Organ-Specific Innate Immune Responses in a Mouse Model of Invasive Candidiasis

Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
Journal of Innate Immunity (Impact Factor: 4.35). 11/2010; 3(2):180-99. DOI: 10.1159/000321157
Source: PubMed


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. We defined leukocyte accumulation in the blood, kidney, brain, spleen, and liver after infection using fluorescent-activated cell sorting (FACS) and immunohistochemistry. Accumulation of Ly6c(int)CD11b(+) neutrophils predominated in all organs except the brain, where CD45(int)CD11b(+)CD11c(-) microglia were the major leukocytes detected, surrounding foci of invading Candida. Significantly more neutrophils accumulated in the spleen and liver than in the kidney during the first 24 h after infection, when neutrophil presence is critical for Candida control. Conversely, at later time points only the kidney continued to accumulate neutrophils, associated with immunopathology and organ failure. The distribution of neutrophils was completely different in each organ, with large abscesses exclusively forming in the kidney. Candida filamentation, an essential virulence factor, was seen in the kidney but not in the spleen or liver. IC induced Ly6c(hi)CD11b(+) inflammatory monocyte and NK1.1(+) cell expansion in the blood and all organs tested, and MHCII(+)F4/80(+)CD11c(-) macrophage accumulation, mainly in the spleen and liver. This study is the first detailed analysis of leukocyte subsets accumulating in different target organs during IC. The results delineate immune responses to the same pathogen that are highly idiosyncratic for each organ tested. The work provides novel insights into the balance between effective host defense and immunopathology in IC.

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    • "21. Take a small aliquot before the last wash to determine neutrophil count, viability by trypan blue exclusion and FACS analysis using a fluorescent viability dye (Lionakis et al., 2011), and purity by flow cytometry using staining with APC-conjugated anti-CD45, PE-conjugated anti-Ly6G and APC-Cy7–conjugated anti-CD11b. "
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    • "More recently, it was proposed that Candida, sequestered in nonneuronal tissues, could release toxins that would destroy astrocytes and oligodendrocytes generating myelin debris that would then trigger a pathogenic immune response in the CNS [19]. Furthermore, the presence of yeast and hyphae in the brain recruits inflammatory cells and elicits expansion of microglia cells [20]. Considering that the possible contribution of C. albicans to MS needs to be investigated and that elucidation of this could affect the treatment of this disease, we evaluated the possible deleterious effect of a previous C. albicans infection on EAE development. "
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    • "Additionally, as yeast cells are less immuno-stimulatory, these cells may disseminate within the bloodstream without causing an extensive host immune activation, compared to hyphae. However, in the final stages of systemic infection in mouse models, development of hyphae is favored (Lionakis et al., 2011). "
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