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.