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- Title
Iron availability and oxygen tension regulate the Yersinia Ysc type III secretion system to enable disseminated infection.
- Authors
Hooker-Romero, Diana; Mettert, Erin; Schwiesow, Leah; Balderas, David; Alvarez, Pablo A.; Kicin, Anadin; Gonzalez, Azuah L.; Plano, Gregory V.; Kiley, Patricia J.; Auerbuch, Victoria
- Abstract
The enteropathogen Yersinia pseudotuberculosis and the related plague agent Y. pestis require the Ysc type III secretion system (T3SS) to subvert phagocyte defense mechanisms and cause disease. Yet type III secretion (T3S) in Yersinia induces growth arrest and innate immune recognition, necessitating tight regulation of the T3SS. Here we show that Y. pseudotuberculosis T3SS expression is kept low under anaerobic, iron-rich conditions, such as those found in the intestinal lumen where the Yersinia T3SS is not required for growth. In contrast, the Yersinia T3SS is expressed under aerobic or anaerobic, iron-poor conditions, such as those encountered by Yersinia once they cross the epithelial barrier and encounter phagocytic cells. We further show that the [2Fe-2S] containing transcription factor, IscR, mediates this oxygen and iron regulation of the T3SS by controlling transcription of the T3SS master regulator LcrF. IscR binds directly to the lcrF promoter and, importantly, a mutation that prevents this binding leads to decreased disseminated infection of Y. pseudotuberculosis but does not perturb intestinal colonization. Similar to E. coli, Y. pseudotuberculosis uses the Fe-S cluster occupancy of IscR as a readout of oxygen and iron conditions that impact cellular Fe-S cluster homeostasis. We propose that Y. pseudotuberculosis has coopted this system to sense entry into deeper tissues and induce T3S where it is required for virulence. The IscR binding site in the lcrF promoter is completely conserved between Y. pseudotuberculosis and Y. pestis. Deletion of iscR in Y. pestis leads to drastic disruption of T3S, suggesting that IscR control of the T3SS evolved before Y. pestis split from Y. pseudotuberculosis. Author summary: The Yersinia type III secretion system (T3SS) is an important virulence factor of the enteropathogen Yersinia pseudotuberculosis as well as Yersinia pestis, the causative agent of plague. Although the T3SS promotes Yersinia survival in the host, its activity is not compatible with bacterial growth. Therefore, Yersinia must control where and when to express the T3SS to optimize fitness within the mammalian host. Here we show that Yersinia sense iron availability and oxygen tension, which vary between the intestinal environment and deeper tissues. Importantly, we show that eliminating the ability of Y. pseudotuberculosis to control its T3SS in response to iron and oxygen does not affect colonization of the intestine, where the T3SS is dispensable for growth. However, loss of T3SS control by iron and oxygen severely decreases disseminated infection. We propose that Y. pseudotuberculosis senses iron availability and oxygen tension to detect crossing the intestinal epithelial barrier. As the mechanism by which iron and oxygen control the T3SS is completely conserved between Y. pseudotuberculosis and Y. pestis, yet Y. pestis is not transmitted through the intestinal route, we propose that Y. pestis has retained this T3SS regulatory mechanism to suit its new infection cycle.
- Subjects
YERSINIA pseudotuberculosis; YERSINIA; YERSINIA pestis; SECRETION; IMMUNE recognition; TIGHT junctions; ZINC; NITROGEN in soils
- Publication
PLoS Pathogens, 2019, Vol 15, Issue 12, pN.PAG
- ISSN
1553-7366
- Publication type
Article
- DOI
10.1371/journal.ppat.1008001