Wednesday, April 2, 2025
4/2/2025
Inter-kingdom interactions of Salmonella Typhimurium and Candida albicans in the gut - PROJECT SUMMARY Polymicrobial infections are a significant health concern to humans. Multi-species biofilms exhibit greatly increased antibiotic resistance, and systemic infections with more than one etiologic agent are difficult to treat and often more lethal than infections with a single pathogen. Salmonella enterica serovar Typhimurium (STm) is a food-borne bacterial pathogen that causes gastroenteritis in over 1.35 million people in the US every year. Recently, a clinical study with 2500 patients uncovered that the under-studied fungal component of the microbiome is an important modulator of Salmonella enterica infections. When patients were colonized with the opportunistic pathogenic yeast Candida spp, they were more likely to be infected with S. Typhi or S. Paratyphi. C. albicans is a frequent gut colonizer and can be found more than 60% of people. The commensal yeast can easily transition to become pathogenic and breach epithelial barriers with its filamentous hyphae. It is also associated with gut inflammatory diseases like Crohn’s disease. The two gut pathogens STm and C. albicans thrive in an inflamed intestine and are likely to co-occur frequently. Nevertheless, the role of C. albicans during Salmonella infection is currently completely unknown. Our long-term goal is to understand the role of gastrointestinal fungi during STm pathogenesis. The specific goal of this proposal is to elucidate the mechanism of how the presence of C. albicans in the gut increase STm colonization and systemic dissemination. Our data show that commensal C. albicans abundance in the mycobiota increased after STm infection of mice and positively correlated with disease severity. During co-infection with STm and C. albicans, mice showed significantly increased STm load in cecum, spleen and liver, and more weight loss compared to STm single infection. Despite two pathogens present, the early host immune response to co-infection was significantly blunted compared to single infections. The lower inflammatory response might result in inefficient clearance and increased dissemination of STm. In the presence of C. albicans in vitro, STm upregulated virulence genes and showed significantly increased invasion of colonic epithelial cells. We hypothesize that the increased virulence of STm in the presence of C. albicans is the result of two distinct mechanisms: (A) direct bacteria- fungi and (B) host-dependent interactions. With this proposal, we will therefore determine in Aim 1 which C. albicans factors directly modulate STm virulence gene expression, mediate binding to STm, and result in higher STm dissemination in two mouse models. In Aim 2 we will elucidate which host cells, signaling molecules and microbial determinants are involved in modulation of the immune response during co-infection. In summary, we will study the cross-kingdom interaction of two important gut pathogens and will provide mechanistic detail on how the presence of C. albicans modulates STm pathogenicity.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).