Pathogenic diversification of the gut commensalProvidencia alcalifaciensvia acquisition of a second type III secretion system

Author:

Klein Jessica A.,Predeus Alexander V.ORCID,Greissl Aimee R.,Clark-Herrera Mattie M.,Cruz Eddy,Cundiff Jennifer A.,Haeberle Amanda L.,Howell Maya,Lele Aaditi,Robinson Donna J.,Westerman Trina L.,Wrande Marie,Wright Sarah J.,Green Nicole M.,Vallance Bruce A.,McClelland Michael,Mejia Andres,Goodman Alan G.ORCID,Elfenbein Johanna R.,Knodler Leigh A.ORCID

Abstract

AbstractProvidencia alcalifaciensis a Gram-negative bacterium found in a wide variety of water and land environments and organisms. It has been isolated as part of the gut microbiome of animals and insects, as well as from stool samples of patients with diarrhea. SpecificP. alcalifaciensstrains encode gene homologs of virulence factors found in other pathogenic members of the same Enterobacterales order, such asSalmonella entericaserovar Typhimurium andShigella flexneri.Whether these genes are also pathogenic determinants inP. alcalifaciensis not known. Here we have usedP. alcalifaciens205/92, a clinical isolate, within vitroandin vivoinfection models to investigateP. alcalifaciens-host interactions at the cellular level. Our particular focus was the role of two type III secretion systems (T3SS) belonging to the Inv-Mxi/Spa family. T3SS1bis widespread inProvidenciaspp. and encoded on the chromosome. T3SS1ais encoded on a large plasmid that is present in a subset ofP. alcalifaciensstrains, which are primarily isolates from diarrheal patients. Using a combination of electron and fluorescence microscopy and gentamicin protection assays we show thatP. alcalifaciens205/92 is internalized into eukaryotic cells, rapidly lyses its internalization vacuole and proliferates in the cytosol. This triggers caspase-4 dependent inflammasome responses in gut epithelial cells. The requirement for the T3SS1ain entry, vacuole lysis and cytosolic proliferation is host-cell type specific, playing a more prominent role in human intestinal epithelial cells as compared to macrophages. In a bovine ligated intestinal loop model,P. alcalifacienscolonizes the intestinal mucosa, inducing mild epithelial damage with negligible fluid accumulation. No overt role for T3SS1aor T3SS1bwas seen in the calf infection model. However, T3SS1bwas required for the rapid killing ofDrosophila melanogaster. We propose that the acquisition of two T3SS by horizontal gene transfer has allowedP. alcalifaciensto diversify its host range, from a highly virulent pathogen of insects to an opportunistic gastrointestinal pathogen of animals.

Publisher

Cold Spring Harbor Laboratory

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