The goal of this project is to address basic knowledge gaps relating to memory CD8 T cell mediated protection against respiratory virus infections. Our goal is to provide mechanistic experimental insight into the cellular basis for immunity to respiratory virus infection and thus, we will employ the sophisticated reagents and range of respiratory virus infection models available in mice. In this way, we expect to identify both common and pathogen-specific aspects of memory CD8 T cell immunity against viruses that cause respiratory infection. These studies cannot be carried out in humans for ethical reasons;however, we anticipate that our mechanistic data will provide important information to inform new generation vaccine development. Additionally, to date, efforts devoted towards developing translatable efficient vaccine delivery systems to induce memory CD8 T cell responses against respiratory virus infections remain at their infancy. The long-term goal of this proposal is to utilize our expertise in memory CD8 T cell biology to identify characteristics that permit optimal protective immunity against a spectrum of respiratory viruses. In addition, we will build on novel preliminary data to evaluate translatable approaches (such as the nasal influenza vaccine, Flumist") to prime CD8 T cell responses that can be boosted to provide high level, subtype transcending immunity to respiratory infection. In this proposal, we will build on our exciting preliminary data to address these long-term goals through the following specific aims:
Aim 1. Determine the magnitude and cellular interactions required for memory CD8 T cell immunity against a spectrum of respiratory viral infections including IAV, RSV and MHV- 1.
Aim 2. Define the optimal characteristics for memory CD8 T cell immunity against a spectrum of respiratory viral infections.
Aim 3. Develop novel translational approaches to generate memory CD8 T cells that provide optimal protection against respiratory viral infections.
Respiratory viruses cause severe morbidity and substantial mortality worldwide. Our goals are to understand the basic characteristics of memory CD8 T cells that provide optimal protective immunity against respiratory viruses and develop means to induce protective memory CD8 T cells. Our studies have the potential to inform ongoing efforts to vaccinate against respiratory viruses and thus, improve human health
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|Hartwig, Stacey M; Holman, Kaitlyn M; Varga, Steven M (2014) Depletion of alveolar macrophages ameliorates virus-induced disease following a pulmonary coronavirus infection. PLoS One 9:e90720|
|Slutter, Bram; Pewe, Lecia L; Kaech, Susan M et al. (2013) Lung airway-surveilling CXCR3(hi) memory CD8(+) T cells are critical for protection against influenza A virus. Immunity 39:939-48|
|Fulton, Ross B; Weiss, Kayla A; Pewe, Lecia L et al. (2013) Aged mice exhibit a severely diminished CD8 T cell response following respiratory syncytial virus infection. J Virol 87:12694-700|