Candida albicans 감염에 의한 선천성 면역 방어에서 CCR5 및 IL-33에 의해 형성된 신장 면역 네트워크의 역할

Abstract

Candida albicans (C. albicans) is a crucial pathogen that cause a serious health problem, inducing high mortality rates in immunocompromised patients. Understanding the innate immune pathway that controls antifungal defense in kidney, a major target organs, remains to be clarified. In this thesis, using in vitro and in vivo experiments systems, I demonstrated that C-C chemokine receptor type 5 (CCR5) and Interleukin- 33 (IL-33) played a critical role in innate defense to systemic C.albicans infection. In the first part of study, I showed that using CCR5-deficient (Ccr5-/-) mice, CCR5 contributes to an effective defense mechanism against systemic C. albicans infection. CCR5 was required for recruitment of NK cells to the kidney after systemic C. albicans infection. In Ccr5-/- mice, there were lower levels of GM-CSF in the kidney, which resulted in impaired neutrophils’ fungal clearance. Taken together with previous results showing that C. albicans activated the dendritic cell (DC)  IL-23  NK cell  GM-CSF  neutrophil defense axis, the results obtained form this study indicates that CCR5 play a main role in recruiting NK cells to the kdiney during systemic C. albicans infection. In the second part, I investigated in vivo function of endogenous Il-33 in systemic C. albicans infection using Il33-/- mice. IL-33 initiated an innate defense mechanism by co-stimulating DCs to produce IL-23 after systemic C. albicans infection. As a result, NK cells could not secrete amounts of GM-CSF suffieint to stimulate nuetrophils to phagocytize proliferating C. albicans. The susceptibility of Il33-/- mice was also associated with increased levels of IL-10 and neutralization of IL-10 resulted in enhanced fungal clearance in these mice. However, depletion of IL-10 overrided the effect of IL-33 on fungal clearance. There were abnormally differentiationed MHCII+F4/80+ macrophages in Il10-/- mouse kidnneys, which were superior to MHCII-F4/80+ macrophage that were presnt in WT mouse kidneys, in killing of extracellular hyphal form of C. albicans. Taken together, our results identify IL-33 and CCR5 as critical regulator creating an innate immune network cirtical for defense during systemic C. albicans infection.