High-depth sequencing characterization of viral dynamics across tissues in fatal COVID-19 reveals compartmentalized infection

Erica Normandin (), Melissa Rudy, Nikolaos Barkas, Stephen F. Schaffner, Zoe Levine, Robert F. Padera, Mehrtash Babadi, Shibani S. Mukerji, Daniel J. Park, Bronwyn L. MacInnis, Katherine J. Siddle (), Pardis C. Sabeti and Isaac H. Solomon ()
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Erica Normandin: Broad Institute of Harvard and MIT
Melissa Rudy: Broad Institute of Harvard and MIT
Nikolaos Barkas: Broad Institute of Harvard and MIT
Stephen F. Schaffner: Broad Institute of Harvard and MIT
Zoe Levine: Broad Institute of Harvard and MIT
Robert F. Padera: Brigham and Women’s Hospital
Mehrtash Babadi: Broad Institute of Harvard and MIT
Shibani S. Mukerji: Massachusetts General Hospital
Daniel J. Park: Broad Institute of Harvard and MIT
Bronwyn L. MacInnis: Broad Institute of Harvard and MIT
Katherine J. Siddle: Broad Institute of Harvard and MIT
Pardis C. Sabeti: Broad Institute of Harvard and MIT
Isaac H. Solomon: Brigham and Women’s Hospital

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract SARS-CoV-2 distribution and circulation dynamics are not well understood due to challenges in assessing genomic data from tissue samples. We develop experimental and computational workflows for high-depth viral sequencing and high-resolution genomic analyses from formalin-fixed, paraffin-embedded tissues and apply them to 120 specimens from six subjects with fatal COVID-19. To varying degrees, viral RNA is present in extrapulmonary tissues from all subjects. The majority of the 180 viral variants identified within subjects are unique to individual tissue samples. We find more high-frequency (>10%) minor variants in subjects with a longer disease course, with one subject harboring ten such variants, exclusively in extrapulmonary tissues. One tissue-specific high-frequency variant was a nonsynonymous mutation in the furin-cleavage site of the spike protein. Our findings suggest adaptation and/or compartmentalized infection, illuminating the basis of extrapulmonary COVID-19 symptoms and potential for viral reservoirs, and have broad utility for investigating human pathogens.

Date: 2023
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DOI: 10.1038/s41467-022-34256-y

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