The elderly have the highest tuberculosis (TB) case rate compared to other age groups and are the most susceptible group for TB-associated death. However, we do not yet understand the specific mechanisms by which persistent Mycobacterium tuberculosis (M.tb) infection impacts the aging immune system or conversely, how aging contributes to the progression of latent M.tb infection to active disease. The goal of the current project is to determine the impact of aging and inflammaging on T cell control of M.tb in mice. Similar to humans, mice become more susceptible to developing primary TB or to reactivation of latent M.tb as they grow older. Thus, the aged mouse model is a good model for understanding basic principles of TB infection and immune control in the elderly. Our preliminary data show an enhanced inflammatory signature in the lung and circulation of old M.tb infected mice, and that senescence-associated immune parameters of T cells are elevated in M.tb infected mice as they age. To fully address both primary infection and reactivation of TB in the elderly, the following Aims will be performed.
Aim 1 : Determine the impact of inflammaging on susceptibility of old mice to infection with M.tb.
Aim 2 : Determine the role of senescence mediators on persistent M.tb infection. At the completion of these studies we will have provided mechanistic information on how inflammaging and immune senescence impact M.tb infection. This information is likely to be essential for understanding and managing TB disease in the elderly.
Our understanding of how aging of the immune system impacts control of M. tuberculosis infection is limited. The studies in Project 3 will use the mouse model to elucidate the mechanism of immune control during primary TB and reactivation of latent M.tb infection in old age. Our findings are likely to extend our understanding and management of TB disease in the elderly as well as other infectious diseases.
