title: The ShiA protein encoded by the Shigella flexneri SHI-2 pathogenicity island attenuates inflammation.
abstract: Shigella spp. are the aetiologic agents of dysentery, a severe diarrhoeal syndrome characterized by acute inflammation in the colon. The inflammatory response, which includes recruitment of polymorphonuclear leukocytes (PMN), damages the colonic mucosa and exacerbates the infection. Shigella encodes a pathogenicity island (PAI), SHI-2, which is localized in a region of the chromosome linked to the induction of inflammation. Surprisingly, SHI-2 deletion mutants induce a stronger inflammatory response than wild-type Shigella as measured by increased villus blunting, increased PMN infiltration and induction of apoptosis in a rabbit ileal loop model of shigellosis. Mutational analysis mapped the hyper-inflammatory phenotype to a single gene, shiA. Similar to SHI-2 deletion mutants, infection with a shiA mutant strain induces dramatically elevated levels of inflammation when compared to the wild-type strain. Furthermore, infection with a wild-type strain containing multiple copies of shiA results in fewer infiltrating PMN and apoptotic cells, as well as preservation of a normal villus architecture at the site of infection, thus acting in a dominant fashion over the pro-inflammatory mechanisms of Shigella. The molecular mechanism of action of ShiA is independent of any in vitro phenotype associated with Shigella virulence. Our data suggest that ShiA allows Shigella to attenuate the host inflammatory response in a novel manner.
authors.affiliation: Max Planck Institute for Infection Biology, 21/22 Schumannstrasse, 10117 Berlin, Germany.
authors.forename: Molly A
authors.initials: MA
authors.lastname: Ingersoll
authors.forename: Jeremy E
authors.initials: JE
authors.lastname: Moss
authors.forename: Yvette
authors.initials: Y
authors.lastname: Weinrauch
authors.forename: Peter E
authors.initials: PE
authors.lastname: Fisher
authors.forename: Eduardo A
authors.initials: EA
authors.lastname: Groisman
authors.forename: Arturo
authors.initials: A
authors.lastname: Zychlinsky
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D004405:Dysentery, Bacillary / Q000276:immunology / Q000378:metabolism; D044404:Genomic Islands; D006801:Humans; D007082:Ileum / Q000166:cytology / Q000382:microbiology / Q000473:pathology; D007223:Infant; D007249:Inflammation / Q000378:metabolism*; D008297:Male; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D011817:Rabbits; D012763:Shigella flexneri / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity
chemical_list: D001426:Bacterial Proteins