Efferocytosis of SARS-CoV-2-infected dying cells impairs macrophage anti-inflammatory functions and clearance of apoptotic cells

Abstract
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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

1. Liao M
2. Liu Y
3. Yuan J
4. Wen Y
5. Xu G
6. Zhao J
7. Cheng L
8. Li J
9. Wang X
10. Wang F
11. Liu L
12. Amit I
13. Zhang S
14. Zhang Z.
(2020) Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19
NCBI Gene Expression Omnibus, GSE145926.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE145926
1. Ren X
2. Wen W
3. Fan X
4. Hou W
5. Su Bin
6. Cai P
7. Li J
8. Liu Y
9. Tang F
10. Zhang F
11. Yang Y
12. He Jiangping
13. Ma W
14. He Jingjing
15. Wang P
16. Cao Q
17. Chen F
18. Chen Y
19. Cheng X
20. Deng G
21. Deng X
22. Ding W
23. Feng Y
24. Gan R
25. Guo C
26. Guo W
27. He S
28. Jiang C
29. Liang J
30. Li Y
31. Lin J
32. Ling Y
33. Liu H
34. Liu J
35. Liu N
36. Liu S-Q
37. Luo M
38. Ma Q
39. Song Q
40. Sun W
41. Wang G
42. Wang F
43. Wang Y
44. Wen X
45. Wu Q
46. Xu G
47. Xie X
48. Xiong X
49. Xing X
50. Xu H
51. Yin C
52. Yu D
53. Yu K
54. Yuan J
55. Zhang B
56. Zhang P
57. Zhang T
58. Zhao J
59. Zhao Peidong
60. Zhou J
61. Zhou W
62. Zhong S
63. Zhong X
64. Zhang S
65. Zhu L
66. Zhu P
67. Zou B
68. Zou J
69. Zuo Z
70. Bai F
71. Huang X
72. Zhou P
73. Jiang Q
74. Huang Z
75. Bei J-X
76. Wei L
77. Bian X-W
78. Liu X
79. Cheng T
80. Li X
81. Zhao Pingsen
82. Wang F-S
83. Wang H
84. Su Bing
85. Zhang Zheng
86. Qu K
87. Wang X
88. Chen J
89. Jin R
90. Zhang Zemin.
(2021) COVID-19 immune features revealed by a large-scale single-cell transcriptome atlas.
NCBI Gene Expression Omnibus, GSE158055.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE158055

Article and author information

Author details

Ana Carolina G Salina

Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil

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"This ORCID iD identifies the author of this article:" 0000-0003-3220-0413
Douglas dos Santos

Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil

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Tamara S Rodrigues

Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil

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Marlon Fortes-Rocha

Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil

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"This ORCID iD identifies the author of this article:" 0000-0002-2055-2000
Edismauro G Freitas-Filho

Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil

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"This ORCID iD identifies the author of this article:" 0000-0002-1910-1085
Daniel L Alzamora-Terrel

Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil

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Icaro MS Castro

Department of Clinical and Toxicological Analysis, University of Sao Paulo, Ribeirão Preto, Brazil

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Thais Fernanda Fraga-Silva

Department of Biochemistry and Immunology, University of Sao Paulo, Ribeirão Preto, Brazil

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Mikhael HF de Lima

Department of Pharmacology, University of Sao Paulo, Ribeirão Preto, Brazil

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Daniele C Nascimento

Department of Pharmacology, University of Sao Paulo, Ribeirão Preto, Brazil

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Camila M Silva

Department of Pharmacology, University of Sao Paulo, Ribeirão Preto, Brazil

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Juliana E Toller-Kawahisa

Department of Pharmacology, University of Sao Paulo, Ribeirão Preto, Brazil

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Amanda Becerra

Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil

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Samuel Oliveira

Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil

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Diego B Caetite

Department of Pharmacology, University of Sao Paulo, Ribeirão Preto, Brazil

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Leticia Almeida

Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil

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Adriene Y Ishimoto

Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil

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Thais M Lima

Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil

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"This ORCID iD identifies the author of this article:" 0000-0002-5714-6057
Ronaldo B Martins

Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil

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Flavio P Veras

Department of Pharmacology, University of Sao Paulo, Ribeirão Preto, Brazil

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Natália B do Amaral

Division of Clinical Immunology, University of Sao Paulo, Ribeirão Preto, Brazil

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Marcela C Giannini

Division of Clinical Immunology, University of Sao Paulo, Ribeirão Preto, Brazil

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Letícia P Bonjorno

Division of Clinical Immunology, University of Sao Paulo, Ribeirão Preto, Brazil

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Maria Isabel F Lopes

Division of Clinical Immunology, University of Sao Paulo, Ribeirão Preto, Brazil

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Maira N Benatti

Department of Pathology and Forensic Medicine, University of Sao Paulo, Ribeirão Preto, Brazil

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Sabrina S Batah

Department of Pathology and Forensic Medicine, University of Sao Paulo, Ribeirão Preto, Brazil

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Rodrigo C Santana

Division of Clinical Immunology, University of Sao Paulo, Ribeirão Preto, Brazil

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Fernando C Vilar

Division of Clinical Immunology, University of Sao Paulo, Ribeirão Preto, Brazil

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Maria Auxiliadora Martins

Department of Pathology and Forensic Medicine, University of Sao Paulo, Ribeirão Preto, Brazil

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Rodrigo L Assad

Division of Clinical Immunology, University of Sao Paulo, Ribeirão Preto, Brazil

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"This ORCID iD identifies the author of this article:" 0000-0002-8430-8357
Sergio CL deAlmeida

Division of Clinical Immunology, University of Sao Paulo, Ribeirão Preto, Brazil

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Fabiola R de Oliveira

Division of Clinical Immunology, University of Sao Paulo, Ribeirão Preto, Brazil

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Eurico Arruda Neto

Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil

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Thiago M Cunha

Department of Pharmacology, University of Sao Paulo, Ribeirao Preto, Brazil

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"This ORCID iD identifies the author of this article:" 0000-0003-1084-0065
Jose C Alves-Filho

Department of Pharmacology, University of Sao Paulo, Ribeirao Preto, Brazil

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Vania LD Bonato

Department of Biochemistry and Immunology, University of Sao Paulo, Ribeirão Preto, Brazil

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Fernando Q Cunha

Department of Pharmacology, University of Sao Paulo, Ribeirão Preto, Brazil

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Alexandre T Fabro

Department of Pathology and Forensic Medicine, University of Sao Paulo, Ribeirão Preto, Brazil

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Helder I Nakaya

Department of Clinical and Toxicological Analysis, University of São Paulo, São Paulo, Brazil

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"This ORCID iD identifies the author of this article:" 0000-0001-5297-9108
Dario S Zamboni

Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of São Paulo, Ribeirão Preto, Brazil

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"This ORCID iD identifies the author of this article:" 0000-0002-7856-7512
Paulo Louzada-Junior

Center of Research in Inflammatory Diseases, University of Sao Paulo, Ribeirão Preto, Brazil

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Renê DR de Oliveira

Division of Clinical Immunology, University of Sao Paulo, Ribeirão Preto, Brazil

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Larissa D Cunha

Department of Cellular and Molecular Biology and Pathogenic Bioagents, University of Sao Paulo, Ribeirão Preto, Brazil

For correspondence
larissacunha@usp.br

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"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

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.