Inflammatory Dendritic Cells in Influenza Virus Infection

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Description (provided by applicant): Influenza virus causes severe respiratory infections leading to morbidity and mortality worldwide. Virus replication is limited to the epithelial layers of the respiratory tract and recovery is dependent upon the generation of an effective cellular immune response. Dendritic cells (DC) are immune system sentinels found in a network below the epithelium making them ideally suited to interact with invading pathogens. DC activation occurs when they engulf microbes and identify microbial structures using genetically coded pathogen recognition receptors. Following activation the DCs traffic to peripheral lymphoid tissue where they stimulate specific T cells. In influenza virus infection, the activated T cells return to the lungs and kill infected target cells leading to viral clearance and host recovery. In our mouse studies DCs bearing viral antigens began to arrive in draining lymph nodes (LN) 48 hours after infection (PI) with influenza virus and a concomitant upregulation of genes that code for inflammatory mediators was observed in the lungs of infected mice. This delay in adaptive immunity seems excessive in light of the high viral titers (105 in 25 ul lung lysates at 24 hours) and the close proximity of resident DCs to epithelial cells. The NS1 protein of influenza virus prevents the release of innate effectors such as type I interferon from infected cells. We have shown that it also blocks activation of DCs in vitro inhibiting the release of cytokines, chemokines and other inflammatory mediators. In infected animals, the inhibition by NS1 may allow virus to replicate without triggering immune intervention. However, beginning 48 hours after infection there is a rapid influx of mononuclear cells to the lungs that greatly increases the cell numbers in this organ. A significant proportion of these cells are monocytes known to give rise to both DCs and resident macrophages. We hypothesize that immune attractants and inflammatory mediators are released from a cell population in the lungs when virus titers reach very high levels and trigger the cellular influx. Furthermore, we speculate that the newly arriving monocytes are primarily responsible for carrying viral antigens to the draining lymph nodes and activating virus specific T cells. Which mediators are responsible for the recruitment of mononuclear cells to the infected lungs and what role the infiltrating cells play in the generation of adaptive immunity are the primary questions we will attempt to answer in this application.