Human Enteric α-Defensin 5 Promotes Shigella Infection by Enhancing Bacterial Adhesion and Invasion

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2018 Jun 3

PMID 29858013

Citations 28

Authors

Dan Xu

Chongbing Liao

Bing Zhang

W David Tolbert

Wangxiao He

Zhijun Dai

Wei Zhang

Weirong Yuan

Marzena Pazgier

Jiankang Liu

Jun Yu

Philippe J Sansonetti

Charles L Bevins

Yongping Shao

Wuyuan Lu

Affiliations

Soon will be listed here.

Abstract

Shigella is a Gram-negative bacterium that causes bacillary dysentery worldwide. It invades the intestinal epithelium to elicit intense inflammation and tissue damage, yet the underlying mechanisms of its host selectivity and low infectious inoculum remain perplexing. Here, we report that Shigella co-opts human α-defensin 5 (HD5), a host defense peptide important for intestinal homeostasis and innate immunity, to enhance its adhesion to and invasion of mucosal tissues. HD5 promoted Shigella infection in vitro in a structure-dependent manner. Shigella, commonly devoid of an effective host-adhesion apparatus, preferentially targeted HD5 to augment its ability to colonize the intestinal epithelium through interactions with multiple bacterial membrane proteins. HD5 exacerbated infectivity and Shigella-induced pathology in a culture of human colorectal tissues and three animal models. Our findings illuminate how Shigella exploits innate immunity by turning HD5 into a virulence factor for infection, unveiling a mechanism of action for this highly proficient human pathogen.

Citing Articles

Shigella infection is facilitated by interaction of human enteric α-defensin 5 with colonic epithelial receptor P2Y11.

Xu D, Guo M, Xu X, Luo G, Liu Y, Bush S Nat Microbiol. 2025; 10(2):509-526.

PMID: 39901059 DOI: 10.1038/s41564-024-01901-9.

Alpha-defensin binding expands human adenovirus tropism.

Zhao C, Porter J, Burke P, Arnberg N, Smith J PLoS Pathog. 2024; 20(6):e1012317.

PMID: 38900833 PMC: 11230588. DOI: 10.1371/journal.ppat.1012317.

Subversion of a family of antimicrobial proteins by .

Gerlach R, Wittmann I, Heinrich L, Pinkenburg O, Meyer T, Elpers L Front Cell Infect Microbiol. 2024; 14:1375887.

PMID: 38505286 PMC: 10948614. DOI: 10.3389/fcimb.2024.1375887.

Understanding the Dynamics of Human Defensin Antimicrobial Peptides: Pathogen Resistance and Commensal Induction.

Kumaresan V, Kamaraj Y, Subramaniyan S, Punamalai G Appl Biochem Biotechnol. 2024; 196(10):6993-7024.

PMID: 38478321 DOI: 10.1007/s12010-024-04893-8.

Mechanisms and regulation of defensins in host defense.

Fu J, Zong X, Jin M, Min J, Wang F, Wang Y Signal Transduct Target Ther. 2023; 8(1):300.

PMID: 37574471 PMC: 10423725. DOI: 10.1038/s41392-023-01553-x.

References

Salzman N, Ghosh D, Huttner K, Paterson Y, Bevins C . Protection against enteric salmonellosis in transgenic mice expressing a human intestinal defensin. Nature. 2003; 422(6931):522-6. DOI: 10.1038/nature01520. View

Hauser A . The type III secretion system of Pseudomonas aeruginosa: infection by injection. Nat Rev Microbiol. 2009; 7(9):654-65. PMC: 2766515. DOI: 10.1038/nrmicro2199. View

Rapista A, Ding J, Benito B, Lo Y, Neiditch M, Lu W . Human defensins 5 and 6 enhance HIV-1 infectivity through promoting HIV attachment. Retrovirology. 2011; 8:45. PMC: 3146398. DOI: 10.1186/1742-4690-8-45. View

Arena E, Campbell-Valois F, Tinevez J, Nigro G, Sachse M, Moya-Nilges M . Bioimage analysis of Shigella infection reveals targeting of colonic crypts. Proc Natl Acad Sci U S A. 2015; 112(25):E3282-90. PMC: 4485126. DOI: 10.1073/pnas.1509091112. View

