Grant: Operating Grant

Influenza virus remains a serious threat to human health. Each year, seasonal epidemics are estimated kill approximately 500,000 people worldwide, mainly those with the weakest immune systems, such as the very young and the very old. Periodically, new variants of influenza arise to which most people are not immune and these cause pandemics that infect large segments of the population and can have devastating impact, such as occurred with the 1918 influenza pandemic. In addition, there are concerns about new avian influenza strains that are highly lethal to humans, but so far have not shown ability to easily spread between people. There is much interest in developing a universal influenza vaccine that would protect against multiple influenza variants. The immune systems uses two major mechanisms to control an influenza infection. One is to make antibodies that block the binding of the virus to cells, such that virus can't infect. The second is to use T cells to kill infected cells and prevent those cells from becoming a factory to produce more virus and infect neighboring cells. Although the influenza virus mutates rapidly to avoid antibody responses, the parts of the virus recognized by T cells do not change as much and thus T cells can recognize many variants of influenza virus. However, a limitation of a universal influenza vaccine based on inducing T cell responses is that T cell responses to influenza are only transiently boosted by reinfection and in old age become weak. Our laboratory is studying ways to improve the longevity of the T cell response to influenza virus. We focus on a family of molecules called tumor necrosis factor receptors (TNFRs). We recently showed that two members of this family play a key role in enhancing T cell immunity to influenza virus. In this study we will investigate how these molecules improve immunity to influenza virus, with a view to designing better, longer lasting vaccines and ways of measuring a protective response.