Schmid Michael A, Glasner Dustin R, Shah Sanjana, Michlmayr Daniela, Kramer Laura D, Harris Eva
Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, California, United States of America.
Wadsworth Center, New York State Department of Health, Albany, New York, United States of America.
PLoS Pathog. 2016 Jun 16;12(6):e1005676. doi: 10.1371/journal.ppat.1005676. eCollection 2016 Jun.
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.
登革热仍然是人类中最普遍的节肢动物传播病毒性疾病。埃及伊蚊和白纹伊蚊在探测血管时，通过将含有病毒的唾液注入皮肤来传播登革病毒的四种血清型（DENV1 - 4）。尽管已知节肢动物唾液有助于传播并调节宿主对其他病原体的反应，但蚊子唾液对登革热发病机制的全面影响仍未得到充分了解。给缺乏干扰素 - α/β受体的小鼠皮内接种登革病毒发现，蚊子唾液腺提取物（SGE）在存在增强血清型交叉反应抗体的情况下会加剧登革热发病机制，而此时个体已经面临患严重疾病的风险增加。我们进一步证实，SGE会增加皮肤中的病毒滴度，增强真皮中树突状细胞和巨噬细胞的抗体增强型登革病毒感染，并放大树突状细胞向皮肤引流淋巴结的迁移。我们证明SGE在体外直接破坏内皮屏障功能，并在体内诱导皮肤中的内皮通透性。最后，我们表明在4小时后手术切除皮肤中登革病毒传播部位可使小鼠在没有SGE的情况下免于疾病，但当存在SGE时不再预防致命的抗体增强型疾病。这些结果表明，SGE在病毒在皮肤中传播后加速登革热发病机制的动态变化，并系统性地诱导严重的抗体增强型疾病。我们的研究揭示了登革热发病机制的新方面，并表明登革热动物模型和登革热疫苗的临床前测试应考虑蚊子衍生因素以及增强抗体。
