Kulkarni Raveendra R, Rasheed Mohammed Ata Ur, Bhaumik Siddhartha Kumar, Ranjan Priya, Cao Weiping, Davis Carl, Marisetti Krishna, Thomas Sunil, Gangappa Shivaprakash, Sambhara Suryaprakash, Murali-Krishna Kaja
Department of Pediatrics and Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA.
Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA.
J Virol. 2014 Dec;88(24):13990-4001. doi: 10.1128/JVI.02273-14. Epub 2014 Sep 24.
Pattern recognition receptors (PRR) sense certain molecular patterns uniquely expressed by pathogens. Retinoic-acid-inducible gene I (RIG-I) is a cytosolic PRR that senses viral nucleic acids and induces innate immune activation and secretion of type I interferons (IFNs). Here, using influenza vaccine antigens, we investigated the consequences of activating the RIG-I pathway for antigen-specific adaptive immune responses. We found that mice immunized with influenza vaccine antigens coadministered with 5'ppp-double-stranded RNA (dsRNA), a RIG-I ligand, developed robust levels of hemagglutination-inhibiting antibodies, enhanced germinal center reaction, and T follicular helper cell responses. In addition, RIG-I activation enhanced antibody affinity maturation and plasma cell responses in the draining lymph nodes, spleen, and bone marrow and conferred protective immunity against virus challenge. Importantly, activation of the RIG-I pathway was able to reduce the antigen requirement by 10- to 100-fold in inducing optimal influenza-specific cellular and humoral responses, including protective immunity. The effects induced by 5'ppp-dsRNA were significantly dependent on type I IFN and IPS-1 (an adapter protein downstream of the RIG-I pathway) signaling but were independent of the MyD88- and TLR3-mediated pathways. Our results show that activation of the RIG-I-like receptor pathway programs the innate immunity to achieve qualitatively and quantitatively enhanced protective cellular adaptive immune responses even at low antigen doses, and this indicates the potential utility of RIG-I ligands as molecular adjuvants for viral vaccines.
The recently discovered RNA helicase family of RIG-I-like receptors (RLRs) is a critical component of host defense mechanisms responsible for detecting viruses and triggering innate antiviral cytokines that help control viral replication and dissemination. In this study, we show that the RLR pathway can be effectively exploited to enhance adaptive immunity and protective immune memory against viral infection. Our results show that activation of the RIG-I pathway along with influenza vaccination programs the innate immunity to induce qualitatively and quantitatively superior protective adaptive immunity against pandemic influenza viruses. More importantly, RIG-I activation at the time of vaccination allows induction of robust adaptive responses even at low vaccine antigen doses. These results highlight the potential utility of exploiting the RIG-I pathway to enhance viral-vaccine-specific immunity and have broader implications for designing better vaccines in general.
模式识别受体（PRR）可识别病原体独特表达的某些分子模式。视黄酸诱导基因I（RIG-I）是一种胞质PRR，可识别病毒核酸并诱导先天免疫激活和I型干扰素（IFN）分泌。在此，我们使用流感疫苗抗原，研究了激活RIG-I途径对抗原特异性适应性免疫反应的影响。我们发现，用与RIG-I配体5'ppp双链RNA（dsRNA）共同给药的流感疫苗抗原免疫的小鼠，产生了高水平的血凝抑制抗体、增强的生发中心反应和T滤泡辅助细胞反应。此外，RIG-I激活增强了引流淋巴结、脾脏和骨髓中的抗体亲和力成熟和浆细胞反应，并赋予了针对病毒攻击的保护性免疫。重要的是，RIG-I途径的激活能够在诱导最佳流感特异性细胞和体液反应（包括保护性免疫）时将抗原需求降低10至100倍。5'ppp-dsRNA诱导的效应显著依赖于I型IFN和IPS-1（RIG-I途径下游的衔接蛋白）信号传导，但独立于MyD88和TLR3介导的途径。我们的结果表明，激活RIG-I样受体途径可调节先天免疫，即使在低抗原剂量下也能在质量和数量上增强保护性细胞适应性免疫反应，这表明RIG-I配体作为病毒疫苗分子佐剂的潜在效用。
最近发现的RIG-I样受体（RLR）的RNA解旋酶家族是宿主防御机制的关键组成部分，负责检测病毒并触发有助于控制病毒复制和传播的先天抗病毒细胞因子。在这项研究中，我们表明RLR途径可被有效利用以增强针对病毒感染的适应性免疫和保护性免疫记忆。我们的结果表明，RIG-I途径的激活与流感疫苗接种一起可调节先天免疫，以诱导针对大流行性流感病毒的质量和数量上更优越的保护性适应性免疫。更重要的是，接种疫苗时RIG-I的激活即使在低疫苗抗原剂量下也能诱导强烈的适应性反应。这些结果突出了利用RIG-I途径增强病毒疫苗特异性免疫的潜在效用，并对一般设计更好的疫苗具有更广泛的意义。
