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 Jr; Mehrtash Babadi; Shibani S Mukerji; Daniel J Park; Bronwyn L MacInnis; Katherine J Siddle; Pardis C Sabeti; Isaac H Solomon

doi:10.1038/s41467-022-34256-y

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

Nat Commun. 2023 Feb 2;14(1):574. doi: 10.1038/s41467-022-34256-y.

Authors

Erica Normandin^{1

2}, Melissa Rudy³, Nikolaos Barkas³, Stephen F Schaffner³, Zoe Levine^{3

4}, Robert F Padera Jr⁵, Mehrtash Babadi³, Shibani S Mukerji⁶, Daniel J Park³, Bronwyn L MacInnis^{3

7

8}, Katherine J Siddle^{9

10}, Pardis C Sabeti^{3

7

8

11}, Isaac H Solomon¹²

Affiliations

¹ Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA, 02142, USA. [email protected].
² Department of Systems Biology, Harvard Medical School, Boston, MA, 02115, USA. [email protected].
³ Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA, 02142, USA.
⁴ Harvard Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, 02115, USA.
⁵ Department of Pathology, Brigham and Women's Hospital, Boston, MA, 02115, USA.
⁶ Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA.
⁷ Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Harvard University, Boston, MA, 02115, USA.
⁸ Massachusetts Consortium on Pathogen Readiness, Boston, MA, 02115, USA.
⁹ Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA, 02142, USA. [email protected].
¹⁰ Department of Systems Biology, Harvard Medical School, Boston, MA, 02115, USA. [email protected].
¹¹ Howard Hughes Medical Institute, Chevy Chase, MD, 20815, USA.
¹² Department of Pathology, Brigham and Women's Hospital, Boston, MA, 02115, USA. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

COVID-19*
Humans
Mutation
SARS-CoV-2 / genetics
SARS-CoV-2 / metabolism
Spike Glycoprotein, Coronavirus / genetics
Spike Glycoprotein, Coronavirus / metabolism

Substances

Spike Glycoprotein, Coronavirus
spike protein, SARS-CoV-2

Abstract

Publication types

MeSH terms

Substances

Grants and funding