Immunization of mice with recombinant mosquito salivary protein D7 enhances mortality from subsequent West Nile virus infection via mosquito bite.
Immunization of mice with recombinant mosquito salivary protein D7 enhances mortality from subsequent West Nile virus infection via mosquito bite.
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DOI：
10.1371/journal.pntd.0001935
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发表时间：
2012
影响因子：
3.8
通讯作者：
Blair CD
中科院分区：
文献类型：
--
作者：
Reagan KL;Machain-Williams C;Wang T;Blair CD
苔藓唾液蛋白（MSP）调节宿主的免疫反应，导致虫媒病毒感染的增强。鉴定唾液中负责免疫调节并抵消其对宿主免疫反应的影响的蛋白质是预防虫媒病毒疾病的潜在策略。我们选择了D 7蛋白家族的一个成员，这是蚊子唾液中最丰富和免疫原性最强的，作为候选疫苗，目的是中和在虫媒病毒传播过程中通常由蚊子唾液组分引起的哺乳动物免疫应答。我们鉴定了西尼罗河病毒（WNV）在北美的载体--跗库蚊（Culex tarsalis）的D 7唾液蛋白，并表达了36 kDa的重组D 7（rD 7）蛋白用作疫苗。接种疫苗的小鼠在未感染的蚊子叮咬后表现出增强的干扰素-γ和降低的白细胞介素-10表达;然而，我们意外地发现，rD 7疫苗接种导致蚊子传播的WNV感染的发病机制增强。将接种疫苗的小鼠血清被动转移给未接种的小鼠也导致随后蚊子传播的WNV感染的死亡率增加，这表明对疫苗的体液免疫应答增强了病毒的发病机制。接种疫苗的小鼠在蚊子叮咬感染西尼罗河病毒后，干扰素-γ减少，脾细胞产生调节性细胞因子IL-10增加。媒介唾液疫苗已经成功地预防了其他吸血节肢动物传播的疾病。然而，rD 7唾液蛋白疫苗不是针对WNV疾病的保护的良好候选者，因为通过受感染的蚊子叮咬感染的免疫小鼠表现出增加的死亡率。根据丰度和免疫原性选择唾液蛋白疫苗不能预测疗效。西尼罗河病毒（WNV）是一种蚊媒黄病毒，在除南极洲以外的所有大陆都有发现。人类和马不是自然传播周期的一部分，但当它们被感染时，可能会导致严重的疾病或死亡。目前还没有针对西尼罗河病毒的人类疫苗，因此需要新的方法来预防感染。沉积有西尼罗河病毒的苔藓唾液改变了被叮咬宿主的免疫反应，并增强了病毒的传播和致病性。先前的研究与预先暴露于节肢动物唾液蛋白显示出有希望的结果，在阻断疟疾和利什曼原虫寄生虫的传播，因此，我们假设一个类似的结果与MSP疫苗接种保护虫媒病毒疾病。出乎意料的是，我们的研究结果表明，由重组蚊子唾液蛋白（rD 7）组成的疫苗的管理和随后的蚊子传播的西尼罗河病毒导致更严重的疾病和小鼠死亡率增加。此外，当接种疫苗的小鼠的血清转移到幼稚小鼠时，这些动物也死于严重的蚊子传播的WNV疾病，这表明疫苗引发的抗rD 7抗体在增强疾病中发挥了作用。我们的结论是，我们开发的rD 7蛋白疫苗不是一个合适的候选人，改变宿主对西尼罗河病毒感染的免疫反应，以提供更多的保护免受疾病。
Mosquito salivary proteins (MSPs) modulate the host immune response, leading to enhancement of arboviral infections. Identification of proteins in saliva responsible for immunomodulation and counteracting their effects on host immune response is a potential strategy to protect against arboviral disease. We selected a member of the D7 protein family, which are among the most abundant and immunogenic in mosquito saliva, as a vaccine candidate with the aim of neutralizing effects on the mammalian immune response normally elicited by mosquito saliva components during arbovirus transmission. We identified D7 salivary proteins of Culex tarsalis, a West Nile virus (WNV) vector in North America, and expressed 36 kDa recombinant D7 (rD7) protein for use as a vaccine. Vaccinated mice exhibited enhanced interferon-γ and decreased interleukin-10 expression after uninfected mosquito bite; however, we found unexpectedly that rD7 vaccination resulted in enhanced pathogenesis from mosquito-transmitted WNV infection. Passive transfer of vaccinated mice sera to naïve mice also resulted in increased mortality rates from subsequent mosquito-transmitted WNV infection, implicating the humoral immune response to the vaccine in enhancement of viral pathogenesis. Vaccinated mice showed decreases in interferon-γ and increases in splenocytes producing the regulatory cytokine IL-10 after WNV infection by mosquito bite. Vector saliva vaccines have successfully protected against other blood-feeding arthropod-transmitted diseases. Nevertheless, the rD7 salivary protein vaccine was not a good candidate for protection against WNV disease since immunized mice infected via an infected mosquito bite exhibited enhanced mortality. Selection of salivary protein vaccines on the bases of abundance and immunogenicity does not predict efficacy. West Nile virus (WNV) is a mosquito-borne flavivirus found on all continents except Antarctica. Humans and equines are not part of the natural transmission cycle, but when they become infected severe illness or death can result. There is no human vaccine for WNV available, so novel approaches to preventing infection are needed. Mosquito saliva deposited with WNV alters the immune response of the bitten host and potentiates virus transmission and pathogenesis. Previous research with pre-exposure to arthropod salivary proteins showed promising results in blocking the transmission of malaria and Leishmania parasites, thus we hypothesized a similar outcome for vaccination with a MSP in protection from arbovirus disease. Unexpectedly, our results showed that administration of a vaccine consisting of a recombinant mosquito salivary protein (rD7) and subsequent mosquito transmission of WNV led to more severe disease and increased death rates in mice. Additionally, when serum from vaccinated mice was transferred to naïve mice, those animals also succumbed to severe mosquito-transmitted WNV disease, suggesting that anti-rD7 antibodies elicited by the vaccine played a role in enhanced disease. We conclude that the rD7 protein vaccine we developed is not a suitable candidate for altering the host immune response to WNV infection to provide increased protection from disease.
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影响因子：
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