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

Philpott D, Edgeworth J, Sansonetti P . The pathogenesis of Shigella flexneri infection: lessons from in vitro and in vivo studies. Philos Trans R Soc Lond B Biol Sci. 2000; 355(1397):575-86. PMC: 1692768. DOI: 10.1098/rstb.2000.0599. View

Lehrer R, Lu W . α-Defensins in human innate immunity. Immunol Rev. 2011; 245(1):84-112. DOI: 10.1111/j.1600-065X.2011.01082.x. View

Wu Z, Hoover D, Yang D, Boulegue C, Santamaria F, Oppenheim J . Engineering disulfide bridges to dissect antimicrobial and chemotactic activities of human beta-defensin 3. Proc Natl Acad Sci U S A. 2003; 100(15):8880-5. PMC: 166407. DOI: 10.1073/pnas.1533186100. View

Jin Q, Yuan Z, Xu J, Wang Y, Shen Y, Lu W . Genome sequence of Shigella flexneri 2a: insights into pathogenicity through comparison with genomes of Escherichia coli K12 and O157. Nucleic Acids Res. 2002; 30(20):4432-41. PMC: 137130. DOI: 10.1093/nar/gkf566. View

10.

Maurelli A, Blackmon B, Curtiss 3rd R . Temperature-dependent expression of virulence genes in Shigella species. Infect Immun. 1984; 43(1):195-201. PMC: 263409. DOI: 10.1128/iai.43.1.195-201.1984. View

11.

Li Y, Poole S, Nishio K, Jang K, Rasulova F, McVeigh A . Structure of CFA/I fimbriae from enterotoxigenic Escherichia coli. Proc Natl Acad Sci U S A. 2009; 106(26):10793-8. PMC: 2705562. DOI: 10.1073/pnas.0812843106. View

12.

Cossart P, Sansonetti P . Bacterial invasion: the paradigms of enteroinvasive pathogens. Science. 2004; 304(5668):242-8. DOI: 10.1126/science.1090124. View

13.

Mounier J, Vasselon T, Hellio R, Lesourd M, Sansonetti P . Shigella flexneri enters human colonic Caco-2 epithelial cells through the basolateral pole. Infect Immun. 1992; 60(1):237-48. PMC: 257528. DOI: 10.1128/iai.60.1.237-248.1992. View

14.

Chu H, Pazgier M, Jung G, Nuccio S, Castillo P, de Jong M . Human α-defensin 6 promotes mucosal innate immunity through self-assembled peptide nanonets. Science. 2012; 337(6093):477-81. PMC: 4332406. DOI: 10.1126/science.1218831. View

15.

Chen V, Arendall 3rd W, Headd J, Keedy D, Immormino R, Kapral G . MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr D Biol Crystallogr. 2010; 66(Pt 1):12-21. PMC: 2803126. DOI: 10.1107/S0907444909042073. View

16.

Hansson G, Libby P . The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol. 2006; 6(7):508-19. DOI: 10.1038/nri1882. View

17.

Edwards R, Puente J . Fimbrial expression in enteric bacteria: a critical step in intestinal pathogenesis. Trends Microbiol. 1998; 6(7):282-7. DOI: 10.1016/s0966-842x(98)01288-8. View

18.

Murshudov G, Vagin A, Dodson E . Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr D Biol Crystallogr. 1997; 53(Pt 3):240-55. DOI: 10.1107/S0907444996012255. View

19.

Ericksen B, Wu Z, Lu W, Lehrer R . Antibacterial activity and specificity of the six human {alpha}-defensins. Antimicrob Agents Chemother. 2004; 49(1):269-75. PMC: 538877. DOI: 10.1128/AAC.49.1.269-275.2005. View

20.

Morita-Ishihara T, Ogawa M, Sagara H, Yoshida M, Katayama E, Sasakawa C . Shigella Spa33 is an essential C-ring component of type III secretion machinery. J Biol Chem. 2005; 281(1):599-607. DOI: 10.1074/jbc.M509644200. View