{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T06:01:05Z","timestamp":1792648865828,"version":"4.5.0"},"posted":{"date-parts":[[2026,8,10]]},"group-title":"Immunology","reference-count":112,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Long COVID (LC) \u2013 a chronic condition characterized by persistent, debilitating symptoms following SARS-CoV-2 infection \u2013 has emerged as a major public health challenge. Although many interrelated mechanisms have been proposed as drivers of LC, the root causes have yet to be identified, posing significant challenges for therapeutic development. While many blood-based studies have been conducted, they have not yielded conclusive mechanistic insights into LC pathogenesis. Attention has therefore turned toward direct tissue investigation, with the gastrointestinal (GI) tract becoming a major focus due to evidence that virus or viral components can persist at this site for months to years following an episode of COVID-19. Here, we performed a high-dimensional characterization of colorectal tissue and peripheral blood in a highly characterized cohort of 44 people with LC and 13 recovered controls. We profiled SARS-CoV-2 persistence, host immune responses, and tissue inflammation using bulk and single-cell RNA sequencing, nCounter RNA probe hybridization, quantitative PCR, metagenomic next-generation sequencing, plasma proteomics, high-dimensional spectral flow cytometry, in situ-hybridization\/immunohistochemistry, and single-cell digital spatial omics. Our results support a model in which LC is driven by long-term immune dysregulation and perturbations of the regulatory gut immune environment which imply ongoing viral persistence, although direct viral detection was only observed in a subset of participants. Specifically, we identify a tissue-based transcriptional environment in which SARS-CoV-2 activates innate myeloid immune signaling, driving chronic inflammation while simultaneously downregulating pathways responsible for immune-mediated clearance of infected cells, including antigen presentation, phagocytosis, cytotoxic immune cell trafficking, and granzyme production. Importantly, signatures in peripheral blood are considerably weaker than those observed in tissue. Together, these findings provide a direct biological rationale for therapeutic strategies in LC aimed at enhancing or redirecting cytotoxic immune function to overcome immune dysregulation and clear persistent viral reservoirs.<\/jats:p>","DOI":"10.64898\/2026.08.07.743616","type":"posted-content","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T03:45:14Z","timestamp":1786419914000},"source":"Crossref","is-referenced-by-count":1,"title":["Multiomic and Spatial Profiling of Colorectal Tissue Reveals Viral Persistence and Immune Dysregulation in Long COVID"],"prefix":"10.64898","author":[{"given":"Brian","family":"LaFranchi","sequence":"first","affiliation":[{"name":"Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3428-1931","authenticated-orcid":false,"given":"David P.","family":"Maison","sequence":"additional","affiliation":[{"name":"Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6425-589X","authenticated-orcid":false,"given":"Joanna","family":"Vinden","sequence":"additional","affiliation":[{"name":"Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio E.","family":"Rodriguez","sequence":"additional","affiliation":[{"name":"Division of HIV, Infectious Diseases and Global Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2778-996X","authenticated-orcid":false,"given":"Ali","family":"Tout","sequence":"additional","affiliation":[{"name":"Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7080-6810","authenticated-orcid":false,"given":"Lilian","family":"Grimbert","sequence":"additional","affiliation":[{"name":"Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-6129-0327","authenticated-orcid":false,"given":"Emanuel","family":"Velazquez","sequence":"additional","affiliation":[{"name":"Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Urmila","family":"Vudali","sequence":"additional","affiliation":[{"name":"Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Belen