Interaction between influenza virus and H. influenzae

描述（由申请方提供）：流感病毒感染与细菌继发感染（如流感嗜血杆菌）之间存在明确的联系。这些继发性细菌感染引起肺炎或脑膜炎，并导致相当大的发病率和死亡率，特别是在幼儿、虚弱的老年人和免疫功能低下的个体中。在流感大流行期间，继发性细菌感染也可能显著增加整个人群的死亡率。因此，无论是天然存在的还是工程改造的高毒力流感毒株，在继发性细菌感染时，甚至可能使正常免疫活性个体易患严重疾病。然而，尽管这一问题对人类健康的重要性，这些代理之间的相互作用，导致更严重的疾病知之甚少。我们已经建立了一个小鼠模型，在该模型中我们观察到流感和H。当两种药剂顺序施用时，流感病毒的感染是可能的。在目前的应用中，我们将进一步发展这种小动物模型，以剖析流感和H.流感。我们的假设是流感病毒和H.流感破坏了免疫反应，导致肺部致命的组织损伤。我们认为，异常的细胞因子和趋化因子的产生在这一过程中发挥了重要作用，并将集中在这方面的反应，在这两年的申请。我们将确定i）与单独的任一种试剂相反，在用两种试剂感染期间细胞因子/趋化因子谱如何不同，ii）增加的细菌或病毒载量是否在改变的细胞因子产生中起作用，iii）促成炎症的细胞类型和在肺中诱导的损伤类型，以及iv）选定的细胞因子在H.流感和流感。这些研究中获得的数据将进一步加深我们对这两种感染因子如何相互作用的理解，并为进一步的研究提供坚实的基础。这与R21应用的探索/开发性质一致。这些研究可能最终导致特定干预措施的发展，以防止病毒和细菌共同感染的个体过度肺损伤。这在流感大流行期间可能特别重要，并且可能更广泛地适用于其他呼吸道病毒。

DESCRIPTION (provided by applicant): There is a well-established link between influenza virus infection and secondary infections with bacteria, such as Haemophilus influenzas. These secondary bacterial infections cause pneumonia or meningitis and result in considerable morbidity and mortality, particularly in young children, debilitated elderly and immunocompromised individuals. Secondary bacterial infections may also significantly increase mortality in the human population as whole during influenza pandemics. Thus highly virulent strains of influenza whether naturally-occurring or engineered, could even predispose normal immunocompetent individuals to severe illness upon secondary bacterial infection. However, in spite of the significance of this problem for human health, the interactions between these agents that lead to more severe illness are poorly understood. We have established a mouse model in which we have observed lethal synergy between influenza and H. influenzae when the two agents are administered sequentially. In the current application, we will further develop this small animal model to dissect the mechanisms underlying severe illness or lethality induced by the interaction of influenza and H. Influenzae. Our hypothesis is that sequential administration of influenza and H. Influenzae subverts the immune response resulting in lethal tissue damage in the lung. We suggest that aberrant cytokine and chemokine production plays a major role in this process and will focus on this aspect of the response in this two-year application. We will determine i) how the cytokine/chemokine profile differs during infection with both agents as oppose to either agent alone, ii) whether increased bacterial or viral loads play a role in altered cytokine production iii) the cell types contributing to inflammation and the type of damage induced in the lung and iv) the role of selected cytokines in lethal synergy between H. influenzae and influenza. The data obtained in these studies will further our understanding of how the two infectious agents interact and will provide a firm basis for additional studies. This is consistent with the exploratory/developmental nature of the R21 application. Such studies may ultimately lead to the development of specific interventions to prevent excessive lung damage in individuals co-infected with viruses and bacteria. This could be particularly important during an influenza pandemic and may be more broadly applicable to other respiratory viruses.