Lai Chih-Yun, Strange Daniel P, Wong Teri Ann S, Lehrer Axel T, Verma Saguna
Department of Tropical Medicine, Medical Microbiology and Pharmacology, John A Burns School of Medicine, University of Hawaii at ManoaHonolulu, HI, United States.
Front Microbiol. 2017 Aug 17;8:1571. doi: 10.3389/fmicb.2017.01571. eCollection 2017.
Ebola virus (EBOV), a member of the family, causes the most severe form of viral hemorrhagic fever. Although no FDA licensed vaccine or treatment against Ebola virus disease (EVD) is currently available, Ebola virus glycoprotein (GP) is the major antigen used in all candidate Ebola vaccines. Recent reports of protection as quickly as within 6 days of administration of the rVSV-based vaccine expressing EBOV GP before robust humoral responses were generated suggests that the innate immune responses elicited early after vaccination may contribute to the protection. However, the innate immune responses induced by EBOV GP in the absence of viral vectors or adjuvants have not been fully characterized . Our recent studies demonstrated that immunization with highly purified recombinant GP in the absence of adjuvants induced a robust IgG response and partial protection against EBOV infection suggesting that GP alone can induce protective immunity. In this study we investigated the early immune response to purified EBOV GP alone and . We show that GP was efficiently internalized by antigen presenting cells and subsequently induced production of key inflammatory cytokines. , immunization of mice with EBOV GP triggered the production of key Th1 and Th2 innate immune cytokines and chemokines, which directly governed the recruitment of CD11b macrophages and CD11c dendritic cells to the draining lymph nodes (DLNs). Pre-treatment of mice with a TLR4 antagonist inhibited GP-induced cytokine production and recruitment of immune cells to the DLN. EBOV GP also upregulated the expression of costimulatory molecules in bone marrow derived macrophages suggesting its ability to enhance APC stimulatory capacity, which is critical for the induction of effective antigen-specific adaptive immunity. Collectively, these results provide the first evidence that early innate immune responses to EBOV GP are mediated via the TLR4 pathway and are able to modulate the innate-adaptive interface. These mechanistic insights into the adjuvant-like property of EBOV GP may help to develop a better understanding of how optimal prophylactic efficacy of EBOV vaccines can be achieved as well as further explore the potential post-exposure use of vaccines to prevent filoviral disease.
埃博拉病毒（EBOV）是该病毒家族的成员之一，可引发最严重形式的病毒性出血热。尽管目前尚无美国食品药品监督管理局（FDA）批准的针对埃博拉病毒病（EVD）的疫苗或治疗方法，但埃博拉病毒糖蛋白（GP）是所有候选埃博拉疫苗中使用的主要抗原。最近有报道称，在产生强烈的体液反应之前，接种表达EBOV GP的基于重组水疱性口炎病毒（rVSV）的疫苗后6天内即可获得保护，这表明接种疫苗后早期引发的先天免疫反应可能有助于提供保护。然而，在没有病毒载体或佐剂的情况下，EBOV GP诱导的先天免疫反应尚未得到充分表征。我们最近的研究表明，在没有佐剂的情况下，用高度纯化的重组GP进行免疫可诱导强烈的IgG反应，并对EBOV感染提供部分保护，这表明单独的GP即可诱导保护性免疫。在本研究中，我们单独研究了对纯化的EBOV GP的早期免疫反应以及……我们发现，GP被抗原呈递细胞有效内化，随后诱导关键炎症细胞因子的产生。此外，用EBOV GP免疫小鼠会触发关键的Th1和Th2先天免疫细胞因子及趋化因子的产生，这些因子直接控制CD11b巨噬细胞和CD11c树突状细胞向引流淋巴结（DLN）的募集。用TLR4拮抗剂对小鼠进行预处理可抑制GP诱导的细胞因子产生以及免疫细胞向DLN的募集。EBOV GP还上调了骨髓来源巨噬细胞中共刺激分子的表达，表明其具有增强抗原呈递细胞刺激能力的作用，这对于诱导有效的抗原特异性适应性免疫至关重要。总体而言，这些结果首次证明，对EBOV GP的早期先天免疫反应是通过TLR4途径介导的，并且能够调节先天-适应性免疫界面。这些对EBOV GP佐剂样特性的机制性见解可能有助于更好地理解如何实现EBOV疫苗的最佳预防效果，以及进一步探索疫苗在暴露后预防丝状病毒病的潜在用途。
