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.

登革热仍是人类中最为流行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）在探测血管取血时，会将携带病毒的唾液注入皮肤，从而传播四种登革病毒血清型（DENV1-4）。尽管已知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，但蚊子唾液对登革热发病机制的完整影响仍未得到充分阐明。我们对缺失α/β干扰素受体的小鼠进行皮内登革病毒接种实验后发现，蚊子唾液腺提取物（SGE）仅在存在增强型血清型交叉反应抗体——即个体已面临重症疾病风险时——会加重登革热的发病进程。我们进一步证实，SGE可提升皮肤内的病毒滴度，增强真皮内树突状细胞与巨噬细胞的抗体依赖性登革病毒感染，并促进树突状细胞向皮肤引流淋巴结迁移。我们还证明，SGE在体外可直接破坏内皮屏障功能，并在体内诱导皮肤内皮通透性升高。最后我们发现，在病毒接种4小时后手术移除皮肤内登革病毒的传播位点，可使未接触SGE的小鼠免于发病，但在存在SGE的情况下则无法阻止致死性抗体增强型疾病的发生。上述结果表明，SGE可加速皮肤内病毒传播后登革热的发病进程，并在全身范围内诱导严重的抗体增强型疾病。本研究揭示了登革热发病机制的全新层面，并提示登革热动物模型及登革疫苗的临床前测试应同时纳入蚊子来源的因子与增强型抗体。