Unique molecular signatures sustained in circulating monocytes and regulatory T cells in convalescent COVID-19 patients

Andrew D. Hoffmann; Sam E. Weinberg; Suchitra Swaminathan; Shuvam Chaudhuri; Hannah Faisal Almubarak; Matthew J. Schipma; Chengsheng Mao; Xinkun Wang; Lamiaa El-Shennawy; Nurmaa K. Dashzeveg; Juncheng Wei; Paul J. Mehl; Laura J. Shihadah; Ching Man Wai; Carolina Ostiguin; Yuzhi Jia; Paolo D'Amico; Neale R. Wang; Yuan Luo; Alexis R. Demonbreun; Michael G. Ison; Huiping Liu; Deyu Fang

doi:10.1016/j.clim.2023.109634

Unique molecular signatures sustained in circulating monocytes and regulatory T cells in convalescent COVID-19 patients

Andrew D. Hoffmann, Sam E. Weinberg, Suchitra Swaminathan, Shuvam Chaudhuri, Hannah Faisal Almubarak, Matthew J. Schipma, Chengsheng Mao, Xinkun Wang, Lamiaa El-Shennawy, Nurmaa K. Dashzeveg, Juncheng Wei, Paul J. Mehl, Laura J. Shihadah, Ching Man Wai, Carolina Ostiguin, Yuzhi Jia, Paolo D'Amico, Neale R. Wang, Yuan Luo, Alexis R. DemonbreunMichael G. Ison^*, Huiping Liu^*, Deyu Fang^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

Over two years into the COVID-19 pandemic, the human immune response to SARS-CoV-2 during the active disease phase has been extensively studied. However, the long-term impact after recovery, which is critical to advance our understanding SARS-CoV-2 and COVID-19-associated long-term complications, remains largely unknown. Herein, we characterized single-cell profiles of circulating immune cells in the peripheral blood of 100 patients, including convalescent COVID-19 and sero-negative controls. Flow cytometry analyses revealed reduced frequencies of both short-lived monocytes and long-lived regulatory T (Treg) cells within the patients who have recovered from severe COVID-19. sc-RNA seq analysis identifies seven heterogeneous clusters of monocytes and nine Treg clusters featuring distinct molecular signatures in association with COVID-19 severity. Asymptomatic patients contain the most abundant clusters of monocytes and Tregs expressing high CD74 or IFN-responsive genes. In contrast, the patients recovered from a severe disease have shown two dominant inflammatory monocyte clusters featuring S100 family genes: one monocyte cluster of S100A8 & A9 coupled with high HLA-I and another cluster of S100A4 & A6 with high HLA-II genes, a specific non-classical monocyte cluster with distinct IFITM family genes, as well as a unique TGF-β high Treg Cluster. The outpatients and seronegative controls share most of the monocyte and Treg clusters patterns with high expression of HLA genes. Surprisingly, while presumably short-lived monocytes appear to have sustained alterations over 4 months, the decreased frequencies of long-lived Tregs (high HLA-DRA and S100A6) in the outpatients restore over the tested convalescent time (≥ 4 months). Collectively, our study identifies sustained and dynamically altered monocytes and Treg clusters with distinct molecular signatures after recovery, associated with COVID-19 severity.

Original language	English (US)
Article number	109634
Journal	Clinical Immunology
Volume	252
DOIs	https://doi.org/10.1016/j.clim.2023.109634
State	Published - Jul 2023

