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How does Yersinia coordinate iron/oxygen sensing with virulence regulation?


Iron is an essential element for most bacterial pathogens, including Yersinia. During infection, the mammalian immune system sequesters iron from invading pathogens; yet in response to this “nutritional immunity”, many pathogenic bacteria are able to colonize host tissue despite the decrease in iron availability. Additionally, when these pathogens travel from the outside environment into a mammalian host, they also encounter varying levels of oxygen depending on the tissue, or inflammation state. The aim of this dissertation is to improve our understanding of how bacterial pathogens couple iron and oxygen sending with virulence regulation. Specifically, I used the bacterial pathogen Yersinia pseudotuberculosis to determine how the type III secretion system (T3SS) is controlled in response to iron and oxygen. The T3SS is a bacterial injectisome apparatus used by human pathogenic Yersinia spp., to manipulate host defenses. Some of our recent studies suggest that Yersinia pseudotuberculosis uses the transcriptional regulator IscR to control the T3SS through direct regulation of the T3SS master regulator LcrF. IscR is a transcriptional regulator that binds different DNA sequence motifs, depending on its [2Fe-2S] cluster-coordinating (holo-) or clusterless (apo-) form. Iron availability and oxygen tension have been shown to affect E. coli IscR [2Fe-2S] cluster integrity, therefore impacting expression of IscR target genes4. Collectively, these data suggest that Y. pseudotuberculosis may use IscR to sense changes in oxygen tension and iron bioavailability to control critical virulence genes. However, it is not yet known whether changes in iron and oxygen availability alter expression or function of the T3SS or other virulence factors in Yersinia. Understanding how iron impacts microbial virulence can contribute to better guidelines for patient care in the context of anemia, iron supplementation, iron overload and inflammation.

The main goal of this dissertation is to determine the role of IscR on the regulation of the T3SS master regulator LcrF. The first part of my dissertation sought to study in vitro how both iron and oxygen availability affect the expression of iscR, lcrF and T3SS. We demonstrated that the presence of oxygen drives expression of iscR and this in turn upregulates lcrF expression and T3SS activity. Additionally, we showed that under anaerobic conditions, iscR expression is upregulated when iron is depleted, activating lcrF expression and, thus, T3SS expression. The second part of this dissertation was to determine if IscR control on T3SS is important for virulence in the mouse model of infection. To test this, we performed a bread feeding model of infection, which mimics oral intake of contaminated food. Our results suggest that regulation of the T3SS in response to iron and oxygen through IscR is critical for virulence.

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