Intra-abdominal candidiasis (IAC) is a common, but understudied disease associated with mortality rates of 20%- 40%. Pathogenesis of IAC is poorly understood, in part due to the lack of clinically relevant experimental disease models. We developed a reproducible mouse model of C. albicans IAC, which recapitulates progression of human disease from peritonitis to intra-abdominal abscesses (IAAs). Utilizing the model, we have begun to define pathogenesis mechanisms by identifying relevant C. albicans genes through transcriptional profiling. We have tested inferences from these studies by characterizing the pathogenicity of select C. albicans gene mutant strains. Our results show that IAC presents a distinct infection environment compared to other types of IC, as both gene expression modules and functional pathway relationships differ from those observed in models of candidemia and invasive kidney infection. The objective of this project is to identify transcriptional regulators, transcriptional regulator targets, and genetic pathways that serve as virulence determinants during peritonitis and within IAAs. We demonstrated previously that deletion of C. albicans RIM101, which encodes a transcriptional regulator of alkaline pH responses, significantly attenuated the course of IAC in mice. Follow-up epistasis tests showed that Rim101 exerts its virulence effects in part through regulation of SAP5, which encodes a secreted protease. We hypothesize that a group of transcriptional regulators, including Rim101, govern virulence in IAC, and that novel infection environments encountered during the disease modulate their functionally relevant target genes. We will use an unbiased approach to identify IAC-relevant transcriptional regulators, and then pursue a prioritized subset for dissection of functional pathway relationships. In our first specific aim, we will identify C. albicans transcriptional regulators that contribute to the pathogenesis of IAC by screening a library of oligonucleotide signature-tagged, homozygous deletion mutants in our mouse model. Transcriptional regulator mutants that are significantly attenuated during IAC will be validated as virulence determinants by independently creating null mutant and complementation strains, and testing them in the mouse model. In the second aim, we will identify C. albicans transcriptional regulator target genes and genetic pathways that contribute to the pathogenesis of IAC. We will use RNA-Seq to profile global gene expression by Rim101 and other transcriptional regulator null mutant and complementation strains temporal-spatially during IAC. Prioritized genes targeted by transcriptional regulators during IAC will be validated as virulence determinants by testing null mutant and complementation strains in both peritoneal fluid and IAAs, as well as gene over-expression strains in the transcriptional regulator null background. Genetic pathways contributing to virulence will be validated by epistasis experiments. This will be the first study to systematically identify and validate C. albicans genes and genetic pathways involved in the pathogenesis of IAC. Our findings will provide new insights into site-specific and more generalized pathogenesis during IAC, which will be investigated in detail in follow-up mechanistic studies.

Public Health Relevance

Intra-abdominal infections due to the yeast Candida albicans (intra-abdominal candidiasis (IAC)) are common in U.S. hospitals, and lead to death in 20%-40% of patients. In this project, we will identify C. albicans genes and genetic pathways that contribute to different stages of IAC. Our findings will improve our understanding of the mechanisms by which C. albicans causes IAC, which will facilitate the development of new diagnostic tests, and treatment and prevention strategies in the future.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Pathogenic Eukaryotes Study Section (PTHE)
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Love, Dona
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University of Pittsburgh
Internal Medicine/Medicine
Schools of Medicine
United States
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