Long COVID (LC) - a chronic condition characterized by persistent, debilitating symptoms following SARS-CoV-2 infection - 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." />
Multiomic and Spatial Profiling of Colorectal Tissue Reveals Viral Persistence and Immune Dysregulation in Long COVID | bioRxiv
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Multiomic and Spatial Profiling of Colorectal Tissue Reveals Viral Persistence and Immune Dysregulation in Long COVID
Brian LaFranchi, View ORCID ProfileDavid P. Maison, View ORCID ProfileJoanna Vinden, Antonio E. Rodriguez, View ORCID ProfileAli Tout, View ORCID ProfileLilian Grimbert, View ORCID ProfileEmanuel Velazquez, Urmila Vudali, Belen Altamirano Poblano, View ORCID ProfileThomas Dalhuisen, Javier Cattle, Tony R. Figueroa, Yuki Fudotan, Michael Luna, View ORCID ProfileDylan Ryder, Monika Deswal, View ORCID ProfileBrent S. Abel, View ORCID ProfileJames Lynch, View ORCID ProfileAmanda Lipford, View ORCID ProfileNabeel Razi, View ORCID ProfileCarly B. Steifman, Henry N. McCann, Nick Kataria, View ORCID ProfileValerie Girling, Reuben Thomas, View ORCID ProfileChao Wang, Amelia N. Deitchman, Shreya Patel, Michela Traglia, View ORCID ProfileZian H. Tseng, Gyula Szabo, Zoltan Laszik, View ORCID ProfileAlex Farrow, Nicolaas Zwart, Nanami Sumimoto, View ORCID ProfileVenice Servellita, Rebecca Hoh, Emily A. Fehrman, View ORCID ProfileJ. Daniel Kelly, Jeffrey N. Martin, View ORCID ProfileSteven G. Deeks, Charles Y. Chiu, View ORCID ProfileMa Somsouk, View ORCID ProfileMichael J. Peluso, Timothy J. Henrich
doi: https://doi.org/10.64898/2026.08.07.743616
Brian LaFranchi<br>1Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
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David P. Maison<br>1Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
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Joanna Vinden<br>1Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
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Antonio E. Rodriguez<br>2Division of HIV, Infectious Diseases and Global Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
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Ali Tout<br>1Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
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