Mucosal Mechanisms of Control of Influenza

描述（由申请人提供）：流感每年在当地和全球传播，导致呼吸道疾病和死亡。新的和可传播的流感毒株（突变的或重组的）迅速传入易感人群，会助长流行病。流感是一种粘膜疾病，其目标是不同的解剖部位，上呼吸道和下呼吸道粘膜，每一个都可能是疫苗介导保护的独立目标。可通过接触手上的大颗粒污染物（到结膜和鼻子）、中等大小的颗粒从上呼吸道（到鼻子和气管）以及非常小的颗粒从肺深处（到肺肺泡）传播。带有传染性病毒的病毒血症不太常见。在血液中检测到的病毒RNA，例如在患有严重H5N1禽流感的患者中，可能来自肺部的高病毒负担。天然免疫和疫苗诱导免疫抵抗原发性感染的机制包括：1)病毒特异性粘膜（特别是分泌IgA [S-IgA]）和来自记忆B细胞的全身（特别是IgG）抗体；2)粘膜先天免疫因子延缓病毒结合和上皮感染；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，CD4+ T细胞调节CD8+ T细胞和B细胞。基于病毒对鼻腔、气管和肺泡唾液酸受体的选择性，人类流感毒株可感染上呼吸道和下呼吸道，而禽流感毒株可能更有选择性地感染下呼吸道。发病率和死亡率与下呼吸道感染的关系更大。这种部位特异性感染和并发症强调需要评估室特异性防御。在儿童和成人中，减毒鼻用活疫苗对流感的保护作用与灭活肠外疫苗相当或更好。然而，每种疫苗的体液反应在全身和粘膜部位是不同的，而体液反应是防御初次流感感染最重要的。据报道，与灭活的肠外疫苗相比，鼻减毒活疫苗在血液中引起的流感特异性IgG水平较低，而在鼻咽部引起的特异性粘膜S-IgA水平略高。IgG可能有助于肺部的保护，而特异性S-IgA则有助于上呼吸道和下呼吸道的防御。我们建议表征这两种解剖学上不同的疫苗在人类中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，特别是在肺部。

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.