Igh locus function in immunosenescent mice

ABSTRACT COVID-19 (coronavirus infectious disease 19) is now a global pandemic with over 49.1 million cases to date. COVID-19 is caused by severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2, a member of the coronavirus family. It is striking that eighty percent of COVID-19 related deaths occur in patients aged 65 and over. Immune responses of aged adults undergo immunosenescence which expresses with multiple age dependent changes. Immune senescence is linked to restricted Ig repertoire formation and susceptibility to a variety of virally induced diseases. Older individuals are particularly vulnerable to a range of new and emerging infectious agents perhaps as a result of a less diverse antibody repertoire. However, to identify clinical interventions that mitigate the effects of immunosenescence it is critical to characterize the underlying environmental and cell intrinsic mechanisms leading to the muted adaptive immune responses. Here we propose an exploratory series of studies to examine the pre-selected Ig repertoire in early and mature B cells in young and aged mice to establish whether repertoire deficiencies observed in peripheral B cells of aged individuals originate, at least in part, from impaired V(D)J recombination, class switch recombination, locus conformation and/or Igh enhancer function. Results obtained from this exploratory project will shed light on whether a) limited Ig repertoire diversification results from impaired Igh locus function during V(D)J recombination and class switch recombination, and b) whether Igh locus dysfunction is cell intrinsic.