Interaction between influenza virus and H. influenzae

描述（由申请人提供）：流感病毒感染与继发性细菌感染（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可引起肺炎或脑膜炎，并导致相当高的发病率和死亡率，特别是在幼儿、衰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，高毒力的流感毒株，无论是自然产生的还是经过改造的，甚至可能使正常免疫能力的个体在继发性细菌感染后易患严重疾病。然而，尽管这一问题对人类健康具有重要意义，但人们对导致更严重疾病的这些物质之间的相互作用知之甚少。我们已经建立了一个小鼠模型，在这个模型中，我们观察到了流感和流感嗜血杆菌之间的致命协同作用，当这两种药物被顺序施用时。在目前的应用中，我们将进一步发展这个小动物模型，以剖析流感和流感嗜血杆菌相互作用导致严重疾病或致死的机制。我们的假设是，流感和流感嗜血杆菌的连续注射破坏了免疫反应，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起主要作用，并将在这两年的应用中关注这方面的反应。我们将确定i)与单独使用任何一种药物相比，两种药物感染期间细胞因子/趋化因子谱有何不同；ii)细菌或病毒载量的增加是否在细胞因子产生改变中起作用；iii)导致炎症的细胞类型和在肺部诱导的损伤类型；iv)选定的细胞因子在流感嗜血杆菌和流感之间致命协同作用中的作用。在这些研究中获得的数据将进一步加深我们对这两种传染因子如何相互作用的理解，并将为进一步的研究提供坚实的基础。这与R21应用程序的探索性/发展性是一致的。这些研究可能最终导致特定干预措施的发展，以防止同时感染病毒和细菌的个体过度肺部损伤。这在流感大流行期间尤其重要，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.