Mucosal Mechanisms of Control of Influenza

描述(申请人提供)：流感每年传播为呼吸系统疾病和死亡的局部和全球流行。新的、可传播的流感毒株(突变或重组)迅速传入易感人群，从而助长了流行病。流感是一种粘膜疾病，其目标是不同的解剖部位，即上呼吸道和下呼吸道粘膜，每个粘膜都可能是疫苗介导的保护的独立靶点。传播可通过接触手上的大颗粒(到结膜和鼻子)、来自上呼吸道的中等大小的颗粒(到鼻子和气管)以及从肺深处的很小的颗粒(到肺中的肺泡)来传播。带有传染性病毒的病毒血症较少见。在血液中检测到的病毒RNA，例如患有严重H5N1禽流感的患者，可能来自肺部的高病毒负荷。针对初次感染的自然免疫和疫苗诱导免疫机制包括：1)病毒特异性粘膜(尤其是。分泌型免疫球蛋白A[S-免疫球蛋白A])和全身性(尤其是来自记忆B细胞的抗体，2)粘膜天然免疫因子，以延缓病毒结合和上皮感染，以及3)T细胞。细胞毒性CD8+T细胞[CTL]可能最重要的是解决已建立的感染，而CD4+T细胞调节CD8+T细胞和B细胞。根据病毒对鼻腔、气管和肺泡唾液酸受体的选择性，人类流感病毒株可能同时感染上呼吸道和下呼吸道，而禽类病毒株可能更有选择性地感染下呼吸道。发病率和死亡率更多地与下呼吸道感染有关。这种特定部位的感染和并发症强调了评估特定间隔防御的必要性。在儿童和成人中，减毒活鼻疫苗与灭活非肠道疫苗相比，提供了与流感疾病相当或更好的保护。然而，在防御最初的流感感染中最重要的体液反应，对每种疫苗的全身和粘膜部位的反应是不同的。据报道，与灭活疫苗相比，减毒活疫苗在血液中诱导出较低水平的流感特异性Ig G，在鼻咽中诱导出较高水平的粘膜特异性S-Ig A。免疫球蛋白可能对肺部有保护作用，而S-免疫球蛋白A可能对上呼吸道和下呼吸道有保护作用。我们建议表征这两种解剖上不同的疫苗在人类体内与流感控制相关的不同部位引发的功能性抗病毒活性，为预测保护性反应提供必要的工具，包括异型全身和粘膜反应，特别是在肺中。

DESCRIPTION (provided by applicant): Influenza disseminates each year into local and global epidemics of respiratory illness and death. Epidemics are fostered by the rapid introduction of new and transmissible influenza strains (mutated or recombinant) into susceptible human populations. Influenza is a mucosal disease which targets distinct anatomic sites, the upper and lower respiratory mucosae, each of which may be an independent target for vaccine-mediated protection. Transmission may occur from contact with large particle fomites on hands (to conjunctiva and nose), with moderate size particles from the upper respiratory tract (to nose and trachea), and with very small particles from deep in the lung (to alveoli in lung). Viremia with infectious virus is less common. Viral RNA detected in blood, e.g., with severe avian H5N1 disease, likely derives from a high viral burden in the lung. Mechanisms of natural and vaccine-induced immunity against primary infection include 1) virus- specific mucosal (esp. secretory IgA [S-IgA]) and systemic (esp. IgG) antibodies from memory B cells, 2) mucosal innate immune factors to retard viral binding and infection of epithelium, and 3) T cells. Cytotoxic CD8+ T cells [CTL] may be most important is resolving established infection, and CD4+ T cells regulate both CD8+ T and B cells. Based on viral selectivity for nasal, tracheal and alveolar sialic acid receptors, human influenza strains may infect both the upper and lower airways, whereas avian strains may more selectively infect the lower. Morbidity and mortality are related more to infection of the lower respiratory tract. Such site- specific infection and complications stress the need to evaluate compartment-specific defenses. Live attenuated nasal vaccine provides comparable or better protection than inactivated parenteral vaccines vs. influenza disease in children and adults. However, humoral responses, which are most important in defense against initial influenza infection, to each vaccine differ at systemic and mucosal sites. Compared with inactivated parenteral vaccine, live attenuated nasal vaccine is reported to elicit lower levels of influenza- specific IgG in blood and somewhat higher levels of specific mucosal S-IgA in the nasopharynx. IgG likely contributes to protection in the lung, and specific S-IgA to both upper and lower respiratory defenses. We propose to characterize functional antiviral activities elicited by these 2 anatomically-diverse vaccines in humans in distinct sites relevant to control of influenza, providing tools essential for predicting protective responses, including heterotypic systemic and mucosal responses, especially in the lung.