Invasive candidiasis (IC), the most common fungal infection in U.S. hospitals, is associated with mortality rates as high as 40%. Bloodstream infections (candidemia) are generally accepted as the most important type of IC. Intra-abdominal candidiasis (IAC) and other non-bloodstream IC are less well-studied. IAC encompasses two entities: peritonitis (infection of the peritoneum) and abscesses (collections of Candida and pus that are walled-off from healthy tissue). Data from recent papers and our center indicate that IAC is at least as common as candidemia, and mortality rates are similar. Nevertheless, the diseases differ in important ways. The most common portals of entry for candidemia are translocation from the gastrointestinal (GI) lumen through the mucosa into the vasculature or direct introduction from vascular catheters. IAC, on the other hand, follows the introduction of Candida into the normally sterile peritoneal cavity as a complication of peritoneal dialysis or, more commonly, as a result of GI tract leakage or perforation. In the latter scenarios, Candida is admixed with fecal material and, in most cases, GI bacteria such as E. coli. Candida albicans remains the most common cause of IAC, whereas non-C. albicans species are now predominant in candidemia. The cellular and molecular mechanisms by which C. albicans causes IAC are poorly understood. We have adapted a simple and reproducible mouse model of C. albicans IAC that replicates the pathophysiology and progression of infection from generalized peritonitis to localized intra-abdominal abscesses. We used nanoString nCounter assays to measure expression of 145 C. albicans genes during peritonitis. Moreover, we demonstrated that the mouse model is sensitive at distinguishing the relative virulence of mutant C. albicans strains, indicating that it is well-suited to studies of pathogenesis. These data provided valuable insights into biologic processes that are activated by C. albicans in vivo, and revealed that C. albicans gene expression during IAC differs substantially from DC or OPC. More recently, we have performed RNA-Seq (deep sequencing of cDNA) to comprehensively define C. albicans gene expression within peritoneal fluid recovered from a patient with peritonitis. In this project, we will test two hypotheses: 1) C. albicans elaborates stage-specific gene expression profiles within the peritoneal cavity and abscesses;and 2) C. albicans genes that are temporal-spatially regulated during IAC make distinct contributions to pathogenesis. In our first specific aim, we will use RNA-Seq to measure C. albicans gene expression during IAC in mice and humans. In our second specific aim, we will use our mouse model to implicate specific C. albicans genes in the pathogenesis of IAC. In addition to providing insights into genes and biologic processes that contribute to IAC, the project will lead to future studies of specific mechanisms of pathogenesis. This study will generate new hypotheses about pathogenesis, and help inform choices of genes and pathways that can be pursued by investigators in the field. In addition, the data may identify priority targets for the development of novel therapeutic, diagnostic and vaccine strategies.

Public Health Relevance

This project studies intra-abdominal candidiasis (IAC), a prevalent form of invasive candidiasis that carries high mortality but is not very well-studied. Ou study is important because we will identify Candida genes that are important in causing IAC, which may represent novel therapeutic, diagnostic and vaccine targets.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI107290-01A1
Application #
8642813
Study Section
Special Emphasis Panel (ZRG1-IDM-P (02))
Program Officer
Duncan, Rory A
Project Start
2014-04-01
Project End
2016-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$253,895
Indirect Cost
$67,823
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213