Program Director/Principal Investigator (Last, First, Middle): Harty, John T. Influenza infection is a major public health menace and our current strategies of seasonal influenza vaccination provide suboptimal protection. Thus, it is critical to provide basic, mechanistic insights into the possibility of universal influenza vaccines. In the absence of neutralizing antibodies, the presence of IAV-specific memory CD8 T cells targeting conserved viral proteins such as NP or M2, which are maintained systemically as well as in the lung correlate with control of viral titers and reduction of disease symptoms in humans. Mouse models confirm the potency of IAV specific memory CD8 T cells to provide strain-transcending heterosubtypic immunity, but also suggest it is the lung resident memory CD8 T cells (Trm) that enable swift and robust protection against IAV infection. Thus, establishing a robust long-term Trm population in the lung may be an important goal for an IAV vaccine. However, evidence from our own lab and others shows that lung Trm gradually wane in numbers with time, resulting in a loss of protective immunity. Our long-term goal is to understand the biology of IAV-induced Trm and how these cells can be manipulated to enhance immunity. We will address this long-term goal with the following specific aims: Specific Aim 1. Dissect the metabolic and genetic factors underlying compromised Trm survival in the lung compared to skin. Specific Aim 2. Determine if lung Trm can be efficiently restored by boosting and the consequences on lung physiology and protection from IAV. Specific Aim 3. Visualize the dynamics of Trm responses to secondary infection in lung OMB No. 0925-0001/0002 (Rev. 03/16 Approved Through 10/31/2018) Page Continuation Format Page