Laura Haynes, Ph.D.
Professor of Immunology, UConn Center on Aging
My research is focused on trying to understand how aging impacts the immune response to viral infections such as influenza. Older people are much more vulnerable to influenza and exhibit higher levels of morbidity and mortality upon infection. Importantly, age-related changes in the immune system contribute to this and are responsible for the slower clearance of virus and resolution of infection. Our work is focused on understanding these changes, identifying the mechanisms involved and proposing strategies to prevent or overcome these age-related deficiencies.
We were the first to demonstrate that intrinsic age-related changes in CD4 T cells contribute significantly to reduced immune responses in older individuals. This is important because CD4 T cells are critical for generating a high quality, robust immune response to infections such as influenza. Age-related changes compromise the ability of CD4 T cells to differentiate into specific functional subsets resulting in a multitude of dysregulated responses, including delayed viral clearance and prolonged inflammation during influenza infection. Most notably, the ability of aged influenza-specific CD4 T cells to differentiate into highly functional T follicular helper (Tfh) and type 1 helper (Th1) subsets is significantly impaired. Importantly, we have also demonstrated that naïve CD4 T cells have a longer post-thymic lifespan in aged mice and that during their extended sojourn in the aged periphery, naïve CD4 T cells develop functional defects. This suggests that the aged environment might be having a negative impact on CD4 T cell function. One of the hallmarks of the aged environment is the accumulation of senescent cells. The number of senescent cells increases with chronological aging, resulting in many age-related pathologies and diseases. Factors secreted by senescent cells can also have a direct impact on surrounding cells, driving dysfunction and influencing cell subset differentiation. Interestingly, many of these factors are cytokines that also drive Type 2 helper (Th2) and regulatory CD4 T cell subset differentiation, both of which are not conducive to rapid viral clearance. Thus, we are using a mouse model to explore the impact of senescent cells on the immune response to influenza vaccination and subsequent infection. Understanding the role of senescent cells in the development of an anti-viral immune response can help us develop strategies to mitigate their influence and keep older folks healthier during influenza season.
Another aspect of our work is focused on examining how influenza infection negatively impacts skeletal muscle gene expression and function. Using a well-established mouse model, we have described the first known pathophysiological link between flu infection and declining mobility performance and strength. Active flu infection is entirely localized to the lungs, yet it results in clear functional (voluntary activity, walking, strength) decrements with upregulation of muscle inflammatory and atrophy genes, combined with downregulation of positive regulators of muscle growth. Importantly, the impact of flu infection on these molecular changes and overall functional declines is more pronounced and prolonged with aging. Our primary goal is to identify specific mechanisms linking pulmonary flu infection to declines in muscle health and functional ability. Since there is no direct viral infection of skeletal muscle, we believe systemic factors are at the crux of flu-induced muscle atrophy. Additionally, we believe aged muscle is more sensitive to these factors, resulting in increased flu-induced muscle-localized inflammation, cellular infiltration, and muscle atrophy. Understanding the mechanisms involved can help us develop strategies to preserve muscle strength with aging so that older folks can remain mobile and independent longer.