Data from: Monocyte recruitment to the dermis and differentiation to dendritic cells increases the targets for Dengue virus replication

Dengue virus (DENV) causes the most prevalent arthropod-borne viral disease in humans. Although Aedes mosquitoes transmit DENV when probing for blood in the skin, no information exists on DENV infection and immune response in the dermis, where the blood vessels are found. DENV suppresses the interferon response, replicates, and causes disease in humans but not wild-type mice. Here, we used mice lacking the interferon-α/β receptor (Ifnar–/–), which had normal cell populations in the skin and were susceptible to intradermal DENV infection, to investigate the dynamics of early DENV infection of immune cells in the skin. CD103+ classical dendritic cells (cDCs), Ly6C– CD11b+ cDCs, and macrophages in the steady-state dermis were initial targets of DENV infection 12-24 hours post-inoculation but then decreased in frequency. We demonstrated recruitment of adoptively-transferred Ly6Chigh monocytes from wild-type and Ifnar–/– origin to the DENV-infected dermis and differentiation to Ly6C+ CD11b+ monocyte-derived DCs (moDCs), which became DENV-infected after 48 hours, and were then the major targets for virus replication. Ly6Chigh monocytes that entered the DENV-infected dermis expressed chemokine receptor CCR2, likely mediating recruitment. Further, we show that ~100-fold more hematopoietic cells in the dermis were DENV-infected compared to Langerhans cells in the epidermis. Overall, these results identify the dermis as the main site of early DENV replication and show that DENV infection in the skin occurs in two waves: initial infection of resident cDCs and macrophages, followed by infection of monocytes and moDCs that are recruited to the dermis. Our study reveals a novel viral strategy of exploiting monocyte recruitment to increase the number of targets for infection at the site of invasion in the skin and highlights the skin as a potential site for therapeutic action or intradermal vaccination.登革病毒（Dengue virus, DENV）是引发人类感染率最高的虫媒病毒性疾病的病原。尽管伊蚊在皮肤内刺吸血液时会传播登革病毒，但目前尚无针对皮肤真皮层（血管所在部位）内登革病毒感染与免疫应答的相关研究报道。登革病毒可抑制干扰素应答、完成复制并引发人类疾病，但无法感染野生型小鼠。本研究选取皮肤细胞群体正常且对皮内登革病毒感染易感的α/β干扰素受体缺陷型（Ifnar–/–）小鼠作为模型，探究皮肤内免疫细胞早期登革病毒感染的动态变化过程。接种后12-24小时，稳态真皮层中的CD103+ 经典树突状细胞（CD103+ classical dendritic cells, cDCs）、Ly6C– CD11b+ 经典树突状细胞以及巨噬细胞是登革病毒感染的初始靶标，随后其占比逐渐降低。本研究证实，野生型与Ifnar–/–来源的过继转移Ly6Chigh单核细胞可被招募至登革病毒感染的真皮层，并分化为Ly6C+ CD11b+ 单核细胞衍生树突状细胞（monocyte-derived DCs, moDCs）；该类细胞在接种后48小时发生登革病毒感染，随后成为病毒复制的主要靶标。侵入登革病毒感染真皮层的Ly6Chigh单核细胞表达趋化因子受体CCR2，该受体可能介导了单核细胞的招募过程。此外，本研究发现，与表皮层的朗格汉斯细胞相比，真皮层内被登革病毒感染的造血细胞数量高出约100倍。综上，本研究结果证实真皮层是登革病毒早期复制的主要部位，同时揭示皮肤内的登革病毒感染存在两个阶段：首先是定居的经典树突状细胞与巨噬细胞被感染，随后是被招募至真皮层的单核细胞与单核细胞衍生树突状细胞发生感染。本研究揭示了登革病毒通过利用单核细胞招募机制，在皮肤入侵部位增加感染靶标数量的新型病毒策略，并强调皮肤可作为治疗干预或皮内疫苗接种的潜在靶点。