1335. Organ-Specific Innate Immune Responses in a Mouse Model of Invasive Candidiasis
Session: Oral Abstract Session: Fungal Pathogenesis, Virulence, and Anti-fungal Therapy
Saturday, October 22, 2011: 2:00 PM
Room: 151AB
Background: In a fatal mouse model of invasive candidiasis (IC), fungal burden changes with variable dynamics in the kidney, brain, spleen, and liver and declines in all organs except for the kidney, which inexorably loses function. Since leukocytes are required to control Candida, we hypothesized that differential leukocyte infiltration determines organ-specific outcome of the infection.

Methods: 8 week old female C57Bl/6 mice were infected iv with 2.5 x 105 yeast cells of C. albicans SC5314 (i.e., LD100 by day 10). Control uninfected (n=3) and infected mice were euthanized on day 1, 4, and 7 post-infection (n=3/time point) and leukocyte accumulation was assessed in the blood, brain, kidney, liver and spleen by flow cytometry and immunohistochemistry.

Results: Accumulation of Ly6cintLy6G+7/4+CD11b+ neutrophils predominated in all organs except brain, where CD45intCD11b+CD11c- microglia were the major leukocytes detected, surrounding infiltrating neutrophils and foci of invading Candida. Significantly more neutrophils accumulated in the spleen and liver than in the kidney during the first 24 hrs post-infection, when neutrophils are critical for Candida control. Conversely, at later time-points only the kidney continued to accumulate neutrophils, associated with tissue destruction and renal failure. The distribution of neutrophils was completely different in each organ with large abscesses and immunopathology exclusively seen in the kidney. Candida filamentation, an important virulence trait, was seen in the kidney but not in the spleen or liver. IC induced Ly6chi7/4+CD11b+ monocyte and NK1.1+CD3- NK cell expansion in the blood and all organs tested, and MHCII+F4/80+CD11cmacrophage, MHCII+CD11cdendritic cell, and NK1.1+CD3+ NKT cell accumulation, mainly in the spleen and liver. 

Conclusion: In a mouse model of IC there is profound variability in the ability of different organs to control Candida, associated with highly idiosyncratic organ-specific innate immune responses. This work provides novel insight into the balance between effective host defense and immunopathology in IC and highlights the need for further research on organ-specific cellular and molecular factors that shape and modulate the immune response to fungi.


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

Michail Lionakis, MD, ScD and Philip Murphy, MD, Laboratory of Molecular Immunology, NIH, Bethesda, MD

Disclosures:

M. Lionakis, None

P. Murphy, None

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