T Cell Homeostasis and Function in Immune Senescence

The premise of this project is that studying immune aging in laboratory mice that are experiencing a natural burden of major infectious, psychological and physical stressors will better mirror and inform immune aging in humans. Old age is accompanied by increased vulnerability to infectious diseases, due to the aging of the immune system. Immune aging is, in turn, substantially influenced by the presence of a lifelong, persistent infection with the cytomegalovirus (CMV). In the past period of this award, we studied mouse CMV (mCMV) in isolation (as a latent persistent mono-insult). We concluded that mCMV substantially degraded the healthspan of mice, but only in the presence of major stressors, such as ionizing radiation or another infection. We propose to advance studies of mCMV and immune aging in mice experiencing a natural burden of major infectious, psychological and physical stressors that are likely to be encountered by humans repeatedly during the lifespan. We hypothesize that life-long latent mCMV infection contributes to the demise of T-cell and global immune function, directly proportional to the stress-induced viral reactivation and loss of immune control over mCMV. To test this, animals will be exposed to (i) low dose ionizing radiation; or (ii) low dose stress hormone corticosterone; (iii) non- specific pathogen free (non-SPF) microbiota, which has been shown to induce the immune system in SPF mice to become similar to that of humans. We will test how this impacts mCMV reactivation and immune responses to vaccination and lethal infection. We will ask: SA1. Do repeated individual stressors, commonly experienced by humans, worsen the impact of mCMV on immune function with age? SA2. Is the impact of life stressors on immune aging and overall health in mCMV-positive mice caused by CMV DNA replication/reactivation? These experiments will, for the first time, introduce key physiological variables of importance to human immune aging into a well-controlled murine model of mCMV, aging and infection. We anticipate that this poly-insult model will substantially mirror immune aging in humans, and provide ground for new discoveries that will pave the way for combined antiviral and stress-control therapies to improve T cell and overall immunity and healthspan outcomes in aging.