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Published on: February 18, 2015
CD47 Promotes Protective Innate and Adaptive Immunity in a Mouse Model of Disseminated Candidiasis
Dhammika H M L P Navarathna1, Erica V Stein2, Elizabeth C Lessey-Morillon1
1Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, United States of America.
Abstract:
CD47 is a widely expressed receptor that regulates immunity by engaging its counter-receptor SIRPα on phagocytes and its secreted ligand thrombospondin-1. Mice lacking CD47 can exhibit enhanced or impaired host responses to bacterial pathogens, but its role in fungal immunity has not been examined. cd47-/- mice on a C57BL/6 background showed significantly increased morbidity and mortality following Candida albicans infection when compared with wild-type mice. Despite normal fungal colonization at earlier times, cd47-/- mice at four days post-infection had increased colonization of brain and kidneys accompanied by stronger inflammatory reactions. Neutrophil and macrophage numbers were significantly elevated in kidneys and neutrophils in the brains of infected cd47-/- mice. However, no defect in phagocytic activity towards C. albicans was observed in cd47-/- bone-marrow-derived macrophages, and neutrophil and macrophage killing of C. albicans was not impaired. CD47-deficiency did not alter the early humoral immune response to C. albicans. Th1, Th2, and Th17 population of CD4+ T cells were expanded in the spleen, and gene expression profiles of spleen and kidney showed stronger pro-inflammatory signaling in infected cd47-/- mice. The chemoattractant chemokines MIP-2α and MIP-2β were highly expressed in infected spleens of cd47-/- mice. G-CSF, GM-CSF, and the inflammasome component NLRP3 were more highly expressed in infected cd47-/- kidneys than in infected wild-type controls. Circulating pro- (TNF-α, IL-6) and anti-inflammatory cytokines (IL-10) were significantly elevated, but IL-17 was decreased. These data indicate that CD47 plays protective roles against disseminated candidiasis and alters pro-inflammatory and immunosuppressive pathways known to regulate innate and T cell immunity.
Insights
Mice lacking CD47 (the immune checkpoint protein) showed increased mortality and inflammation when infected with Candida albicans. CD47 deficiency impairs the host immune response to fungal infections.
Area of Science:
- Immunology
- Infectious Diseases
- Cell Biology
Background:
- CD47 is a widely expressed immune receptor involved in regulating host defense.
- Its role in fungal immunity, particularly against Candida albicans, remains largely unexplored.
- Previous studies suggest CD47 influences responses to bacterial pathogens.
Purpose of the Study:
- To investigate the role of CD47 in host immunity against disseminated candidiasis.
- To determine the impact of CD47 deficiency on morbidity, mortality, and immune cell responses during Candida albicans infection.
Main Methods:
- Utilized CD47-deficient (cd47-/-) and wild-type mice on a C57BL/6 background.
- Inoculated mice with Candida albicans and assessed fungal burden, inflammatory markers, and immune cell populations.
- Analyzed phagocytic activity, cytokine profiles, and gene expression in immune cells and tissues.
Main Results:
- CD47-deficient mice exhibited significantly increased morbidity and mortality post-Candida albicans infection.
- Elevated fungal colonization in the brain and kidneys, coupled with heightened inflammatory responses, was observed in cd47-/- mice.
- While innate immune cell numbers increased, phagocytic and killing activities against Candida albicans were not impaired in CD47-deficient macrophages and neutrophils.
- Pro-inflammatory signaling, chemokine expression (MIP-2α, MIP-2β), and inflammasome components (NLRP3) were upregulated in infected cd47-/- mice.
- Expanded Th1, Th2, and Th17 CD4+ T cell populations were noted in the spleen, but circulating IL-17 levels were decreased.
Conclusions:
- CD47 plays a critical protective role in combating disseminated candidiasis.
- CD47 deficiency exacerbates Candida albicans infection by altering pro-inflammatory and immunosuppressive pathways.
- These findings highlight CD47 as a potential therapeutic target for fungal infections.
