Data from: Mosquito saliva increases endothelial permeability in the skin, immune cell migration, and dengue pathogenesis during antibody-dependent enhancement

Dengue remains the most prevalent arthropod-borne viral disease in humans. While probing for blood vessels, Aedes aegypti and Ae. albopictus mosquitoes transmit the four serotypes of dengue virus (DENV1-4) by injecting virus-containing saliva into the skin. Even though arthropod saliva is known to facilitate transmission and modulate host responses to other pathogens, the full impact of mosquito saliva on dengue pathogenesis is still not well understood. Inoculating mice lacking the interferon-α/β receptor intradermally with DENV revealed that mosquito salivary gland extract (SGE) exacerbates dengue pathogenesis specifically in the presence of enhancing serotype-cross-reactive antibodies—when individuals already carry an increased risk for severe disease. We further establish that SGE increases viral titers in the skin, boosts antibody-enhanced DENV infection of dendritic cells and macrophages in the dermis, and amplifies dendritic cell migration to skin-draining lymph nodes. We demonstrate that SGE directly disrupts endothelial barrier function in vitro and induces endothelial permeability in vivo in the skin. Finally, we show that surgically removing the site of DENV transmission in the skin after 4 hours rescued mice from disease in the absence of SGE, but no longer prevented lethal antibody-enhanced disease when SGE was present. These results indicate that SGE accelerates the dynamics of dengue pathogenesis after virus transmission in the skin and induces severe antibody-enhanced disease systemically. Our study reveals novel aspects of dengue pathogenesis and suggests that animal models of dengue and pre-clinical testing of dengue vaccines should consider mosquito-derived factors as well as enhancing antibodies.登革热（Dengue）仍是人类最普遍的节肢动物传播性病毒性疾病。埃及伊蚊（Aedes aegypti）与白纹伊蚊（Ae. albopictus）在探查宿主血管时，会将携带病毒的唾液注入皮肤，从而传播四种血清型的登革病毒（dengue virus, DENV1-4）。尽管已有研究证实节肢动物唾液可促进病毒传播，并调节宿主对其他病原体的免疫应答，但蚊唾液对登革热发病机制的完整影响仍未被完全阐明。我们对缺失α/β干扰素受体（interferon-α/β receptor）的小鼠进行皮内（intradermally）接种登革病毒的实验后发现，蚊唾液腺提取物（mosquito salivary gland extract, SGE）仅在存在增强型血清型交叉反应性抗体——即个体已处于重症风险升高的状态下——时，会特异性加重登革热的发病进程。我们进一步证实，蚊唾液腺提取物可提升皮肤内的病毒滴度（viral titers），增强真皮（dermis）内树突状细胞（dendritic cells）与巨噬细胞（macrophages）的抗体介导登革病毒感染增强效应，并促进树突状细胞向皮肤引流淋巴结（skin-draining lymph nodes）迁移。体外实验表明，蚊唾液腺提取物可直接破坏内皮屏障功能（endothelial barrier function），且在小鼠体内可诱导皮肤组织的内皮通透性（endothelial permeability）升高。最后，我们发现，在病毒接种4小时后手术移除皮肤内的登革病毒感染位点，可使未接触蚊唾液腺提取物的小鼠免于发病；但当存在蚊唾液腺提取物时，该操作无法阻止致死性抗体增强型疾病的发生。上述结果表明，蚊唾液腺提取物可加速皮肤内病毒传播后的登革热发病进程，并在全身范围内诱导重症抗体增强型疾病。本研究揭示了登革热发病机制的全新维度，并提示登革热动物模型与登革疫苗的临床前测试，应同时考虑蚊源因子与增强型抗体的影响。