Age-dependent differences in the immune response to human metapneumovirus

ABSTRACT Human metapneumovirus (HMPV) is a leading cause of lower respiratory infections in young children, immunocompromised persons, and the elderly, resulting in high morbidity and mortality. Few studies have investigated why HMPV is more severe in the elderly. This proposal aims to fill this knowledge gap about HMPV pathogenesis. My preliminary data discovered that aged mice infected with HMPV exhibit delayed viral clearance, increased lung inflammation, and increased CD8+ HMPV-tetramer+ cells co-expressing the inhibitory markers PD-1, TIM-3, and LAG-3. I hypothesize that severe HMPV infection in the elderly is caused by impairment of the CD8+ T cell response. In Aim 1, I will investigate the intrinsic causes of the CD8+ T cell impairment observed in the aged host infected with HMPV using 10X Multiomics studies on murine lung directly ex vivo and syngeneic transplants. 10X Multiomics will elucidate age-related epigenetic changes in CD8+ T cells while syngeneic transplants will transfer young CD8+ T cells into an aged host and vice versa to determine if CD8+ T cells are the primary immune cells causing the impaired immune response to HMPV (i.e. increased weight loss, clinical severity, delayed viral clearance). In Aim 2, I will investigate extrinsic causes of the CD8+ T cell impairment, namely by alveolar macrophages (AMs). I will use a 21-color multispectral flow cytometry panel to enumerate M1 and M2 macrophage populations in the aged host. In vitro co-culture and transwell assays of AMs and CD8+ T cells will determine if AMs directly impair CD8+ T cells. Selective depletion of AMs in aged mice and adoptive transfer of young macrophages will determine how AMs contribute to the impaired immune response in the aged host. 10X Multiomics will also be performed in this aim to investigate the age-related epigenetic changes in AMs that may contribute to their aberrant M2 accumulation, which I have also observed in my preliminary data. This proposal aims to understand the mechanistic differences in the aged host response to HMPV, which will help elucidate why HMPV infection in the elderly is more severe. These studies have the potential to translate into the clinical setting and contribute to better management and treatment for HMPV infection, such as immunomodulation. Identifying molecular targets in the aged host will guide development of a safe and effective vaccine against HMPV for all at-risk populations. In addition, this proposal has tremendous training opportunities, contributing towards my career goals of becoming a clinician scientist and independent principal investigator in immunology and infectious disease.