Funding

We are thankful to the team of Northwestern COVID-19 Antibody and Cancer Collaborative Group and advisory members, especially Drs. Alfred L. George Jr., Richard D'Aquila, Leonidas C. Platanias, Rex L. Chishom, and William A. Muller for their scientific input and resourceful support for the project. The work was partially funded by The National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases (NIAID) R01AI167272 and Chicago Biomedical Consortium Accelerator Award A-017 (H.L. and D.F.), Northwestern University Feinberg School of Medicine Emerging and Re-emerging Pathogens Program (EREPP) (H.L.), Department of Pharmacology Start-up fund (H.L.), and the R.H. Lurie Comprehensive Cancer Center Blood Biobank fund and Northwestern University Clinical & Translational Sciences Institute (NUCATS) grant UL1TR001422 (M.I.). We gratefully acknowledge the support from the NUseq Core Facility . This work was supported by the Northwestern University RHLCCC Flow Cytometry Facility and a Cancer Center Support Grant National Cancer Institute (NCI) ( CA060553 ). Flow Cytometry Cell Sorting was performed on a BD FACSAria SORP system and BD FACSymphony S6 SORP system, purchased through the support of NIH 1S10OD011996-01 and 1S10OD026814-01 . We are thankful to the team of Northwestern COVID-19 Antibody and Cancer Collaborative Group and advisory members, especially Drs. Alfred L. George Jr. Richard D'Aquila, Leonidas C. Platanias, Rex L. Chishom, and William A. Muller for their scientific input and resourceful support for the project. The work was partially funded by The National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases (NIAID) R01AI167272 and Chicago Biomedical Consortium Accelerator Award A-017 (H.L. and D.F.), Northwestern University Feinberg School of Medicine Emerging and Re-emerging Pathogens Program (EREPP) (H.L.), Department of Pharmacology Start-up fund (H.L.), and the R.H. Lurie Comprehensive Cancer Center Blood Biobank fund and Northwestern University Clinical & Translational Sciences Institute (NUCATS) grant UL1TR001422 (M.I.). We gratefully acknowledge the support from the NUseq Core Facility. This work was supported by the Northwestern University RHLCCC Flow Cytometry Facility and a Cancer Center Support Grant National Cancer Institute (NCI) (CA060553). Flow Cytometry Cell Sorting was performed on a BD FACSAria SORP system and BD FACSymphony S6 SORP system, purchased through the support of NIH 1S10OD011996-01 and 1S10OD026814-01.

Keywords

COVID-19
Monocytes
Sustained immunity
Tregs

ASJC Scopus subject areas

Immunology and Allergy
Immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.clim.2023.109634

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Hoffmann, A. D., Weinberg, S. E., Swaminathan, S., Chaudhuri, S., Almubarak, H. F., Schipma, M. J., Mao, C., Wang, X., El-Shennawy, L., Dashzeveg, N. K., Wei, J., Mehl, P. J., Shihadah, L. J., Wai, C. M., Ostiguin, C., Jia, Y., D'Amico, P., Wang, N. R., Luo, Y., ... Fang, D. (2023). Unique molecular signatures sustained in circulating monocytes and regulatory T cells in convalescent COVID-19 patients. Clinical Immunology, 252, Article 109634. https://doi.org/10.1016/j.clim.2023.109634

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title = "Unique molecular signatures sustained in circulating monocytes and regulatory T cells in convalescent COVID-19 patients",

abstract = "Over two years into the COVID-19 pandemic, the human immune response to SARS-CoV-2 during the active disease phase has been extensively studied. However, the long-term impact after recovery, which is critical to advance our understanding SARS-CoV-2 and COVID-19-associated long-term complications, remains largely unknown. Herein, we characterized single-cell profiles of circulating immune cells in the peripheral blood of 100 patients, including convalescent COVID-19 and sero-negative controls. Flow cytometry analyses revealed reduced frequencies of both short-lived monocytes and long-lived regulatory T (Treg) cells within the patients who have recovered from severe COVID-19. sc-RNA seq analysis identifies seven heterogeneous clusters of monocytes and nine Treg clusters featuring distinct molecular signatures in association with COVID-19 severity. Asymptomatic patients contain the most abundant clusters of monocytes and Tregs expressing high CD74 or IFN-responsive genes. In contrast, the patients recovered from a severe disease have shown two dominant inflammatory monocyte clusters featuring S100 family genes: one monocyte cluster of S100A8 & A9 coupled with high HLA-I and another cluster of S100A4 & A6 with high HLA-II genes, a specific non-classical monocyte cluster with distinct IFITM family genes, as well as a unique TGF-β high Treg Cluster. The outpatients and seronegative controls share most of the monocyte and Treg clusters patterns with high expression of HLA genes. Surprisingly, while presumably short-lived monocytes appear to have sustained alterations over 4 months, the decreased frequencies of long-lived Tregs (high HLA-DRA and S100A6) in the outpatients restore over the tested convalescent time (≥ 4 months). Collectively, our study identifies sustained and dynamically altered monocytes and Treg clusters with distinct molecular signatures after recovery, associated with COVID-19 severity.",