Altamirano","family":"Poblano","sequence":"additional","affiliation":[{"name":"Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9132-0496","authenticated-orcid":false,"given":"Thomas","family":"Dalhuisen","sequence":"additional","affiliation":[{"name":"Division of HIV, Infectious Diseases and Global Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Cattle","sequence":"additional","affiliation":[{"name":"Division of HIV, Infectious Diseases and Global Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tony R.","family":"Figueroa","sequence":"additional","affiliation":[{"name":"Division of HIV, Infectious Diseases and Global Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Fudotan","sequence":"additional","affiliation":[{"name":"Division of HIV, Infectious Diseases and Global Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Luna","sequence":"additional","affiliation":[{"name":"Division of HIV, Infectious Diseases and Global Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4873-2493","authenticated-orcid":false,"given":"Dylan","family":"Ryder","sequence":"additional","affiliation":[{"name":"Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA"},{"name":"Division of HIV, Infectious Diseases and Global Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Deswal","sequence":"additional","affiliation":[{"name":"Division of HIV, Infectious Diseases and Global Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3598-0542","authenticated-orcid":false,"given":"Brent S.","family":"Abel","sequence":"additional","affiliation":[{"name":"Division of HIV, Infectious Diseases and Global Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5491-3804","authenticated-orcid":false,"given":"James","family":"Lynch","sequence":"additional","affiliation":[{"name":"Division of HIV, Infectious Diseases and Global Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3165-3701","authenticated-orcid":false,"given":"Amanda","family":"Lipford","sequence":"additional","affiliation":[{"name":"Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2080-1688","authenticated-orcid":false,"given":"Nabeel","family":"Razi","sequence":"additional","affiliation":[{"name":"Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5055-9898","authenticated-orcid":false,"given":"Carly B.","family":"Steifman","sequence":"additional","affiliation":[{"name":"Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry N.","family":"McCann","sequence":"additional","affiliation":[{"name":"Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nick","family":"Kataria","sequence":"additional","affiliation":[{"name":"Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2355-9438","authenticated-orcid":false,"given":"Valerie","family":"Girling","sequence":"additional","affiliation":[{"name":"Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reuben","family":"Thomas","sequence":"additional","affiliation":[{"name":"Gladstone Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9304-1217","authenticated-orcid":false,"given":"Chao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, School of Pharmacy, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amelia N.","family":"Deitchman","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, School of Pharmacy, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shreya","family":"Patel","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Traglia","sequence":"additional","affiliation":[{"name":"Gladstone Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5996-4099","authenticated-orcid":false,"given":"Zian H.","family":"Tseng","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gyula","family":"Szabo","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoltan","family":"Laszik","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1486-3227","authenticated-orcid":false,"given":"Alex","family":"Farrow","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolaas","family":"Zwart","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nanami","family":"Sumimoto","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1745-4012","authenticated-orcid":false,"given":"Venice","family":"Servellita","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Hoh","sequence":"additional","affiliation":[{"name":"Division of HIV, Infectious Diseases and Global Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily