WHAT WE DO
Research efforts in my laboratory center on the “One Health” paradigm, defined as “….a worldwide strategy for expanding interdisciplinary collaborations and communications in all aspects of health care for humans, animals and the environment.”
Under this umbrella, our goal is to study gastrointestinal tract pathogens and commensals. My training in microbial genetics and host-pathogen interactions has enabled us to characterize novel virulence mechanisms, and develop technologies to mitigate pathogen establishment in the GI tract.
Precision Epidemiology: Healthcare-Associated Infection Surveillance
We have partnered with a system-wide team of Clinicians, Clinician-Scientists and Trainees to develop a precision epidemiology consortium that is currently actively engaged in healthcare-associated infection surveillance in Tucson, AZ and Phoenix, AZ. Using a combination of molecular typing, whole-genome sequencing, and animal studies, we have identified new variants of Clostridioides difficile including virulent NAP1/RT027 and NAP11/RT106 isolates that are “discrepant” on diagnostic tests.
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Elucidation of Clostridioides difficile Pathogenic Factors
In 2009, and in collaboration with colleagues in Australia and the US, we published the first molecular assessment of the contribution of large clostridial toxins to Clostridioides difficile virulence. This work spearheaded a paradigm shift in C. difficile biology, since genetic tools to derive CD mutants were successfully employed. In 2013, we demonstrated that epidemic-associated clinical isolates of C. difficile could be hyper-sporulators, and that toxin production alone does not predict overall virulence.
Finally, in 2012, and in collaboration with colleagues in Chicago, we showed that immunization of hamsters with a toxoid preparation of just one C. difficile toxin (TcdB) fully protects animals against challenge by lethal C. difficile strains. These studies clearly implicated both toxin and non-toxin factors are being important for C. difficile pathogenesis.
One focus of our laboratory is the discovery of novel therapeutic strategies against enteric pathogens including C. difficile.
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Development of Methodologies and Assays to Interrogate Enteric Pathogen Biology
Our team has optimized multiple approaches to assess Clostridioides difficile interaction(s) with host cells. These include attachment assays under hypoxic conditions, fully-quantitative mass spectrometry, and transmission—and scanning—electron microscopic visualizations in vitro and in vivo.
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Identification of Novel Non-toxin C. difficile, EPEC/EHEC and Bacteroides sp. Virulence Factors
Perhaps one of the most impactful finding of our research is the discovery that Clostridioides difficile elaborates robust systems to evade host innate immunity: one involved in oxygen radical detoxification, and another elaborating unique cell-wall glycopolymers. The former has implications for intestinal colonization, and the latter for targeted immunotherapy.
Similarly, in collaboration with Dr. Viswanathan’s laboratory to elucidate virulence factors of EPEC and EHEC, we devised and optimized "omics"-based methodologies and demonstrated that non-Shiga toxin factors, specifically secreted Type III ffector proteins exquisitely regulate intestinal epithelial cell fate by dynamically balancing host cell survival and apoptosis. We have also characterized large transposable and conjugatable elements in commensal Bacteroides sp. that contribute to the dissemination of antibiotic resistance genes in the gastrointestinal tract.
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Application of Basic Research Findings to Translatable Products
We are also optimizing methods to combat enteric bacterial infections using the power of synthetic biology. We are currently funded by the US Department of Veterans Affairs and the National Institutes of Health to construct multiple versions of a “synthetic biologic” – a safe, bio-controlled bacterium that has been engineered to occupy the same gut niches as Clostridioides difficile, and thus prevent pathogen colonization.
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