W194 - Latent Cytomegalovirus Infection Is Associated with Distinct Single Cell Immune Signatures and Diminished Anti-viral Responses in Older Adults

Chris Verschoor – Health Sciences North Research Institute, Sudbury, ON, Canada; Siddhartha Sharma – The Rockefeller University, New York, NY 10065, USA; Radu Marches – The Jackson Laboratory for Genomic Medicine, Farmington, CT 06030, USA.; Djamel Nehar-Belaid – The Jackson Laboratory for Genomic Medicine, Farmington, CT 06030, USA; Kenneth Schmader – Division of Geriatrics, Department of Medicine and Duke Center for the Study of Aging and Human Development (Aging Center), and GRECC, Durham VA Health Care System, Durham, NC, USA.; Cathleen Colon-Emeric – Division of Geriatrics, Department of Medicine and Duke Center for the Study of Aging and Human Development (Aging Center), and GRECC, Durham VA Health Care System, Durham, NC, USA.; Heather Whitson – Division of Geriatrics, Department of Medicine and Duke Center for the Study of Aging and Human Development (Aging Center), and GRECC, Durham VA Health Care System, Durham, NC, USA.; Jacques Banchereau – Immunoledge LLC, Montclair, NJ, USA; Duygu Ucar – The Jackson Laboratory for Genomic Medicine, Farmington, CT 06030, USA.; George Kuchel – UConn Center on Aging, University of Connecticut School of Medicine, Farmington, CT, USA

Abstract Text: Cytomegalovirus (CMV) is one of the most common chronic viral infections worldwide. Although largely asymptomatic, it is known to be associated with worse outcomes of respiratory infection and vaccine responsiveness in older adults. To date, no systemic studies have described CMV seropositivity-related transcriptional signatures at the single-cell (sc) level in both resting and ex vivo stimulated peripheral blood mononuclear cells (PBMCs). In this study, we employed scRNAseq to investigate the impact of CMV seropositivity on PBMC composition, transcriptional profiles, and cellular responses within an age, sex, and race-matched cohort of healthy adults aged 60 and older (n=27). Our findings confirmed known CMV-associated cell compositional changes, such as the expansion of the CD8+ T effector memory compartment including TEMRAs and GZMK+ cells, and revealed CMV-associated expansions in other populations including age-associated B cells, gamma-delta (γδ) T-cells, and CD56dim NK-cells. Additionally, we uncovered elevated expression of cytotoxicity related genes (GNLY, PRF1, NKG7) in CMV seropositive individuals (n=14) compared to CMV seronegative donors (n=13) in γδ T-cells, TEMRAs, GZMK+ CD8, and CD56dim NK-cells. Interestingly, upon ex vivo stimulation with live influenza virus, cells from CMV+ donors had significantly reduced antiviral responses compared to CMV- donors across all immune subsets, suggesting that CMV infections might negatively affect viral immune resilience. As a whole, our comprehensive single-cell level analysis sheds new light on the complex interactions between CMV and the aging host immune system and the immune responses to the influenza virus.