We are pursuing a number of projects — across the spectrum of basic, translational, and clinical microbiology research — in addition to various internal and external collaborations. Summarized here are some of the main areas of our current work. Potential opportunities for graduate, undergraduate, and/or and house-staff rotation projects exist in many of these areas. For any interested trainees, we are always happy to discuss in greater details these current and upcoming possibilities.
1. Championing the development and operations of a unique, patient-linked microbial biobanking program.
As a major contributor to the efforts and mission of the Center for Personalized Microbiology, we have developed and manage the (ever expanding) operations of microVU: a Vanderbilt initiative through which patient microbial specimens and isolates generated within our Diagnostic Laboratory are banked in mass and networked with the clinical scenarios of the source-patients, through VUMC’s unique institutional resources in medical informatics. Overall, microVU facilitates not only our own primary research activities, but acts as resource for the entire institution and facilitates various exciting collaborations for the group. Notably, these include large-scale sequencing efforts for COVID-19, as part of Vanderbilt’s academic and clinical response to the pandemic.
2. Networking patient phenotypes and electronic health data with bacterial genomic (and other multi-omic) profiles.
We seek to characterize novel bacterial virulence determinants by applying ‘big data’ strategies to the massive diversity of wild-type strains that arise within the clinical laboratory. Notably, these efforts include genome-wide association studies that span the host-pathogen divide, as we connect bacterial genotypes (from whole genome sequencing) to host phenotypes (from electronic health data). At present, much of this work focuses on the classic bacterial opportunist E. coli within the human urinary tract, a choice motivated by [1] the diverse clinical phenotypes of E. coli UTIs, [2] the prominent genomic heterogeneity of this microbial species, and [3] the extremely high prevalence of UTIs in routine clinical practice. In the process, we seek to develop novel strategies for directly interfacing multi-omic microbial data elements with the structured environment of electronic health records, efforts that carry diverse implications for both discovery-driven research and diagnostic care.
3. Expanding molecular models of bacterial pathogenesis to account for the tremendous interstrain and intrastrain diversity of pathogenic species.
Often, the traditional strategy for deciphering an organism’s virulence mechanisms entails molecular manipulation of a chosen model strain, which is then applied to experimental models of infection. While such tried-and-true approaches are invaluable, they may fail to account for the profound genotypic and phenotypic diversity among different strains of that species as they exist in the real world. Indeed, domesticated model strains may be limited in their ability to reflect the true dynamics of wild-type pathogenesis. In this context — and as a ‘wet lab’ counterpart to the above in silico work — we also leverage on an empiric level our massive access to characterized clinical isolates, again with a particular emphasis on uropathogenesis. By broadening traditional experimental techniques with clinical organismal diversity, we seek to provide a more comprehensive and nuanced view of virulence and host interaction. Of note, this includes both the diversity that exists between individual strains of pathogenic species (interstrain diversity), as well as the tendency of strains to evolve in real time with accumulating polymorphisms and additional heterogeneity (interstrain diversity).
4. Defining how commensal microbial species influence the virulence properties of pathogenic microbes toward the human host.
On an individual level, the progression of an infection depends on the genetics and phenotypes of that host, together with the strain-specific properties of the offending pathogen. At the same time, yet another level of personalization can further influence these dynamics: the organisms that comprise patient’s background microbiome. To account for this additional level of complexity, we seek to better define commensal-pathogen interactions within the urogenital tract. Specifically, we wish to characterize how physical and biochemical interactions with urogenital commensals augment the ability of urogenital pathogens to interact with the host.
5. Developing simplified approaches for multiplex molecular pathogen detection that can be deployed in point-of-care and low-resource settings.
PCR and other nucleic acid amplification technologies have transformed the way that many infections are diagnosed within the clinical laboratories in the United States. Continued progress is still needed, however, to maximize the clinical impact of these technologies more broadly. Critical areas for ongoing improvement include transitioning more molecular diagnostics to point-of-care settings, as well as improving accessibility to such testing for resource-limited settings around the world. To these ends — and motivated the resource limitations that all clinical laboratories have faced throughout the coronavirus pandemic — we seek to develop simplified molecular detection pipelines that could be more easily deployed throughout the world, foregoing methodological processes that can be logistically limiting (especially in the context of supply insecurity).
6. Defining the analytic performance characteristics and clinical impact of emergent diagnostic technologies within patient-care settings.
In partnership with both academic and industry collaborators, we participate in various clinical trials (and other R&D) of new diagnostics technologies for infectious diseases. This work represents another important avenue for leveraging the diversity of patient-derived specimens that we process for microVU, providing key evidence for implementation of these technologies in routine clinical care.