无菌（GF）小鼠是探索微生物组在健康和疾病中作用的黄金标准;然而，它们在研究与人类特定病原体相关的问题上的价值有限，因为它们不支持其复制。在这里，我们开发了系统重构人类免疫细胞的GF小鼠，并使用它们评估了共生菌相在两种人类特定病原体（EB病毒和人类免疫缺陷病毒）的获取、复制和发病中的作用。与常规人类化小鼠（CV）相比，共生菌能增强EB病毒感染和EB病毒诱导的肿瘤发生，并增加黏膜HIV的获取和复制。与GF人类化小鼠相比，CV人类化小鼠的血浆和组织中的HIV RNA水平更高。肠道中CCR5+ CD4+ T细胞的频率在CV人类化小鼠中也较高，表明共生菌控制着HIV靶细胞的水平。因此，共生菌促进了两种与临床相关的人类特定病原体的感染和发病。© 2023. 作者（在Springer Nature America, Inc.的独家许可下）。

Germ-free (GF) mice, which are depleted of their resident microbiota, are the gold standard for exploring the role of the microbiome in health and disease; however, they are of limited value in the study of human-specific pathogens because they do not support their replication. Here, we develop GF mice systemically reconstituted with human immune cells and use them to evaluate the role of the resident microbiome in the acquisition, replication and pathogenesis of two human-specific pathogens, Epstein-Barr virus (EBV) and human immunodeficiency virus (HIV). Comparison with conventional (CV) humanized mice showed that resident microbiota enhance the establishment of EBV infection and EBV-induced tumorigenesis and increase mucosal HIV acquisition and replication. HIV RNA levels were higher in plasma and tissues of CV humanized mice compared with GF humanized mice. The frequency of CCR5+ CD4+ T cells throughout the intestine was also higher in CV humanized mice, indicating that resident microbiota govern levels of HIV target cells. Thus, resident microbiota promote the acquisition and pathogenesis of two clinically relevant human-specific pathogens.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.