pathway by Shigella. Cell Microbiol. 2014; 16(12):1757-66. DOI: 10.1111/cmi.12367. View

Kobayashi T, Ogawa M, Sanada T, Mimuro H, Kim M, Ashida H . The Shigella OspC3 effector inhibits caspase-4, antagonizes inflammatory cell death, and promotes epithelial infection. Cell Host Microbe. 2013; 13(5):570-583. DOI: 10.1016/j.chom.2013.04.012. View

West N, Sansonetti P, Mounier J, Exley R, Parsot C, Guadagnini S . Optimization of virulence functions through glucosylation of Shigella LPS. Science. 2005; 307(5713):1313-7. DOI: 10.1126/science.1108472. View

Crowley S, Han X, Allaire J, Stahl M, Rauch I, Knodler L . Intestinal restriction of Salmonella Typhimurium requires caspase-1 and caspase-11 epithelial intrinsic inflammasomes. PLoS Pathog. 2020; 16(4):e1008498. PMC: 7179941. DOI: 10.1371/journal.ppat.1008498. View

Yang J, Zhao Y, Shi J, Shao F . Human NAIP and mouse NAIP1 recognize bacterial type III secretion needle protein for inflammasome activation. Proc Natl Acad Sci U S A. 2013; 110(35):14408-13. PMC: 3761597. DOI: 10.1073/pnas.1306376110. View

Knodler L, Crowley S, Sham H, Yang H, Wrande M, Ma C . Noncanonical inflammasome activation of caspase-4/caspase-11 mediates epithelial defenses against enteric bacterial pathogens. Cell Host Microbe. 2014; 16(2):249-256. PMC: 4157630. DOI: 10.1016/j.chom.2014.07.002. View

Kotloff K, Noriega F, Losonsky G, Sztein M, Wasserman S, Nataro J . Safety, immunogenicity, and transmissibility in humans of CVD 1203, a live oral Shigella flexneri 2a vaccine candidate attenuated by deletions in aroA and virG. Infect Immun. 1996; 64(11):4542-8. PMC: 174410. DOI: 10.1128/iai.64.11.4542-4548.1996. View

Orr N, Katz D, Atsmon J, Radu P, Yavzori M, Halperin T . Community-based safety, immunogenicity, and transmissibility study of the Shigella sonnei WRSS1 vaccine in Israeli volunteers. Infect Immun. 2005; 73(12):8027-32. PMC: 1307051. DOI: 10.1128/IAI.73.12.8027-8032.2005. View

10.

Yum L, Byndloss M, Feldman S, Agaisse H . Critical role of bacterial dissemination in an infant rabbit model of bacillary dysentery. Nat Commun. 2019; 10(1):1826. PMC: 6478941. DOI: 10.1038/s41467-019-09808-4. View

11.

Vance R . The NAIP/NLRC4 inflammasomes. Curr Opin Immunol. 2015; 32:84-9. PMC: 4336817. DOI: 10.1016/j.coi.2015.01.010. View

12.

Kortmann J, Brubaker S, Monack D . Cutting Edge: Inflammasome Activation in Primary Human Macrophages Is Dependent on Flagellin. J Immunol. 2015; 195(3):815-9. PMC: 4505955. DOI: 10.4049/jimmunol.1403100. View

13.

DuPont H, Hornick R, Dawkins A, Snyder M, Formal S . The response of man to virulent Shigella flexneri 2a. J Infect Dis. 1969; 119(3):296-9. DOI: 10.1093/infdis/119.3.296. View

14.

Bernardini M, Mounier J, DHauteville H, Sansonetti P . Identification of icsA, a plasmid locus of Shigella flexneri that governs bacterial intra- and intercellular spread through interaction with F-actin. Proc Natl Acad Sci U S A. 1989; 86(10):3867-71. PMC: 287242. DOI: 10.1073/pnas.86.10.3867. View

15.

Holly M, Han X, Zhao E, Crowley S, Allaire J, Knodler L . Salmonella enterica Infection of Murine and Human Enteroid-Derived Monolayers Elicits Differential Activation of Epithelium-Intrinsic Inflammasomes. Infect Immun. 2020; 88(7). PMC: 7309616. DOI: 10.1128/IAI.00017-20. View

16.

Wang H, Yang H, Shivalila C, Dawlaty M, Cheng A, Zhang F . One-step generation of mice carrying mutations in multiple genes by CRISPR/Cas-mediated genome engineering. Cell. 2013; 153(4):910-8. PMC: 3969854. DOI: 10.1016/j.cell.2013.04.025. View

17.

Yum L, Agaisse H . Mechanisms of bacillary dysentery: lessons learnt from infant rabbits. Gut Microbes. 2019; 11(3):597-602. PMC: 7524307. DOI: 10.1080/19490976.2019.1667726. View

18.

Miyoshi H, Stappenbeck T . In vitro expansion and genetic modification of gastrointestinal stem cells in spheroid culture. Nat Protoc. 2013; 8(12):2471-82. PMC: 3969856. DOI: 10.1038/nprot.2013.153. View

19.

Shim D, Suzuki T, Chang S, Park S, Sansonetti P, Sasakawa C . New animal model of shigellosis in the Guinea pig: its usefulness for protective efficacy studies. J Immunol. 2007; 178(4):2476-82. DOI: 10.4049/jimmunol.178.4.2476. View

20.

Mani S, Wierzba T, Walker R . Status of vaccine research and development for Shigella. Vaccine. 2016; 34(26):2887-2894. DOI: 10.1016/j.vaccine.2016.02.075. View