Academic Section(s):
Microbiology and Immunology
Education:
Ph.D. University of Oklahoma Health Sciences Center
Clinical/Research Interests:
Clostridioides difficile is a leading cause of hospital-acquired infections that routinely infects patients undergoing antibiotic treatments. These infections are initiated by the ingestion of chemically resistant spores that traffic to the colon where C. difficile germinates and produces large proteinaceous toxins. Results of C. difficile colonization range from asymptomatic carriage to deadly disease that manifests as diarrhea and colitis. While dysbiosis from antibiotics is clearly a factor driving C. difficile disease, how the host shapes the pathogenesis of C. difficile disease is less appreciated. As such, the overall goal of our laboratory is to explore how host responses contribute to the pathogenesis of C. difficile disease and devise treatment strategies targeting these host responses.
Targeting CSPG4 expression as a C. difficile therapeutic. These studies are focused on a host signaling pathway that regulates the C. difficile toxin receptor chondroitin sulfate proteoglycan 4 (CSPG4). As a key receptor for C. difficile toxins, CSPG4 is required for the manifestation of C. difficile disease, and studies have demonstrated loss of CSPG4 expression prevents C. difficile disease. In our preliminary work, a toxin-resistant system was used to discover CSPG4 expression is regulated through Hippo signaling. Follow-up experiments demonstrated that small molecule inhibitors of Hippo signaling downregulate CSPG4 and importantly were able to protect mice from C. difficile disease. Current studies are advancing the paradigm of targeting the Hippo-CSPG4 axis as a treatment for C. difficile. As a result, we are investigating the underlying mechanisms utilized by Hippo signaling to regulate CSPG4 and exploring how CSPG4 expression patterns in the colon are connected to C. difficile pathogenesis.
Ongoing research. Because CSPG4 is not only critical for C. difficile infections but also has a prominent role in many types of cancer, we have ongoing work identifying mechanisms regulating CSPG4 and exploring whether these pathways can be targeted during C. difficile disease or cancer.
Future research. Our work on CSPG4 has led to a model in which toxin receptor expression is a dynamic event that shapes the outcome of infectious disease in the host; consequently, targeting the expression of receptors could be a robust means for protecting from disease. Future studies will expand this idea to other classes of toxin receptors.
Select Publications:
Larabee JL, Doyle DA, Ahmed UKB, Shadid TM, Sharp RR, Jones KL, Kim Y, Li S, and Ballard JD. (2023) Discovery of Hippo signaling as a regulator of CSPG4 expression and as a therapeutic target for Clostridioides difficile disease. PLoS Pathogens 19, e1011272. PMID: 36972308 PMCID: PMC10079225.