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）仍是目前人类感染最为普遍的虫媒病毒性疾病。埃及伊蚊（Aedes aegypti）与白纹伊蚊（Ae. albopictus）在叮咬宿主探寻血管时，会将携带病毒的唾液注入皮肤，从而传播登革病毒（dengue virus, DENV）的4种血清型（DENV1-4）。尽管已知虫媒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完全阐明。通过向缺失α/β干扰素受体（interferon-α/β receptor）的小鼠皮内接种登革病毒的实验显示，蚊唾液腺提取物（SGE）仅在血清型交叉反应性增强抗体存在时（即宿主已具备重症疾病高风险时），会加重登革热的发病进程。本研究进一步证实，SGE可提升皮肤内的病毒滴度，增强抗体介导的登革病毒对真皮层树突状细胞（dendritic cells）与巨噬细胞（macrophages）的感染，并促进树突状细胞向皮肤引流淋巴结迁移。研究还表明，SGE可在体外直接破坏内皮屏障功能（endothelial barrier function），并在体内诱导皮肤内皮通透性升高。最后，本研究发现，在接种后4小时手术切除皮肤内的登革病毒感染位点，可在无SGE存在时使小鼠免于发病；但当SGE存在时，该操作无法再阻止致死性抗体增强性疾病的发生。上述结果表明，SGE可加速皮肤内病毒传播后登革热发病的动态进程，并全身性诱导重症抗体增强性疾病。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临床前试验，应同时纳入蚊源性因子与增强抗体的考量因素。