Fig. 3: Transition of SARS-CoV-2 Infection to Virus-free PASC: Pathophysiological Mechanisms.

Post-acute sequelae of COVID-19 (PASC) or long-COVID refers to a broad spectrum of symptoms and signs that are persistent, exacerbated, or new clinical incidents in the period that prolongs after acute SARS-CoV-2 infection. In acute COVID-19, the SARS‐CoV‐2 genome and its products critically reprogram and dysregulate human metabolism (HMRD) at transcription, translation, and post-translational modification (PTM) levels. Interaction of SARS-CoV-2 proteins with specific host cellular targets rewires sugar-, amino acid-, lipid-, and nucleotide-metabolism(s), as well as alters or impairs bioenergetics, immune response, and redox homeostasis in the body, to facilitate viral replication and propagation^21,22. However, several recoverees or survivors of COVID-19 (RT-PCR negative for SARS-CoV-2) continue to exhibit a plethora of clinical symptoms with impairment(s) of multiple organ systems. Accordingly, PASC or long-COVID is a virus-free, ‘new onset’ pathophysiological condition extending from a virus-induced HMRD. The HMRD in PASC pathology is a cumulative clinical outcome of several causative mechanisms comprising both SARS-CoV-2-derived virulence factors, as well as a multitude of host cellular factors and innate responses. A plethora of PASC clinical symptoms and related metabolic impairments indicate an involvement of different pathobiological mechanisms.