Abstract

COVID-19 is a disease of dysfunctional immune responses, but the mechanisms triggering immunopathogenesis are not established. The functional plasticity of macrophages allows this cell type to promote pathogen elimination and inflammation or suppress inflammation and promote tissue remodeling and injury repair. During an infection, the clearance of dead and dying cells, a process named efferocytosis, can modulate the interplay between these contrasting functions. Here, we show that engulfment of SARS-CoV2-infected apoptotic cells exacerbates inflammatory cytokine production, inhibits the expression of efferocytic receptors, and impairs continual efferocytosis by macrophages. We also provide evidence supporting that lung monocytes and macrophages from severe COVID-19 patients have compromised efferocytic capacity. Our findings reveal that dysfunctional efferocytosis of SARS-CoV-2-infected cell corpses suppress macrophage anti-inflammation and efficient tissue repair programs and provide mechanistic insights for the excessive production of pro-inflammatory cytokines and accumulation of tissue damage associated with COVID-19 immunopathogenesis.

Data availability

Source data files containing the numerical values for graphs depicting flow cytometry, ELISA, CBA, RT-qPCR, and imaging quantification data are be uploaded as csv files. All code used for analysis is documented in the Methods section.

The following previously published data sets were used

Article and author information

Author details

  1. Ana Carolina G Salina

    Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3220-0413
  2. Douglas dos Santos

    Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  3. Tamara S Rodrigues

    Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  4. Marlon Fortes-Rocha

    Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2055-2000
  5. Edismauro G Freitas-Filho

    Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1910-1085
  6. Daniel L Alzamora-Terrel

    Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  7. Icaro MS Castro

    Department of Clinical and Toxicological Analysis, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  8. Thais Fernanda Fraga-Silva

    Department of Biochemistry and Immunology, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  9. Mikhael HF de Lima

    Department of Pharmacology, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  10. Daniele C Nascimento

    Department of Pharmacology, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  11. Camila M Silva

    Department of Pharmacology, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  12. Juliana E Toller-Kawahisa

    Department of Pharmacology, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  13. Amanda Becerra

    Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  14. Samuel Oliveira

    Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  15. Diego B Caetite

    Department of Pharmacology, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  16. Leticia Almeida

    Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  17. Adriene Y Ishimoto

    Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  18. Thais M Lima

    Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5714-6057
  19. Ronaldo B Martins

    Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  20. Flavio P Veras

    Department of Pharmacology, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  21. Natália B do Amaral

    Division of Clinical Immunology, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  22. Marcela C Giannini

    Division of Clinical Immunology, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  23. Letícia P Bonjorno

    Division of Clinical Immunology, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  24. Maria Isabel F Lopes

    Division of Clinical Immunology, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  25. Maira N Benatti

    Department of Pathology and Forensic Medicine, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  26. Sabrina S Batah

    Department of Pathology and Forensic Medicine, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  27. Rodrigo C Santana

    Division of Clinical Immunology, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  28. Fernando C Vilar

    Division of Clinical Immunology, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  29. Maria Auxiliadora Martins

    Department of Pathology and Forensic Medicine, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  30. Rodrigo L Assad

    Division of Clinical Immunology, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8430-8357
  31. Sergio CL deAlmeida

    Division of Clinical Immunology, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  32. Fabiola R de Oliveira

    Division of Clinical Immunology, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  33. Eurico Arruda Neto

    Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  34. Thiago M Cunha

    Department of Pharmacology, University of Sao Paulo, Ribeirao Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1084-0065
  35. Jose C Alves-Filho

    Department of Pharmacology, University of Sao Paulo, Ribeirao Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  36. Vania LD Bonato

    Department of Biochemistry and Immunology, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  37. Fernando Q Cunha

    Department of Pharmacology, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  38. Alexandre T Fabro

    Department of Pathology and Forensic Medicine, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  39. Helder I Nakaya

    Department of Clinical and Toxicological Analysis, University of São Paulo, São Paulo, Brazil
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5297-9108
  40. Dario S Zamboni

    Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of São Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7856-7512
  41. Paulo Louzada-Junior

    Center of Research in Inflammatory Diseases, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  42. Renê DR de Oliveira

    Division of Clinical Immunology, University of Sao Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  43. Larissa D Cunha

    Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil
    For correspondence
    larissacunha@usp.br
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1290-0263

Funding

Fundação de Amparo à Pesquisa do Estado de São Paulo (2018/25559-4)

  • Larissa D Cunha

Fundação de Amparo à Pesquisa do Estado de São Paulo (2020/05288-6)

  • Larissa D Cunha

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (88887.507253/2020-00)

  • Dario S Zamboni

Conselho Nacional de Desenvolvimento Científico e Tecnológico (434538/2018-3)

  • Larissa D Cunha

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: The procedures followed in the study were approved by the Research Ethics Committee of Hospital das Clínicas de Ribeirão Preto (CEP-FMRP/USP) and by the National Ethics Committee, Brazil (Comissão Nacional de Ética em Pesquisa (CONEP), protocols 30248420.9.0000.5440 and 39722020.9.0000.5440. Written informed consent was obtained from recruited donors.Ultrasound-guided minimally invasive autopsies for COVID-19 deceased patients were approved by the Research Ethics Committee of Hospital das Clínicas de Ribeirão Preto (CEP, protocol no. 4.089.567).

Copyright

© 2022, Salina et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Ana Carolina G Salina
  2. Douglas dos Santos
  3. Tamara S Rodrigues
  4. Marlon Fortes-Rocha
  5. Edismauro G Freitas-Filho
  6. Daniel L Alzamora-Terrel
  7. Icaro MS Castro
  8. Thais Fernanda Fraga-Silva
  9. Mikhael HF de Lima
  10. Daniele C Nascimento
  11. Camila M Silva
  12. Juliana E Toller-Kawahisa
  13. Amanda Becerra
  14. Samuel Oliveira
  15. Diego B Caetite
  16. Leticia Almeida
  17. Adriene Y Ishimoto
  18. Thais M Lima
  19. Ronaldo B Martins
  20. Flavio P Veras
  21. Natália B do Amaral
  22. Marcela C Giannini
  23. Letícia P Bonjorno
  24. Maria Isabel F Lopes
  25. Maira N Benatti
  26. Sabrina S Batah
  27. Rodrigo C Santana
  28. Fernando C Vilar
  29. Maria Auxiliadora Martins
  30. Rodrigo L Assad
  31. Sergio CL deAlmeida
  32. Fabiola R de Oliveira
  33. Eurico Arruda Neto
  34. Thiago M Cunha
  35. Jose C Alves-Filho
  36. Vania LD Bonato
  37. Fernando Q Cunha
  38. Alexandre T Fabro
  39. Helder I Nakaya
  40. Dario S Zamboni
  41. Paulo Louzada-Junior
  42. Renê DR de Oliveira
  43. Larissa D Cunha
(2022)
Efferocytosis of SARS-CoV-2-infected dying cells impairs macrophage anti-inflammatory functions and clearance of apoptotic cells
eLife 11:e74443.
https://doi.org/10.7554/eLife.74443

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https://doi.org/10.7554/eLife.74443

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