Crosstalk between the Intestinal Microbiota and the C-Type Lectin Receptor-Mincle Modulates Host Immunity against Mycobacterial and Candida Infection

Intestinal microbiota-host mutualism is crucial for establishment of intact host immunity. Eliminating or shifting microbiota by antibiotics treatments has profound impact on the functionality of mucosal and systemic immune systems. Loss of specific gut microbes and their derived pathogens-associated molecular patterns (PAMPs) resulting from intestinal dysbiosis may lead to attenuated innate and adaptive immunity, causing host succumbed to pathogenic infection. Signaling through C-type lectin receptors (CLRs) shapes immune responses and has been linked to host defense against opportunistic pathogens. Among CLRs, Mincle expressed in myeloid immune cells recently is identified involved in controlling mycobacterial and candida infection. However, the role of intestinal microbiota in regulating Mincle-dependent immunity against mycobacterial and candida infection remains unclear. By establishing a murine Mycobacterium kansasii and Candida albicans pulmonary infection, we uncovered that intact intestinal microbiota is vital for controlling pulmonary mycobacterial and candida infection as well as systemic dissemination. Mice orally fed with broad-specturm antibiotics, including vancomycin, metronidazole, ampicillin, and neomycin, exhibited impaired innate and adaptive immunity and became highly susceptible to M. kansasii and C. albicans in comparison with water-fed mice. Intriguingly, when analyzing the expression pattern of numerous pattern-recognition receptors (PRRs), pulmonary myeloid monocytic cells and bone marrow-derived macrophages (BMDM) isolated from antibiotics-treated mice displayed reduced Mincle expression and attenuated innate cytokine responses in response to M. kansasii and C. albicans. Importantly, antibiotics-treated mice recolonized with microbiota from water-fed mice regained intact anti-mycobacterial and anti-candida pulmonary immunity and functional Mincle-dependent signaling. The current evidence suggested gut microbiota induce intact pulmonary and systemic Mincle-dependent immune responses against mycobacteria and candida. In this research proposal, we aim to characterize the underlying mechanism of intestinal microbiota-driven anti-mycobacterial and anti-candida immunity in lung and systemic regions. The research plan will be divided into three parts: (1) Characterization of immune responses and immuno-pathogenicity in pulmonary/systemic mycobacterial or candida infection of specific antibiotic-treated mice; (2) Identification of specific intestinal microbes and components responsible for boosting anti-mycobacterial and anti-candida host immunity; (3) Elucidating the mechanism by which specific microbes regulate Mincle-dependent immune responses. This study will reveal the essential role of gut microbiota and the derived signals in controlling Mincle-driven robust pulmonary and systemic anti-mycobacteria and anti-candida immune responses. Host immune responsiveness to mycobacteria and candida infection depends on homeostasis between intestinal microbiota and innate immunity. The potential probiotics identified in this study will be highly applicable to immunomodulation-based treatment and prevention on mycobacterial and cadida infection.

Project ID:PC10401-0678
External Project ID:MOST103-2321-B182-014-MY3