Global lifespans are longer than ever before and there is an increasing shift towards a more aged global population. Also, the majority of severe disease and deaths in the recent and ongoing COVID-19 pandemic is found in individuals over 60 years of age. Therefore, there is an urgent need to gain insight into how the immune system changes with age; specifically: (1) what are the drivers of chronic, systemic inflammation (‘inflammaging’) that occur in some but not all older individuals and (2) how, in turn, numerical aging and chronic inflammation collide to impact anti-viral immunity and lead to poor infection outcomes. In this body of work, two focused research questions were addressed as part of an overarching goal to determine the links between numerical age, chronic inflammatory status, and immune cell function. First, the role of iNKT cells in the inflammation found with ART-suppressed HIV infection and aging was studied, and second, connections between age and pre-existing immunity to SARS-CoV-2 were investigated.
Invariant natural killer T (iNKT) cells are a unique, innate-like T cell subset known to bridge innate and adaptive immune responses and can exert inflammatory and immunosuppressive effector functions. The role of iNKT cells in the chronic inflammation found with ART-suppressed HIV infection and/or normal aging is unclear. Therefore, iNKT cell frequencies and surface phenotypes were measured from a HIV and Aging cohort comprised of ART-suppressed HIV+ subjects and matched uninfected controls stratified by age into younger and older groups and iNKT cell signature were correlated with plasma markers of chronic inflammation. Specific characteristics of iNKT cells were associated with aviremic HIV infection and/or advanced age, and distinct links between iNKT cell signatures and markers of chronic inflammation were found. Further, multivariate analysis (PLS-DA) of the collected dataset revealed that iNKT cell and plasma markers stratified younger from older subjects within both the uninfected and aviremic HIV+ groups.
Older age is arguably the strongest predictor of severe clinical outcomes and mortality after SARS-CoV-2 infection. The role of pre-existing, cross-reactive immunity in COVID-19 outcomes is unclear to date. A newly developed, highly sensitive serological assay (the BU ELISA) was used to elucidate links between pre-existing immunity to SARS-CoV-2 and age. We found SARS-CoV-2 receptor binding domain (RBD) and/or nucleocapsid protein (N) reactive antibodies (IgG, IgM, and/or IgA isotypes) in all pre-pandemic subjects tested, with a wide range in antibody levels. SARS-CoV-2 reactive immunoglobulin levels tracked with antibodies specific for analogous viral proteins from endemic coronavirus strains and were lowest in subjects over 70 years of age compared with younger counterparts. In sum, these findings provide evidence of lower pre-existing immunity to SARS-CoV-2 in elderly individuals, and this may account for their poor infection outcomes.
In conclusion, the findings in this work provide new insight into the impact of age and chronic inflammation on productive and protective immune responses. These results underscore the need for further investigations into the immune cell mechanisms and inflammaging pathways that subvert healthy aging.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/44028 |
| Date | 15 March 2022 |
| Creators | Yuen, Rachel Ruby |
| Contributors | Snyder-Cappione, Jennifer |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
| Rights | Attribution 4.0 International, http://creativecommons.org/licenses/by/4.0/ |
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