A.","family":"Fehrman","sequence":"additional","affiliation":[{"name":"Division of HIV, Infectious Diseases and Global Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7616-0321","authenticated-orcid":false,"given":"J. Daniel","family":"Kelly","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey N.","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6371-747X","authenticated-orcid":false,"given":"Steven G.","family":"Deeks","sequence":"additional","affiliation":[{"name":"Division of HIV, Infectious Diseases and Global Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles Y.","family":"Chiu","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA"},{"name":"Division of Infectious Diseases, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6116-3645","authenticated-orcid":false,"given":"Ma","family":"Somsouk","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0585-6230","authenticated-orcid":false,"given":"Michael J.","family":"Peluso","sequence":"additional","affiliation":[{"name":"Division of HIV, Infectious Diseases and Global Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy J.","family":"Henrich","sequence":"additional","affiliation":[{"name":"Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026081120403092000_2026.08.07.743616v1.1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMsb2408466"},{"key":"2026081120403092000_2026.08.07.743616v1.2","doi-asserted-by":"crossref","unstructured":"Davis, H. E. et al. Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. EClinicalMedicine 38, 101019 (2021).","DOI":"10.1016\/j.eclinm.2021.101019"},{"key":"2026081120403092000_2026.08.07.743616v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-022-00846-2"},{"key":"2026081120403092000_2026.08.07.743616v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.07.054"},{"key":"2026081120403092000_2026.08.07.743616v1.5","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/S0140-6736(24)01136-X","article-title":"Long COVID: a clinical update","volume":"404","year":"2024","journal-title":"The Lancet"},{"key":"2026081120403092000_2026.08.07.743616v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-023-01601-2"},{"key":"2026081120403092000_2026.08.07.743616v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(24)00171-3"},{"key":"2026081120403092000_2026.08.07.743616v1.8","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2021-324280"},{"key":"2026081120403092000_2026.08.07.743616v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03207-w"},{"key":"2026081120403092000_2026.08.07.743616v1.10","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1007\/s11695-022-06338-9","article-title":"Lingering SARS-CoV-2 in Gastric and Gallbladder Tissues of Patients with Previous COVID-19 Infection Undergoing Bariatric Surgery","volume":"33","year":"2023","journal-title":"Obes Surg"},{"key":"2026081120403092000_2026.08.07.743616v1.11","doi-asserted-by":"publisher","DOI":"10.1038\/S41586-022-05542-Y"},{"key":"2026081120403092000_2026.08.07.743616v1.12","doi-asserted-by":"crossref","unstructured":"Peluso, M. J. et al. Tissue-based T cell activation and viral RNA persist for up to 2 years after SARS-CoV-2 infection. Sci Transl Med 16, eadk3295 (2024).","DOI":"10.1126\/scitranslmed.adk3295"},{"key":"2026081120403092000_2026.08.07.743616v1.13","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(21)00703-9\/ATTACHMENT\/31179DEC-CF64-455B-BD13-6EF0045B7DD6\/MMC1.PDF"},{"key":"2026081120403092000_2026.08.07.743616v1.14","doi-asserted-by":"publisher","DOI":"10.1172\/JCI163669"},{"key":"2026081120403092000_2026.08.07.743616v1.15","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06651-y"},{"key":"2026081120403092000_2026.08.07.743616v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.01.014"},{"key":"2026081120403092000_2026.08.07.743616v1.17","doi-asserted-by":"crossref","unstructured":"Peluso, M. J. et al. Long-term SARS-CoV-2-specific immune and inflammatory responses in individuals recovering from COVID-19 with and without post-acute symptoms. Cell Rep 36, 109518 (2021).","DOI":"10.1016\/j.celrep.2021.109518"},{"key":"2026081120403092000_2026.08.07.743616v1.18","doi-asserted-by":"publisher","DOI":"10.1097\/PAI.0000000000000878"},{"key":"2026081120403092000_2026.08.07.743616v1.19","doi-asserted-by":"crossref","first-page":"9016","DOI":"10.1038\/s41467-024-51470-y","article-title":"Laboratory