Abstract
Gastrointestinal (GI) bacteria sense diverse environmental signals, including host hormones and nutrients, as cues for differential gene regulation and niche adaptation. Although the impact of carbon nutrition on the colonization of the gut by the microbiota has been extensively studied, the extent to which carbon sources affect the regulation of virulence factors by invading pathogens has not been fully defined. The enteric pathogen enterohemorrhagic Escherichia coli (EHEC) gages sugar sources as an important cue to regulate expression of its virulence genes. Specifically, this sugar dependent regulation fine tunes the expression of the locus of enterocyte effacement (LEE) pathogenicity island, which encodes for a type three secretion system, effectors, and an adhesin necessary for the formation of attaching and effacing (AE) lesions on enterocytes. Glycolytic environments inhibit the expression of the LEE genes. Conversely, growth within a gluconeogenic environment activates expression of these genes. Part of this sugar-dependent regulation is achieved through two transcription factors: KdpE and Cra. Cra and KdpE interact to optimally directly activate expression of the LEE genes in a metabolite dependent fashion. This sugar dependent regulation is key during infection of the mammalian host, given that a kdpE mutant is attenuated in vivo. Additionally, a novel two component signal transduction system, named FusKR (where FusK is a membrane bound histidine sensor kinase, and FusR a response regulator) that senses fucose, controls expression of the LEE genes. This fucose-sensing system is required for robust EHEC intestinal colonization. During growth in mucus, the glycophagic prominent member of the GI microbiota, Bacteroides thetaiotaomicron, supplies fucose to EHEC, modulating its virulence gene expression. Our findings suggest that EHEC uses fucose, a host-derived signal made available by the microbiota, to modulate EHEC virulence and metabolism, and suggest a new layer of complexity in the inter kingdom signaling that underlies EHEC pathogenicity.
Biography
I got my Ph.D. in 1995 in the State University of Campinas in Brazil, and finished my post-doctoral training in 2001 at the University of Maryland Medical School of Medicine, when I joined the faculty at the Microbiology Department at UT Southwestern. I was promoted to Associate Professor with tenure in 2007 and joined the faculty of the Biochemistry department as a secondary faculty member in 2008. In 2011 I was promoted to Full Professor with tenure.
Research in my laboratory investigates chemical, stress and nutritional signaling at the interface amongst the mammalian host, beneficial microbiota and invading pathogens. We devise a multi-disciplinary research program utilizing genetic, biochemical, chemical and structural approaches to investigate fundamental biological questions. The main tenant of research in my laboratory are the study of how bacterial cells sense several mammalian hormones as a means to gage the physiological and immune state of the host, leading to rewiring and reprogramming of bacterial transcription towards host and niche adaptation. We have also identified the first bacterial receptors to mammalian hormones, and reported that invading pathogens hijack these inter-kingdom signaling systems to promote virulence expression. We then translated these basic science concepts into strategies to develop novel approaches to anti-microbial therapy. This is a first-in-class anti-virulence approach that targets a bacterial receptor, QseC, to the host epinephrine and norepinephrine hormones that is key to activate virulence in many Gram-negative pathogens. We developed small molecule inhibitors of QseC that are effective in treating and preventing bacterially-mediated disease against several Gram-negative pathogens during mammalian infection. A key point to this therapy is that it is unlikely to lead the development of drug-resistance given that it halts bacterial virulence, but does not interfere with bacterial growth.
I am a Professor in the Departments of Microbiology and Biochemistry at UT Southwestern. I was a Pew Fellow in Biomedical Sciences (1997), an Ellison Foundation New Scholar (2004), a Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Diseases (2006), and Kavli Frontiers of Science Fellow (2007). In 2013 I was elected a fellow of the American Academy of Microbiology. My laboratory explores chemical communication through signaling mechanisms and nutritional cues among the mammalian host, the microbiota and invading pathogens. We investigate the basic science questions related to these interactions and translate this knowledge into new anti-microbial therapies.