Laboratório de Gnotobiologia e Imunologia, Instituto de Ciências Biológicas, Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States.
Front Immunol. 2021 Oct 20;12:730437. doi: 10.3389/fimmu.2021.730437. eCollection 2021.
Innate immune cells present a dual role during leishmaniasis: they constitute the first line of host defense but are also the main host cells for the parasite. Response against the infection that results in the control of parasite growth and lesion healing depends on activation of macrophages into a classical activated phenotype. We report an essential role for the microbiota in driving macrophage and monocyte-derived macrophage activation towards a resistance phenotype against infection in mice. Both germ-free and dysbiotic mice showed a higher number of myeloid innate cells in lesions and increased number of infected cells, mainly dermal resident and inflammatory macrophages. Despite developing a Th1 immune response characterized by the same levels of IFN-γ production as the conventional mice, germ-free mice presented reduced numbers of iNOS macrophages at the peak of infection. Absence or disturbance of host microbiota impaired the capacity of bone marrow-derived macrophage to be activated for killing , even when stimulated by Th1 cytokines. These cells presented reduced expression of mRNA, and diminished production of microbicidal molecules, such as ROS, while presenting a permissive activation status, characterized by increased expression of and mRNA and higher arginase activity. Colonization of germ-free mice with complete microbiota from conventional mice rescued their ability to control the infection. This study demonstrates the essential role of host microbiota on innate immune response against infection, driving host macrophages to a resistance phenotype.
它们构成宿主防御的第一道防线，但也是寄生虫的主要宿主细胞。对抗感染的反应导致寄生虫生长和病变愈合的控制，依赖于将巨噬细胞激活为经典激活表型。我们报告了微生物组在驱动巨噬细胞和单核细胞衍生的巨噬细胞向抵抗感染表型的激活中的重要作用。无菌和失调小鼠在病变中有更多的髓样固有细胞，并且感染细胞的数量增加，主要是皮肤驻留和炎症巨噬细胞。尽管无菌小鼠产生了与常规小鼠相同水平 IFN-γ产生的 Th1 免疫反应，但在感染高峰期，iNOS 巨噬细胞的数量减少。宿主微生物组的缺失或失调损害了骨髓来源的巨噬细胞被激活以杀死 的能力，即使受到 Th1 细胞因子的刺激也是如此。这些细胞的 mRNA 表达减少，杀菌分子如 ROS 的产生减少，而表现出允许的激活状态，其特征是 和 mRNA 的表达增加和精氨酸酶活性升高。用常规小鼠的完整微生物组定植无菌小鼠挽救了它们控制感染的能力。这项研究证明了宿主微生物组在针对 感染的固有免疫反应中的重要作用，它驱动宿主巨噬细胞向抵抗表型发展。