validation of a clinical metagenomic next-generation sequencing assay for respiratory virus detection and discovery","volume":"15","year":"2024","journal-title":"Nat Commun"},{"key":"2026081120403092000_2026.08.07.743616v1.20","doi-asserted-by":"publisher","DOI":"10.1042\/cs20200477"},{"key":"2026081120403092000_2026.08.07.743616v1.21","doi-asserted-by":"crossref","unstructured":"Rabe, D. C. et al. Ultrasensitive detection of intact SARS-CoV-2 particles in complex biofluids using microfluidic affinity capture. Science Advances 11, eadh1167 (2025).","DOI":"10.1126\/sciadv.adh1167"},{"key":"2026081120403092000_2026.08.07.743616v1.22","doi-asserted-by":"crossref","first-page":"e2400622","DOI":"10.1002\/adhm.202400622","article-title":"Integrated Antigenic and Nucleic Acid Detection in Single Virions and Extracellular Vesicles with Viral Content","volume":"14","year":"2025","journal-title":"Adv Healthc Mater"},{"key":"2026081120403092000_2026.08.07.743616v1.23","doi-asserted-by":"publisher","DOI":"10.1093\/CID\/CIAC722"},{"key":"2026081120403092000_2026.08.07.743616v1.24","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.28364"},{"key":"2026081120403092000_2026.08.07.743616v1.25","doi-asserted-by":"publisher","DOI":"10.1002\/ana.26350"},{"key":"2026081120403092000_2026.08.07.743616v1.26","doi-asserted-by":"crossref","unstructured":"Menezes, S. M. et al. Blood transcriptomic analyses reveal persistent SARS-CoV-2 RNA and candidate biomarkers in post-COVID-19 condition. Lancet Microbe 5, 100849 (2024).","DOI":"10.1016\/S2666-5247(24)00055-7"},{"key":"2026081120403092000_2026.08.07.743616v1.27","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1093\/infdis\/jiad395","article-title":"COVID-19 Recovery: Consistent Absence of Cerebrospinal Fluid Biomarker Abnormalities in Patients With Neurocognitive Post-COVID Complications","volume":"229","year":"2024","journal-title":"J Infect Dis"},{"key":"2026081120403092000_2026.08.07.743616v1.28","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.28568"},{"key":"2026081120403092000_2026.08.07.743616v1.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmi.2024.09.001"},{"key":"2026081120403092000_2026.08.07.743616v1.30","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(24)00211-1"},{"key":"2026081120403092000_2026.08.07.743616v1.31","doi-asserted-by":"crossref","unstructured":"Sperber, H. S. et al. The hypoxia-regulated ectonucleotidase CD73 is a host determinant of HIV latency. Cell Rep 42, 113285 (2023).","DOI":"10.1016\/j.celrep.2023.113285"},{"key":"2026081120403092000_2026.08.07.743616v1.32","doi-asserted-by":"crossref","unstructured":"Shraim, R. et al. A Method for Comparing Proteins Measured in Serum and Plasma by Olink Proximity Extension Assay. Mol Cell Proteomics 24, 101000 (2025).","DOI":"10.1016\/j.mcpro.2025.101000"},{"key":"2026081120403092000_2026.08.07.743616v1.33","doi-asserted-by":"publisher","DOI":"10.1101\/gr.171934.113"},{"key":"2026081120403092000_2026.08.07.743616v1.34","doi-asserted-by":"publisher","DOI":"10.1101\/gr.238170.118"},{"key":"2026081120403092000_2026.08.07.743616v1.35","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-024-03275-1"},{"key":"2026081120403092000_2026.08.07.743616v1.36","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.physiol.010908.163145"},{"key":"2026081120403092000_2026.08.07.743616v1.37","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajem.2023.09.051"},{"key":"2026081120403092000_2026.08.07.743616v1.38","unstructured":"Baratta, J. M. , Jensen, K. A. & Cobb, C . Exploring the Effects of Pemivibart Monoclonal Antibody Infusion in Long COVID: A Case Series Offering Initial Clinical Insights. Cureus 17, e96246."