Mucosal Mechanisms of Control of Influenza

描述（由申请人提供）：流感每年传播为呼吸道疾病和死亡的地方和全球流行病。新的和可传播的流感病毒株（突变或重组）迅速引入易感人群，助长了流行病。流感是一种针对不同解剖部位（上呼吸道和下呼吸道粘膜）的粘膜疾病，其中每个部位都可能是疫苗介导的保护的独立靶点。通过接触手上的大颗粒污染物（到结膜和鼻子），通过接触上呼吸道的中等大小颗粒（到鼻子和气管），以及通过接触肺部深处的非常小的颗粒（到肺部的肺泡），可能会发生传播。感染性病毒的病毒血症不太常见。血液中检测到的病毒RNA，例如，严重的禽H5 N1疾病，可能源于肺中的高病毒负荷。针对原发感染的天然和疫苗诱导的免疫机制包括1）来自记忆B细胞的病毒特异性粘膜（特别是分泌型伊加[S-IgA]）和全身（特别是IgG）抗体，2）粘膜先天免疫因子，以延缓病毒结合和上皮感染，和3）T细胞。细胞毒性CD 8 + T细胞[CTL]在解决已建立的感染中可能是最重要的，并且CD 4 + T细胞调节CD 8 + T和B细胞。基于病毒对鼻、气管和肺泡唾液酸受体的选择性，人流感病毒株可感染上呼吸道和下呼吸道，而禽流感病毒株可更具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密切。这种部位特异性感染和并发症强调需要评估隔室特异性防御。在儿童和成人中，减毒鼻用活疫苗提供与灭活肠外疫苗相当或更好的保护。然而，体液反应，这是最重要的防御初始流感感染，每种疫苗不同的全身和粘膜部位。据报道，与灭活的胃肠外疫苗相比，减毒活鼻疫苗在血液中引起较低水平的流感特异性IgG，在鼻咽中引起略高水平的特异性粘膜S-IgA。IgG可能有助于保护肺，特异性S-IgA有助于上呼吸道和下呼吸道防御。我们建议在与流感控制相关的不同部位描述这2种解剖学上不同的疫苗在人体中引起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.