Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
J Virol. 2019 Jun 14;93(13). doi: 10.1128/JVI.00395-19. Print 2019 Jul 1.
Saliva from the mosquito vector of flaviviruses is capable of changing the local immune environment, leading to an increase in flavivirus-susceptible cells at the infected bite site. In addition, an antibody response to specific salivary gland (SG) components changes the pathogenesis of flaviviruses in human populations. To investigate whether antigenic SG proteins are capable of enhancing infection with Zika virus (ZIKV), a reemerging flavivirus primarily transmitted by the mosquito, we screened for antigenic SG proteins using a yeast display library and demonstrate that a previously undescribed SG protein we term neutrophil stimulating factor 1 (NeSt1) activates primary mouse neutrophils Passive immunization against NeSt1 decreases pro-interleukin-1β and CXCL2 expression, prevents macrophages from infiltrating the bite site, protects susceptible IFNAR IFNGR (AG129) mice from early ZIKV replication, and ameliorates virus-induced pathogenesis. These findings indicate that NeSt1 stimulates neutrophils at the mosquito bite site to change the immune microenvironment, allowing a higher level of early viral replication and enhancing ZIKV pathogenesis. When a Zika virus-infected mosquito bites a person, mosquito saliva is injected into the skin along with the virus. Molecules in this saliva can make virus infection more severe by changing the immune system to make the skin a better place for the virus to replicate. We identified a molecule that activates immune cells, called neutrophils, to recruit other immune cells, called macrophages, that the virus can infect. We named this molecule neutrophil-stimulating factor 1 (NeSt1). When we used antibodies to block NeSt1 in mice and then allowed Zika virus-infected mosquitoes to feed on these mice, they survived much better than mice that do not have antibodies against NeSt1. These findings give us more information about how mosquito saliva enhances virus infection, and it is possible that a vaccine against NeSt1 might protect people against severe Zika virus infection.
登革热病毒的蚊媒唾液能够改变局部免疫环境，导致感染部位对黄病毒更易感的细胞增加。此外，针对特定唾液腺 (SG) 成分的抗体反应改变了黄病毒在人类中的发病机制。为了研究抗原性 SG 蛋白是否能够增强寨卡病毒 (ZIKV) 的感染，一种主要由蚊子传播的新兴黄病毒，我们使用酵母展示文库筛选抗原性 SG 蛋白，并证明一种以前未描述的 SG 蛋白，我们称之为中性粒细胞刺激因子 1 (NeSt1)，能够激活原代小鼠中性粒细胞。针对 NeSt1 的被动免疫可降低促白细胞介素-1β和 CXCL2 的表达，阻止巨噬细胞浸润感染部位，保护易感 IFNAR IFNGR (AG129) 小鼠免受早期 ZIKV 复制的影响，并改善病毒引起的发病机制。这些发现表明，NeSt1 刺激蚊子叮咬部位的中性粒细胞改变免疫微环境，允许更高水平的早期病毒复制并增强 ZIKV 发病机制。当感染寨卡病毒的蚊子叮咬人时，蚊子唾液会与病毒一起注入皮肤。这种唾液中的分子可以通过改变免疫系统使皮肤成为病毒更易复制的地方，从而使病毒感染更加严重。我们鉴定了一种能够激活免疫细胞（称为中性粒细胞）的分子，以招募其他免疫细胞（称为巨噬细胞），病毒可以感染这些细胞。我们将这种分子命名为中性粒细胞刺激因子 1 (NeSt1)。当我们使用抗体阻断 NeSt1 后，让感染寨卡病毒的蚊子叮咬这些老鼠时，它们的存活情况明显好于没有针对 NeSt1 的抗体的老鼠。这些发现为我们提供了更多关于蚊子唾液如何增强病毒感染的信息，并且针对 NeSt1 的疫苗可能可以保护人们免受严重的寨卡病毒感染。
