Early-Expressed Chemokines Predict Kidney Immunopathology in Experimental Disseminated Candida albicans Infections

Abstract

BackgroundThe mouse intravenous challenge model of Candida albicans infection is widely used to determine aspects of host-fungus interaction. We investigated the production of cytokines in the kidneys and spleen of animals up to 48 h after challenge with virulent and attenuated isolates and related these responses to semi-quantitative estimations of histopathological changes in the kidney.Methodology/Principal FindingsProgression of Candida albicans infection of the kidney in response to highly virulent fungal strains was characterized by higher levels of host cellular infiltrate, higher lesion densities and greater quantities of fungal elements at 24 and 48 h, and by higher kidney concentrations of IL-1β, MCP-1, KC, IL-6, G-CSF, TNF, MIP-2 and MIP-1β, among the immune effectors measured. Levels of the chemokine KC as early as 12 h after challenge correlated significantly with all later measurements of lesion severity. Early renal IL-6 and MIP-1β concentrations also correlated with subsequent damage levels, but less significantly than for KC. All chemokines tested appeared in kidney homogenates, while most of the cytokines were undetectable in kidney and spleen homogenates. GM-CSF and IL-10 showed inverse correlations with measures of lesion severity, suggesting these alone may have exerted a defensive role. Spleen levels of KC at all times showed significant associations with kidney lesion measurements.Conclusions/SignificanceElevated chemokine levels, including KC, represent the earliest responses to C. albicans infection in the mouse kidney. Fungal strains of low mouse virulence stimulate a lower innate response and less host infiltrate than more virulent strains. These findings are consistent with immunopathological damage to kidneys in the mouse C. albicans infection model and with growing evidence implicating some TLR pathways as the main point of interaction between fungal surface polysaccharides and leukocytes.

Differential Regulation of Kidney and Spleen Cytokine Responses in Mice Challenged with Pathology-Standardized Doses of Candida albicans Mannosylation Mutants

“…Conditions for maintenance of the strains and preparation of challenge inocula have been previously described (5).…”

“…The opposite finding suggests that kidney disease and microabscess formation in the mouse i.v. challenge model are of immunopathological origin, consequent on the extent to which polymorphonuclear leukocytes (PMNs) are attracted to the site of infection (5). The present study is a continuation of our efforts to investigate mechanisms underlying the generation of a host response to C. albicans that is deleterious to host tissues, particularly the kidneys.…”

“…C. albicans challenge (4,5). Kidney levels of some mouse immune modulators, notably keratinocyte-derived chemokine (KC), interleukin 6 (IL-6), granulocyte colony-stimulating factor (G-CSF), and monokine induced by gamma interferon (MIG), showed strong correlations with parameters assessing the degree of kidney disease by 24 h after challenge, with clinical isolates with low virulence in mice and a mannosylation mutant strain stimulating lower chemokine and cytokine responses than isolates with high virulence in mice (5). Strains that activate a low level of host response might be expected to multiply and spread more readily in vivo than those that stimulate a robust and potentially annihilative response.…”

Candida albicansdimorphism as a therapeutic target

“…Similarly, severe immunosuppression is a prerequisite for lethal dissemination of C. albicans from the gastrointestinal tract in mice [55]. On the other hand, an excessive proinflammatory response contributes to the development of sepsis in systemically infected immunocompetent mice [56,57]. Finally, depending on the site of infection, C. albicans likely encounters different components of the immune system, adding to the complexity of possible interactions.…”

Early expression of local cytokines during systemic Candida albicans infection in a murine intravenous challenge model

“…During systemic candidiasis, C. albicans is carried by the bloodstream to almost all the organs of the body, with the immune responses occurring in the kidney influencing the C. albicans infection outcome (5)(6)(7). The brain is the second most affected organ.…”