},{"key":"2026081120403092000_2026.08.07.743616v1.39","first-page":"95","article-title":"Effect of Oral Nirmatrelvir on Long COVID Symptoms: 4 Cases and Rationale for Systematic Studies","volume":"7","year":"2022","journal-title":"Pathog Immun"},{"key":"2026081120403092000_2026.08.07.743616v1.40","doi-asserted-by":"publisher","DOI":"10.14218\/erhm.2022.00045"},{"key":"2026081120403092000_2026.08.07.743616v1.41","doi-asserted-by":"crossref","unstructured":"Cohen, A. K. et al. Impact of extended-course oral nirmatrelvir\/ritonavir in established Long COVID: a case series. Commun Med (Lond) 4, 261 (2025).","DOI":"10.1038\/s43856-024-00668-8"},{"key":"2026081120403092000_2026.08.07.743616v1.42","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1001\/jamainternmed.2024.2007","article-title":"Nirmatrelvir-Ritonavir and Symptoms in Adults With Postacute Sequelae of SARS-CoV-2 Infection: The STOP-PASC Randomized Clinical Trial","volume":"184","year":"2024","journal-title":"JAMA Intern Med"},{"key":"2026081120403092000_2026.08.07.743616v1.43","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1016\/S1473-3099(25)00073-8","article-title":"Nirmatrelvir-ritonavir versus placebo-ritonavir in individuals with long COVID in the USA (PAX LC): a double-blind, randomised, placebo-controlled, phase 2, decentralised trial","volume":"25","year":"2025","journal-title":"Lancet Infect Dis"},{"key":"2026081120403092000_2026.08.07.743616v1.44","doi-asserted-by":"publisher","DOI":"10.64898\/2026.03.07.26347857"},{"key":"2026081120403092000_2026.08.07.743616v1.45","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1954"},{"key":"2026081120403092000_2026.08.07.743616v1.46","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-026-74676-8"},{"key":"2026081120403092000_2026.08.07.743616v1.47","doi-asserted-by":"crossref","unstructured":"Giron, L. B. et al. Markers of fungal translocation are elevated during post-acute sequelae of SARS-CoV-2 and induce NF-\u03baB signaling. JCI Insight 7, (2022).","DOI":"10.1172\/jci.insight.164813"},{"key":"2026081120403092000_2026.08.07.743616v1.48","doi-asserted-by":"crossref","unstructured":"Peluso, M. J. , Abdel-Mohsen, M. , Henrich, T. J. & Roan, N. R . Systems analysis of innate and adaptive immunity in Long COVID. Semin Immunol 72, 101873 (2024).","DOI":"10.1016\/j.smim.2024.101873"},{"key":"2026081120403092000_2026.08.07.743616v1.49","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2009.35"},{"key":"2026081120403092000_2026.08.07.743616v1.50","first-page":"203","article-title":"The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems","volume":"28","year":"2015","journal-title":"Ann Gastroenterol"},{"key":"2026081120403092000_2026.08.07.743616v1.51","doi-asserted-by":"crossref","first-page":"e294","DOI":"10.1016\/S1473-3099(24)00769-2","article-title":"Targeting the SARS-CoV-2 reservoir in long COVID","volume":"25","year":"2025","journal-title":"Lancet Infect Dis"},{"key":"2026081120403092000_2026.08.07.743616v1.52","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(26)00361-0"},{"key":"2026081120403092000_2026.08.07.743616v1.53","doi-asserted-by":"crossref","unstructured":"Oppegaard, O. et al. Nirmatrelvir for acute COVID-19 to prevent long COVID (PANORAMIC Norway): a double-blind, randomised, placebo-controlled trial. The Lancet Infectious Diseases 0, (2026).","DOI":"10.1016\/S1473-3099(26)00244-6"},{"key":"2026081120403092000_2026.08.07.743616v1.54","doi-asserted-by":"publisher","DOI":"10.1136\/bmj-2022-073312"},{"key":"2026081120403092000_2026.08.07.743616v1.55","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/S1473-3099(24)00431-6","article-title":"Health outcomes 3 months and 6 months after molnupiravir treatment for COVID-19 for people at higher risk in the community (PANORAMIC): a randomised controlled trial","volume":"25","year":"2025","journal-title":"The Lancet Infectious Diseases"},{"key":"2026081120403092000_2026.08.07.743616v1.56","doi-asserted-by":"crossref","unstructured":"Peluso, M. J. et al. Persistence, Magnitude, and Patterns of Postacute Symptoms and Quality of Life Following Onset of SARS-CoV-2 Infection: Cohort Description and Approaches for Measurement. Open Forum Infect Dis 9, ofab640 (2022).","DOI":"10.1093\/ofid\/ofab640"},{"key":"2026081120403092000_2026.08.07.743616v1.57","unstructured":"Long Covid Defined | New England Journal of Medicine. https:\/\/www.nejm.org\/doi\/full\/10.1056\/NEJMsb2408466."