1336. The Cell Wall Integrity Regulator Irs4p Maintains Candida albicans Fitness within Mouse Kidneys without Impacting Neutrophil (PMN) or Cytokine (CK) Responses
Session: Oral Abstract Session: Fungal Pathogenesis, Virulence, and Anti-fungal Therapy
Saturday, October 22, 2011: 2:15 PM
Room: 151AB
Background:  C. albicans Irs4 regulates phosphoinositides, cell wall integrity, and invasion, but not colonization of mouse kidneys.  Attenuated virulence of irs4 mutants within kidneys may reflect intrinsic cell defects and/or increased susceptibility to host defenses.  

Methods:  We used qPCR to quantitate wild-type (WT) C. albicans and irs4 cells during competitive mixed infections in vitro and within mouse kidneys, and assessed mouse PMN and CK responses

Results:  Using qPCR, we demonstrated that WT and irs4 strains had similar growth rates in liquid media.  We infected ICR mice via the lateral tail vein with 1x105 CFU/mL of WT alone, irs4 alone, or mixed WT+irs4 (5x104 each).  There were no differences in kidney burdens at 6 hours between groups.  At 1 and 4 days, burdens of irs4 were 1.5-2 log lower than wild-type by qPCR when strains were inoculated alone.  During mixed infections, differences at both time points were >3-log (p<0.001 vs. strains alone).  Mutants were not impaired in hyphal formation in liquid media, but on histopathology of mouse kidneys, they exhibited fewer hyphae and were less tissue penetration.  PMN infiltration of kidneys of mice infected with irs4 was reduced at 6 hours, but similar to WT and mixed infection kidneys at 1 and 4 days despite lower burdens.  Likewise, Th1, Th2 and Th17 responses for mice infected with irs4, mixed or WT strains were similar.  irs4 mutant was significantly more susceptible than WT to killing by human PMN in vitro (p=0.001). 

Conclusion:  Virulence of C. albicans irs4 within mouse kidneys was more attenuated during mixed infection than when inoculated alone, which was not explained by altered PMN or CK responses.  Therefore, attenuated virulence reflected factors intrinsic to mutant cells, rather than altered susceptibility to host defenses.  Since irs4 grows in liquid media and colonizes kidneys comparably to WT C. albicans, the renal parenchyma must present a unique environment in which WT is more competitive.  We hypothesize that impaired cell wall integrity responses of the irs4 mutant exact a fitness cost under conditions of cell wall stress within kidneys. 


Subject Category: M. Mycology including clinical and basic studies of fungal infections

Suresh Raman, PhD1, M. Hong Nguyen, MD1, Hassan Badrane, PhD1, Shaoji Cheng, PhD1 and Cornelius Clancy, MD2, (1)University of Pittsburgh, Pittsburgh, PA, (2)Medicine, University of Pittsburgh, Pittsburgh, PA

Disclosures:

S. Raman, None

M. H. Nguyen, Pfizer: Grant Investigator, Research support
Merck: Grant Investigator, Research grant

H. Badrane, None

S. Cheng, None

C. Clancy, Pfizer: Grant Investigator, Research grant
Merck: Grant Investigator, Research grant
ViraCor-IBT: Grant Investigator, Research support

Findings in the abstracts are embargoed until 12:01 a.m. EST Thursday, Oct. 20 with the exception of research findings presented at IDSA press conferences.