SARS-CoV-2 infection induces pro-fibrotic and pro-thrombotic foam cell formation

Diana M Battaglia^#^{1

2

3

4}, Claire E Post^#^{2

3

4}, Wenbo Yao^#^{2

3

4

5}, Angela Wahl^#^{6

7

8

9}, Lisa E Gralinski^{10

11}, Hongwei Liu^{12

13}, Hong Dang¹⁴, Victoria J Madden¹⁵, Kristen K White¹⁵, Sarah R Leist¹⁰, Kenneth H Dinnion 3rd^{10

11}, Gabriela De la Cruz¹⁶, Bentley R Midkiff¹⁶, Heather M Froggatt¹⁰, Kendra Gully¹⁰, Mark Zweigart¹⁰, J Rachel Reader¹⁷, Katherine J Olstad¹⁷, Jeffrey I Everitt¹⁸, Koen K A Van Rompay¹⁷, Kristina De Paris^{4

11}, Eniko Sajti¹⁹, Raymond J Pickles^{11

14}, Edward P Browne^{3

4

11

20}, Corbin D Jones^{12

13}, Richard C Boucher Jr¹⁴, Ralph S Baric^{10

11

21}, J Victor Garcia^{22

23

24

25}

Affiliations

¹ Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA.
² International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³ Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴ Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁵ Jilin University, The First Hospital, 130021, Changchun, China.
⁶ Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA. awahl@uab.edu.
⁷ International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. awahl@uab.edu.
⁸ Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. awahl@uab.edu.
⁹ Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. awahl@uab.edu.
¹⁰ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹¹ Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹² Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹³ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁴ Marsico Lung Institute, University of North Carolina at Chapel, Chapel Hill, NC, USA.
¹⁵ Microscopy Services Laboratory, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁶ Pathology Services Core, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁷ California National Primate Research Center, University of California Davis, Davis, CA, USA.
¹⁸ Department of Pathology, Duke University, Durham, NC, USA.
¹⁹ Department of Pediatrics, University of California San Diego, San Diego, CA, USA.
²⁰ UNC HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
²¹ Rapidly Emerging Antiviral Drug Discovery Initiative, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
²² Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA. jvgarcia@uab.edu.
²³ International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. jvgarcia@uab.edu.
²⁴ Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. jvgarcia@uab.edu.
²⁵ Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. jvgarcia@uab.edu.

^# Contributed equally.

PMID: 40846999
DOI: 10.1038/s41564-025-02090-9

SARS-CoV-2 infection induces pro-fibrotic and pro-thrombotic foam cell formation

Diana M Battaglia et al. Nat Microbiol. 2025.

. 2025 Aug 22.

doi: 10.1038/s41564-025-02090-9. Online ahead of print.

Authors

Affiliations

¹ Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA.
² International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³ Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴ Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁵ Jilin University, The First Hospital, 130021, Changchun, China.
⁶ Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA. awahl@uab.edu.
⁷ International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. awahl@uab.edu.
⁸ Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. awahl@uab.edu.
⁹ Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. awahl@uab.edu.
¹⁰ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹¹ Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹² Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹³ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁴ Marsico Lung Institute, University of North Carolina at Chapel, Chapel Hill, NC, USA.
¹⁵ Microscopy Services Laboratory, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁶ Pathology Services Core, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁷ California National Primate Research Center, University of California Davis, Davis, CA, USA.
¹⁸ Department of Pathology, Duke University, Durham, NC, USA.
¹⁹ Department of Pediatrics, University of California San Diego, San Diego, CA, USA.
²⁰ UNC HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
²¹ Rapidly Emerging Antiviral Drug Discovery Initiative, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
²² Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA. jvgarcia@uab.edu.
²³ International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. jvgarcia@uab.edu.
²⁴ Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. jvgarcia@uab.edu.
²⁵ Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. jvgarcia@uab.edu.

^# Contributed equally.

PMID: 40846999
DOI: 10.1038/s41564-025-02090-9

Abstract

COVID-19 and long COVID are characterized by a dysregulated immune response. However, the role of macrophages during viral infection is poorly defined. Here we demonstrate that SARS-CoV-2 infection results in increased macrophage numbers and extensive formation of enlarged lipid-laden macrophages or foam cells using humanized mice, rhesus macaques and post-mortem human lung tissue. Notably, infection by other coronaviruses tested, SARS-CoV-1, MERS-CoV and two bat coronaviruses (SHC014-CoV or WIV1-CoV), did not result in macrophage proliferation or foam cell formation. Foam cells in SARS-CoV-2-infected human lung tissue display a pro-fibrotic and pro-thrombotic phenotype as they are enriched for genes associated with platelet activation and aggregation, as well as extracellular matrix organization and collagen synthesis. After viral clearance, macrophage numbers remain elevated, and lung fibrosis and thrombi persist. Importantly, we show that pre-exposure prophylaxis or early treatment with a SARS-CoV-2 antiviral, EIDD-2801, prevents increases in macrophage cell numbers and foam cell formation, and reduces fibrosis markers. These observations highlight the contribution of macrophages to lung inflammation and tissue injury leading to the pulmonary fibrosis observed in COVID-19 patients.

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Conflict of interest statement

Competing interests: The authors declare no competing interests.

References

1. Konno, Y. et al. SARS-CoV-2 ORF3b is a potent interferon antagonist whose activity is increased by a naturally occurring elongation variant. Cell Rep. 32, 108185 (2020). - PubMed - PMC
1. Li, J. Y. et al. The ORF6, ORF8 and nucleocapsid proteins of SARS-CoV-2 inhibit type I interferon signaling pathway. Virus Res. 286, 198074 (2020). - PubMed
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SARS-CoV-2 infection induces pro-fibrotic and pro-thrombotic foam cell formation

Affiliations

SARS-CoV-2 infection induces pro-fibrotic and pro-thrombotic foam cell formation

Authors

Affiliations

Abstract

Conflict of interest statement

References

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