CD11c-expressing Ly6C⁺CCR2⁺ monocytes constitute a reservoir for efficient <i>Leishmania</i> proliferation and cell-to-cell transmission

The virulence of intracellular pathogens such as Leishmania major (L. major) relies largely on their ability to undergo cycles of replication within phagocytes, release, and uptake into new host cells. While all these steps are critical for successful establishment of infection, neither the cellular niche of efficient proliferation, nor the spread to new host cells have been characterized in vivo. Here, using a biosensor for measuring pathogen proliferation in the living tissue, we found that monocyte-derived Ly6C+CCR2+ phagocytes expressing CD11c constituted the main cell type harboring rapidly proliferating L. major in the ongoing infection. Synchronization of host cell recruitment and intravital 2-photon imaging showed that these high proliferating parasites preferentially underwent cell-to-cell spread. However, newly recruited host cells were infected irrespectively of their cell type or maturation state. We propose that among these cells, CD11c-expressing monocytes are most permissive for pathogen proliferation, and thus mainly fuel the cycle of intracellular proliferation and cell-to-cell transfer during the acute infection. Thus, besides the well-described function for priming and activating T cell effector functions against L. major, CD11c-expressing monocyte-derived cells provide a reservoir for rapidly proliferating parasites that disseminate at the site of infection.胞内病原体（如硕大利什曼原虫（Leishmania major, L. major））的毒力，主要依赖其在吞噬细胞内完成复制周期、脱离宿主细胞并被新宿主细胞摄取的能力。尽管上述所有步骤对于成功建立感染均不可或缺，但目前尚未在体内明确病原体高效增殖的细胞微环境，以及其向新宿主细胞扩散的具体过程。本研究借助可在活体组织中检测病原体增殖的生物传感器，发现在持续感染进程中，表达CD11c的单核细胞来源Ly6C+CCR2+吞噬细胞，是携带快速增殖硕大利什曼原虫的主要细胞类群。通过同步化宿主细胞招募环节并结合双光子活体成像，我们观察到这些高增殖能力的寄生虫更倾向于通过细胞间接触完成扩散。不过，新招募的宿主细胞无论其细胞类型或成熟状态如何，均会被感染。我们据此提出：在上述细胞中，表达CD11c的单核细胞对病原体增殖的容纳性最强，因此在急性感染期主要推动胞内增殖周期与细胞间传播过程。综上，除了已被广泛报道的、用于启动并激活抗硕大利什曼原虫T细胞效应功能之外，表达CD11c的单核细胞来源细胞还可作为快速增殖寄生虫的储存库，在感染部位介导病原体的扩散。