Faculty Collaboration Database

A competitive infection model of hematogenously disseminated candidiasis in mice redefines the role of Candida albicans IRS4 in pathogenesis. Infect Immun 2013 May;81(5):1430-8

Date

02/23/2013

Pubmed ID

23429534

Pubmed Central ID

PMC3647996

DOI

10.1128/IAI.00743-12

Scopus ID

2-s2.0-84877804290 (requires institutional sign-in at Scopus site)   7 Citations

Abstract

Candida albicans IRS4 encodes a protein that regulates phosphatidylinositol-(4,5)-bisphosphate, which was shown to contribute to hematogenously disseminated candidiasis (DC) after several days in the standard mouse model. Our objective was to more accurately define the temporal contributions of IRS4 to pathogenesis. During competition assays in vitro, an irs4-null (Δirs4) mutant exhibited wild-type fitness. In DC experiments, mice were infected intravenously with the Δirs4 mutant, strain CAI-12 (1 × 10(5) CFU), or a mixture of the strains (0.5 × 10(5) CFU each). In single-strain infections, quantitative PCR revealed reduced Δirs4 mutant burdens within kidneys at days 1, 4, and 7 but not 6 h. In competitive infections, the Δirs4 mutant was outcompeted by CAI-12 in each mouse at ≥6 h (competitive indices, P ≤ 0.0001). At 4 and 7 days, the Δirs4 mutant burdens during competitive infections were significantly lower than those during single-strain infections (P = 0.01 and P < 0.001, respectively), suggesting increased susceptibility to inflammatory responses. Phagocytic infiltration of kidneys in response to CAI-12 or competitive infections was significantly greater than that in response to Δirs4 mutant infection at days 1 and 4 (P < 0.001), and the Δirs4 mutant was more susceptible to phagocytosis and killing by human polymorphonuclear cells (P = 0.01 and P = 0.006, respectively) and mouse macrophages in vitro (P = 0.04 and P = 0.01, respectively). Therefore, IRS4 contributes to tissue invasion at early stages of DC and mediates resistance to phagocytosis as DC progresses. Microarray analysis revealed remarkably similar gene expression by the Δirs4 mutant and reference strain CAI-12 within blood, suggesting that IRS4 is not significantly involved in the hematogenous stage of disease. A competitive DC model detects attenuated virulence that is not evident with the standard model.

Author List

Raman SB, Nguyen MH, Cheng S, Badrane H, Iczkowski KA, Wegener M, Gaffen SL, Mitchell AP, Clancy CJ

MESH terms used to index this publication - Major topics in bold

Analysis of Variance
Animals
Candida albicans
Candidiasis
Disease Models, Animal
Gene Expression Profiling
Kidney
Male
Mice
Mice, Inbred ICR
Microarray Analysis
Microbial Interactions
Phagocytosis
Polymerase Chain Reaction
Species Specificity