Schmid Michael A, Harris Eva
Division of Infectious Diseases & Vaccinology, School of Public Health, University of California Berkeley, Berkeley, California, United States of America.
PLoS Pathog. 2014 Dec 4;10(12):e1004541. doi: 10.1371/journal.ppat.1004541. eCollection 2014 Dec.
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 Ly6C(high) 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. Ly6C(high) 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（DENV）引发人类中最普遍的节肢动物传播病毒性疾病。尽管伊蚊在皮肤中探测血液时传播DENV，但在发现血管的真皮中，尚无关于DENV感染和免疫反应的信息。DENV可抑制干扰素反应、进行复制并在人类而非野生型小鼠中引发疾病。在此，我们使用缺乏干扰素-α/β受体（Ifnar(-/-)）的小鼠来研究皮肤中免疫细胞早期DENV感染的动态情况，这些小鼠皮肤中的细胞群体正常且易受皮内DENV感染。接种后12 - 24小时，稳态真皮中的CD103(+)经典树突状细胞（cDCs）、Ly6C(-) CD11b(+) cDCs和巨噬细胞是DENV感染的初始靶标，但随后其频率降低。我们证明，来自野生型和Ifnar(-/-)来源的过继转移Ly6C(high)单核细胞会募集到被DENV感染的真皮中，并分化为Ly6C(+) CD11b(+)单核细胞衍生树突状细胞（moDCs），这些细胞在48小时后被DENV感染，随后成为病毒复制的主要靶标。进入被DENV感染真皮的Ly6C(high)单核细胞表达趋化因子受体CCR2，可能介导了募集过程。此外，我们发现真皮中被DENV感染的造血细胞比表皮中的朗格汉斯细胞多约100倍。总体而言，这些结果确定真皮是早期DENV复制的主要部位，并表明皮肤中的DENV感染分两波发生：首先是驻留cDCs和巨噬细胞被感染，随后是募集到真皮中的单核细胞和moDCs被感染。我们的研究揭示了一种新的病毒策略，即利用单核细胞募集来增加皮肤入侵部位感染靶标的数量，并突出了皮肤作为治疗作用或皮内疫苗接种潜在部位的可能性。