},{"key":"2026081120403092000_2026.08.07.743616v1.58","doi-asserted-by":"publisher","DOI":"10.48550\/arXiv.1111.5572"},{"key":"2026081120403092000_2026.08.07.743616v1.59","doi-asserted-by":"publisher","DOI":"10.1089\/cmb.2012.0021"},{"key":"2026081120403092000_2026.08.07.743616v1.60","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3176"},{"key":"2026081120403092000_2026.08.07.743616v1.61","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"2026081120403092000_2026.08.07.743616v1.62","doi-asserted-by":"publisher","DOI":"10.5281\/zenodo.20072251"},{"key":"2026081120403092000_2026.08.07.743616v1.63","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-020-0439-x"},{"key":"2026081120403092000_2026.08.07.743616v1.64","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-018-0046-7"},{"key":"2026081120403092000_2026.08.07.743616v1.65","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btx192"},{"key":"2026081120403092000_2026.08.07.743616v1.66","unstructured":"Babraham Bioinformatics - Trim Galore! https:\/\/www.bioinformatics.babraham.ac.uk\/projects\/trim_galore\/."},{"key":"2026081120403092000_2026.08.07.743616v1.67","unstructured":"Babraham Bioinformatics - FastQC A Quality Control tool for High Throughput Sequence Data. https:\/\/www.bioinformatics.babraham.ac.uk\/projects\/fastqc\/."},{"key":"2026081120403092000_2026.08.07.743616v1.68","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4197"},{"key":"2026081120403092000_2026.08.07.743616v1.69","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.12688\/f1000research.7563.1","article-title":"Differential analyses for RNA-seq: transcript-level estimates improve gene-level inferences","volume":"4","year":"2015","journal-title":"F1000Res"},{"key":"2026081120403092000_2026.08.07.743616v1.70","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp616"},{"key":"2026081120403092000_2026.08.07.743616v1.71","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.2931"},{"key":"2026081120403092000_2026.08.07.743616v1.72","doi-asserted-by":"crossref","unstructured":"Blighe, K. , Rana, S. & Lewis, M. EnhancedVolcano: Publication-Ready Volcano Plots with Enhanced Colouring and Labeling. (2025).","DOI":"10.32614\/CRAN.package.ggvolcano"},{"key":"2026081120403092000_2026.08.07.743616v1.73","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-024-01020-z"},{"key":"2026081120403092000_2026.08.07.743616v1.74","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/iyad031"},{"key":"2026081120403092000_2026.08.07.743616v1.75","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","article-title":"The Molecular Signatures Database (MSigDB) hallmark gene set collection","volume":"1","year":"2015","journal-title":"Cell Syst"},{"key":"2026081120403092000_2026.08.07.743616v1.76","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"2026081120403092000_2026.08.07.743616v1.77","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/28.1.27"},{"key":"2026081120403092000_2026.08.07.743616v1.78","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae909"},{"key":"2026081120403092000_2026.08.07.743616v1.79","doi-asserted-by":"publisher","DOI":"10.1002\/pro.3715"},{"key":"2026081120403092000_2026.08.07.743616v1.80","doi-asserted-by":"publisher","DOI":"10.32614\/CRAN.package.pheatmap"},{"key":"2026081120403092000_2026.08.07.743616v1.81","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-9-559"},{"key":"2026081120403092000_2026.08.07.743616v1.82","doi-asserted-by":"publisher","DOI":"10.1101\/060012"},{"key":"2026081120403092000_2026.08.07.743616v1.83","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007"},{"key":"2026081120403092000_2026.08.07.743616v1.84","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118"},{"key":"2026081120403092000_2026.08.07.743616v1.85","doi-asserted-by":"publisher","DOI":"10.32614\/CRAN.package.msigdbr"},{"key":"2026081120403092000_2026.08.07.743616v1.86","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14049"},{"key":"2026081120403092000_2026.08.07.743616v1.87","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-023-01943-7"},{"key":"2026081120403092000_2026.08.07.743616v1.88","doi-asserted-by":"crossref","unstructured":"Lun, A. T. L. et al. EmptyDrops: distinguishing cells from empty droplets in droplet-based single-cell RNA sequencing data. Genome Biol 20, 63 (2019).","DOI":"10.1186\/s13059-019-1662-y"},{"key":"2026081120403092000_2026.08.07.743616v1.89","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-05083-x"},{"key":"2026081120403092000_2026.08.07.743616v1.90","doi-asserted-by":"publisher","DOI":"10.1038\/S41587-023-01767-Y"},{"key":"2026081120403092000_2026.08.07.743616v1.91","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.cels.2019.03.003","article-title":"DoubletFinder: