Role of γδT cells in skin homeostasis and protective immunity during experimental dermatophytosis

人类真菌疾病仍然是一个主要的全球健康问题，特别是在儿童、老年人和免疫缺陷人群中。近几十年来，我们对控制真菌先天识别和髓细胞引起的抗真菌反应的分子途径的理解有了显着提高。然而，我们对控制真菌生长的器官特异性适应性免疫反应和细胞因子网络的了解仍然较少。皮肤真菌病是由嗜角丝状真菌引起的皮肤感染，约占世界人口的25%，因此是人类疾病的第四大流行原因。尽管发病率很高，但与其他真菌感染相比，疾病发病机制和宿主对皮肤真菌的反应几乎没有研究。在这里，阿根廷和德国合作伙伴将共同研究皮肤对皮肤真菌的免疫反应，并解决共生细菌和致病真菌如何驱动皮肤免疫稳态。先天γδT淋巴细胞在皮肤免疫对抗病原体以及维持与共生微生物的体内平衡中扮演着重要角色。因此，我们将在模拟人类皮肤真菌病的小孢子菌表皮感染实验模型中监测它们对皮肤真菌的抗真菌作用。具体来说，我们将研究皮肤γδT细胞在皮肤真菌感染反应中产生促炎细胞因子白细胞介素-17的作用。此外，我们将研究微生物和代谢因素调节产生白细胞介素17的免疫细胞和皮肤的致病或共生真菌之间的免疫稳态。该提案概述了一个高度协作和互补的研究项目，将使Laura Chiapello博士（CIBICI-CONICET）和Immo Prinz博士（德国汉诺威免疫学研究所）的实验室互利。阿根廷组提供了病原真菌和实验性感染管理方面的经验，德国组在γδT细胞生物学和组织中免疫细胞动力学的体内研究方面经验丰富。

Human fungal diseases continue to represent a major global health problem, in particular in children, in the elderly and in immune-deficient individuals. In recent decades, our understanding of the molecular pathways that control innate recognition of fungi and antifungal responses elicited by myeloid cells has significantly improved. However, we still understand less about organ-specific adaptive immune responses and cytokine networks that control fungal growth. Dermatophytoses are skin infections caused by keratinophilic filamentous fungi affecting approximately 25% of the world population, thereby representing the fourth most prevalent cause of human disease. Despite this enormous incidence, disease pathogenesis and host responses to dermatophytes are scarcely investigated in comparison to other fungal infections. Here, the Argentinean and German partners will jointly investigate the skin’s immune responses to dermatophytosis and address how commensal bacteria and pathogenic fungi drive skin immune homeostasis. Innate γδT lymphocytes are emerging as central players in skin immunity against pathogens as well as in maintaining homeostasis with commensal microorganisms. Therefore, we will monitor their antifungal functions against dermatophytes in an experimental model of epicutaneous infection with Microsporum spp., which mimics human dermatomycosis. Specifically, we will investigate the role of dermal γδT cells that produce the pro-inflammatory cytokine interleukin-17-producing in response to dermatophyte infection. Furthermore, we will study the microbial and metabolic factors that modulate immune homeostasis between interleukin-17-producing immune cells and pathogenic or commensal fungi of the skin. This proposal outlines a highly collaborative and complementary research project that will mutually benefit the laboratories of Dr. Laura Chiapello (CIBICI-CONICET) and Dr. Immo Prinz (Institute of Immunology, Hannover, Germany). The Argentine group provides experience in the management of pathogenic fungi and experimental infections, and the German group is experienced in γδT cell biology and the in vivo study of immune cell dynamics in tissues.