Type A influenza virus (IAV) is a major human pathogen with the capacity to rapidly spread world-wide and to produce severe and sometimes fatal infections resulting in severe pneumonia. Evidence accumulating over the past several decades strongly suggests that disease produced by IAV infection not only reflects the extent of virus replication in the respiratory tract, but also the strength or magnitude of the host innate ad adaptive immune response. Our laboratory has had longstanding interest (over 30 yrs duration) in understanding the role of the adaptive immune CD8+ CTL (CD8+ Te) response in IAV clearance from the infected lungs and in the development of associated pulmonary inflammation and injury. This renewal application builds on recent findings from our laboratory suggesting that pro-inflammatory mediator production by CTL is triggered by recognition of IAV antigen bearing CD45+ inflammatory cells infiltrating the IAV infected pulmonary interstitium while CTL encounter with and recognition of CD45- IAV infected respiratory epithelial cells results in the elimination of these productively-infected cells without triggering inflammatory mediator production of the CTL. The studies described here, which utilize a murine model and primary human cells, are designed to identify the CD45+ inflammatory cell types within the IAV infected respiratory tract that trigger CTL, and the role of costimulatory ligands displayed by these cells in triggering mediator production by CTL. Companion studies will examine the interaction of CTL with CD45- IAV infected respiratory epithelial cells using differentiated primary epithelial cells. We will use this information to explore strategies to selectively suppress excess pulmonary inflammation associated with CTL recognition of CD45+ inflammatory cells in the IAV infected lungs without altering virus clearance from lungs.
The Specific Aims of this program are: 1) To evaluate the contribution of specific CD45+ Inflammatory Cell subsets in the induction of pro-inflammatory mediator production by IAV-specific CTL in the infected RT;2) To determine the properties of murine and human respiratory epithelial cells (REC) which renders these cells capable of triggering CD8+ Te-mediated cytolysis, but not pro-inflammatory cytokine production;3) To assess the impact of modulation of co-stimulatory ligands on CTL effector activity in vivo, virus elimination and pulmonary inflammation. The proposed studies should provide a framework for the development of new therapeutic strategies to control the severity of IAV infection.

Public Health Relevance

Type A influenza virus is a major human pathogen with the capacity to produce epidemic disease (seasonal infections) as well as pandemic disease resulting in infections on a worldwide scale with morbidity and mortality measurable in the millions. The recent outbreak of the novel H1N1 swine influenza infection highlights the speed with which this virus can spread around the world as well as its potential to infect a large fractin of the world's population. Research over the past several decades has provided strong evidence that the disease which influenza virus infection produces is not only due to the ability of the virus to replicate in the human respiratory tract and kill the cells there in which it repliates but also reflects the response of the body's immune system to infection. Consequently the stronger/more vigorous the immune response to influenza infection in the respiratory tract the more likely it is that we will experience severe disease such as influenza pneumonia. The research program described in this application explores in both an experimental mouse model and in the human how infection of different cell types in lungs can affect the ability of the body'immune T-cells to eliminate infected cells and to produce inflammatory products which increase lung inflammation. It also explore strategies by which we can eliminate or decrease the amount of inflammation produced by the immune system during infection without altering the ability of the immune system to clear influenza virus from lungs.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Virology - B Study Section (VIRB)
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Hauguel, Teresa M
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University of Virginia
Schools of Medicine
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