Immune mechanisms underlying COVID-19 pathology and post-acute sequelae of SARS-CoV-2 infection (PASC)

With a global tally of more than 500 million cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections to date, there are growing concerns about the post-acute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Recent studies suggest that exaggerated immune responses are key determinants of the severity and outcomes of the initial SARS-CoV-2 infection as well as subsequent PASC. The complexity of the innate and adaptive immune responses in the acute and post-acute period requires in-depth mechanistic analyses to identify specific molecular signals as well as specific immune cell populations which promote PASC pathogenesis. In this review, we examine the current literature on mechanisms of immune dysregulation in severe COVID-19 and the limited emerging data on the immunopathology of PASC. While the acute and post-acute phases may share some parallel mechanisms of immunopathology, it is likely that PASC immunopathology is quite distinct and heterogeneous, thus requiring large-scale longitudinal analyses in patients with and without PASC after an acute SARS-CoV-2 infection. By outlining the knowledge gaps in the immunopathology of PASC, we hope to provide avenues for novel research directions that will ultimately lead to precision therapies which restore healthy immune function in PASC patients.