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PASC is highly heterogenous and may be associated with multisystem tissue damage\/dysfunction including acute encephalitis, cardiopulmonary syndromes, fibrosis, hepatobiliary damages, gastrointestinal dysregulation, myocardial infarction, neuromuscular syndromes, neuropsychiatric disorders, pulmonary damage, renal failure, stroke, and vascular endothelial dysregulation. A better understanding of the pathophysiologic mechanisms underlying PASC is essential to guide prevention and treatment. This review addresses potential mechanisms and hypotheses that connect SARS-CoV-2 infection to long-term health consequences. Comparisons between PASC and other virus-initiated chronic syndromes such as myalgic encephalomyelitis\/chronic fatigue syndrome and postural orthostatic tachycardia syndrome will be addressed. Aligning symptoms with other chronic syndromes and identifying potentially regulated common underlining pathways may be necessary for understanding the true nature of PASC. The discussed contributors to PASC symptoms include sequelae from acute SARS-CoV-2 injury to one or more organs, persistent reservoirs of the replicating virus or its remnants in several tissues, re-activation of latent pathogens such as Epstein\u2013Barr and herpes viruses in COVID-19 immune-dysregulated tissue environment, SARS-CoV-2 interactions with host microbiome\/virome communities, clotting\/coagulation dysregulation, dysfunctional brainstem\/vagus nerve signaling, dysautonomia or autonomic dysfunction, ongoing activity of primed immune cells, and autoimmunity due to molecular mimicry between pathogen and host proteins. The individualized nature of PASC symptoms suggests that different therapeutic approaches may be required to best manage specific patients.<\/jats:p>","DOI":"10.7554\/elife.86002","type":"journal-article","created":{"date-parts":[[2023,3,10]],"date-time":"2023-03-10T06:15:20Z","timestamp":1678428920000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.86002","source":"Crossref","is-referenced-by-count":234,"title":["Pathogenic mechanisms of post-acute sequelae of SARS-CoV-2 infection (PASC)"],"prefix":"10.7554","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1772-7041","authenticated-orcid":true,"given":"Zaki A","family":"Sherif","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05gt1vc06","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biochemistry & Molecular Biology, Howard University College of Medicine","place":["Washington, District of Columbia, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5323-9507","authenticated-orcid":true,"given":"Christian R","family":"Gomez","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Lung Diseases, National Institutes of Health (NIH), National Heart, Lung and Blood Institute (NHLBI)","place":["Bethesda, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas J","family":"Connors","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00hj8s172","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pediatrics, Division of Critical Care, Columbia University Vagelos College of Physicians and Surgeons and New York - 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