Investigating the Role of Epstein-Barr Virus in Long COVID Pathogenesis

PROJECT SUMMARY/ABSTRACT SARS-CoV-2 infection can result in the development of a constellation of persistent sequelae following acute disease, which is known as Long COVID. Individuals diagnosed with Long COVID frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions; however, the basic biological mechanisms responsible for these debilitating symptoms are unclear. Previously, this research group profiled 177 individuals in an exploratory, cross-sectional study encompassing multi-dimensional immune phenotyping in conjunction with machine learning. Key immunological features distinguishing Long COVID were identified and described in the Mount Sinai Yale -Long COVID (MY-LC) study. A striking finding was an elevation in antibodies to lytic antigens of Epstein-Barr Virus (EBV) in Long COVID participants, which may be indicative of more recent reactivation of EBV in these patients. In addition, levels of these antibodies correlated with IL-4, IL-6 cytokine double-producing CD4+ T- cells, which suggests that EBV reactivation is not merely incidental but reflects, mediates or aggravates immune perturbations in these patients. The overarching goal of this proposal is to provide a thorough insight into whether EBV reactivation contributes to LC disease pathogenesis and symptomatology, building on current literature. The research plan proposed will utilize the Iwasaki lab's expertise in in vitro and in vivo modeling to assess whether SARS-CoV-2 infection can reactivate EBV and contribute to lasting sequelae, as described in Aim 1. Aim 2 will leverage large patient cohorts previously recruited through the MY-LC study and robust sample and data availability to test whether patients with Long COVID characterized by recent EBV reactivation experience unique immune alterations. Aim 2 will also test whether these responses correlate to unique symptoms. The findings uncovered by these studies have the potential to deepen understanding of one cause of Long COVID, and to inform future treatment of a growing, currently largely-untreated patient population. Mentorship from an interdisciplinary group of collaborators, who are experts in the proposed techniques, will facilitate this applicant's training as an independent immunologist.