Doublet Detection in Single-Cell RNA Sequencing Data Using Artificial Nearest Neighbors","volume":"8","year":"2019","journal-title":"Cell Systems"},{"key":"2026081120403092000_2026.08.07.743616v1.92","doi-asserted-by":"crossref","unstructured":"Choudhary, S. & Satija, R . Comparison and evaluation of statistical error models for scRNA-seq. Genome Biol 23, 27 (2022).","DOI":"10.1186\/s13059-021-02584-9"},{"key":"2026081120403092000_2026.08.07.743616v1.93","doi-asserted-by":"publisher","DOI":"10.1023\/A:1010933404324"},{"key":"2026081120403092000_2026.08.07.743616v1.94","unstructured":"Gill, N. , Shin, M. G. , Agrawal, A. & Thomas, R. clustOpt: Optimizing Clustering Resolution for Multi-Subject Single Cell Studies. (2025)."},{"key":"2026081120403092000_2026.08.07.743616v1.95","unstructured":"Thomas R, T. M. , Agrawal A , Elphick N . LODopt: Cell Type Abundance Association Analysis for Single Cell Data. (2025)."},{"key":"2026081120403092000_2026.08.07.743616v1.96","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.22139.2"},{"key":"2026081120403092000_2026.08.07.743616v1.97","doi-asserted-by":"publisher","DOI":"10.1101\/713412"},{"key":"2026081120403092000_2026.08.07.743616v1.98","doi-asserted-by":"publisher","DOI":"10.1038\/75556"},{"key":"2026081120403092000_2026.08.07.743616v1.99","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv1070"},{"key":"2026081120403092000_2026.08.07.743616v1.100","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad960"},{"key":"2026081120403092000_2026.08.07.743616v1.101","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1186\/s12864-023-09816-1","article-title":"Using published pathway figures in enrichment analysis and machine learning","volume":"24","year":"2023","journal-title":"BMC Genomics"},{"key":"2026081120403092000_2026.08.07.743616v1.102","doi-asserted-by":"publisher","DOI":"10.48550\/arXiv.2307.12985"},{"key":"2026081120403092000_2026.08.07.743616v1.103","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-018-0229-21"},{"key":"2026081120403092000_2026.08.07.743616v1.104","doi-asserted-by":"publisher","DOI":"10.1109\/ICDE60146.2024.00323"},{"key":"2026081120403092000_2026.08.07.743616v1.105","doi-asserted-by":"publisher","DOI":"10.48550\/arXiv.1802.03426"},{"key":"2026081120403092000_2026.08.07.743616v1.106","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1609\/aaai.v35i1.16118","article-title":"Bringing UMAP Closer to the Speed of Light with GPU Acceleration","volume":"35","year":"2021","journal-title":"Proceedings of the AAAI Conference on Artificial Intelligence"},{"key":"2026081120403092000_2026.08.07.743616v1.107","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-41695-z"},{"key":"2026081120403092000_2026.08.07.743616v1.108","doi-asserted-by":"crossref","unstructured":"Blondel, V. D. , Guillaume, J.-L. , Lambiotte, R. & Lefebvre, E . Fast unfolding of communities in large networks. J. Stat. Mech. 2008, P10008 (2008).","DOI":"10.1088\/1742-5468\/2008\/10\/P10008"},{"key":"2026081120403092000_2026.08.07.743616v1.109","doi-asserted-by":"publisher","DOI":"10.1016\/j.patcog.2011.04.006"},{"key":"2026081120403092000_2026.08.07.743616v1.110","doi-asserted-by":"crossref","first-page":"vbac016","DOI":"10.1093\/bioadv\/vbac016","article-title":"decoupleR: ensemble of computational methods to infer biological activities from omics data","volume":"2","year":"2022","journal-title":"Bioinform Adv"},{"key":"2026081120403092000_2026.08.07.743616v1.111","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btr260"},{"key":"2026081120403092000_2026.08.07.743616v1.112","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-02391-6"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.08.07.743616","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T03:40:45Z","timestamp":1786506045000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.08.07.743616"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,10]]},"references-count":112,"URL":"https:\/\/doi.org\/10.64898\/2026.08.07.743616","relation":{},"subject":[],"published":{"date-parts":[[2026,8,10]]},"subtype":"preprint"}}