| Summary: | 博士 === 國立臺灣大學 === 免疫學研究所 === 104 === Galectin-3 (Gal3), belonging to the galectin family, has an evolutionarily conserved C-terminal carbohydrate-recognition domain and a unique N-terminal peptide. While it has been reported to modulate host response to autoimmune diseases, cancer metastasis, bacterial and parasite infections, and fibrosis, there are few studies address its role in fungal infection. Fungal infection as a hidden killer for human beings on the Earth leads to more than 50% mortality when disseminated even in patients with anti-fungal treatment. How to control its spread and provide a promising therapeutic strategy are universal issues. My studies on dimorphic Histoplasma capsulatum infection and opportunistic Candida albicans infection reveal the importance of endogenous gal3 in innate cell response to fungi.
While most people live in endemic area infected by Histoplasma without any symptoms, its infection easily disseminates in immuno-depressed or immunocompromised patients and leads to death. The clearance of pulmonary Histoplasma infection is dependent on both Th1 and Th17 responses. My study shows that gal3 negatively regulated bone marrow-derived and splenic dendritic cell IL-17A-axis cytokine production. The level of IL-17A production by both CD4 T cells and neutrophils was higher in gal3-/- mice after systemic Histoplasma infection. IL-17A alone or combined with IFN-γ activates macrophage to inhibit the growth of intracellular Histoplasma. Gal3-/- mice had lower fungal burden in the spleen compared to gal3+/+ mice. Neutralizing IL-17A increased fungal burden in gal3-/- mice to a level comparable to that in gal3+/+ mice, while neutralizing IFN-γ increased fungal burden in both gal3+/+ and gal3-/- mice. Adoptive transfer of dendritic cells showed that cell intrinsic gal3 in dendritic cells negatively regulated host IL-17A-axis cytokine production and fungal clearance. In this study, we demonstrated a negative role of intrinsic gal3 in dendritic cell IL-17A-axis cytokine production as well as in fungal clearance.
Candida albicans is an opportunistic dimorphic fungus, which is a commensal in the mucosa surface and skin in most humans. Invasive candidiasis is the first leading overall health-associated infection as well as bloodstream infection in intensive care units in Taiwan. Neutrophils are the major effector cells to clear fungal infection. We show that unstimulated human and mouse neutrophils express galectin-3 intracellularly, and it becomes detectable on the cell surface after stimulation by opsonized Candida. Upon CR3 engagement with opsonized Candida, galectin-3 downregulates Syk-mediated ROS production and subsequent killing of fungus. Co-immunoprecipitation and immunofluorescence staining reveal that cytosolic gal3 physically interacts with Syk. Moreover, galectin-3 deficiency ameliorates systemic candidiasis by reducing fungal burden, renal pathology, and mortality. Adoptive transfer experiments demonstrate that cell intrinsic gal3 negatively regulates neutrophil effector function in candidiasis. Additionally, the effect of galectin-3 on neutrophil anti-Candida function and host resistance to candidiasis is tested in clinical isolates. Treatment with galectin-3 antagonist or siRNA enhances human neutrophil ROS production. Our work raises the possibility that blocking gal3 in neutrophils may be a promising therapeutic strategy for treating systemic candidiasis.
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