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author = "Hoffmann, {Andrew D.} and Weinberg, {Sam E.} and Suchitra Swaminathan and Shuvam Chaudhuri and Almubarak, {Hannah Faisal} and Schipma, {Matthew J.} and Chengsheng Mao and Xinkun Wang and Lamiaa El-Shennawy and Dashzeveg, {Nurmaa K.} and Juncheng Wei and Mehl, {Paul J.} and Shihadah, {Laura J.} and Wai, {Ching Man} and Carolina Ostiguin and Yuzhi Jia and Paolo D'Amico and Wang, {Neale R.} and Yuan Luo and Demonbreun, {Alexis R.} and Ison, {Michael G.} and Huiping Liu and Deyu Fang",

note = "Publisher Copyright: {\textcopyright} 2023 Elsevier Inc.",

year = "2023",

month = jul,

doi = "10.1016/j.clim.2023.109634",

language = "English (US)",

volume = "252",

journal = "Clinical Immunology",

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Hoffmann, AD, Weinberg, SE , Swaminathan, S, Chaudhuri, S, Almubarak, HF, Schipma, MJ , Mao, C , Wang, X , El-Shennawy, L , Dashzeveg, NK, Wei, J, Mehl, PJ, Shihadah, LJ, Wai, CM, Ostiguin, C, Jia, Y, D'Amico, P, Wang, NR, Luo, Y , Demonbreun, AR, Ison, MG, Liu, H & Fang, D 2023, 'Unique molecular signatures sustained in circulating monocytes and regulatory T cells in convalescent COVID-19 patients', Clinical Immunology, vol. 252, 109634. https://doi.org/10.1016/j.clim.2023.109634

TY - JOUR

T1 - Unique molecular signatures sustained in circulating monocytes and regulatory T cells in convalescent COVID-19 patients

AU - Hoffmann, Andrew D.

AU - Weinberg, Sam E.

AU - Swaminathan, Suchitra

AU - Chaudhuri, Shuvam

AU - Almubarak, Hannah Faisal

AU - Schipma, Matthew J.

AU - Mao, Chengsheng

AU - Wang, Xinkun

AU - El-Shennawy, Lamiaa

AU - Dashzeveg, Nurmaa K.

AU - Wei, Juncheng

AU - Mehl, Paul J.

AU - Shihadah, Laura J.

AU - Wai, Ching Man

AU - Ostiguin, Carolina

AU - Jia, Yuzhi

AU - D'Amico, Paolo

AU - Wang, Neale R.

AU - Luo, Yuan

AU - Demonbreun, Alexis R.

AU - Ison, Michael G.

AU - Liu, Huiping

AU - Fang, Deyu

PY - 2023/7

Y1 - 2023/7

N2 - Over two years into the COVID-19 pandemic, the human immune response to SARS-CoV-2 during the active disease phase has been extensively studied. However, the long-term impact after recovery, which is critical to advance our understanding SARS-CoV-2 and COVID-19-associated long-term complications, remains largely unknown. Herein, we characterized single-cell profiles of circulating immune cells in the peripheral blood of 100 patients, including convalescent COVID-19 and sero-negative controls. Flow cytometry analyses revealed reduced frequencies of both short-lived monocytes and long-lived regulatory T (Treg) cells within the patients who have recovered from severe COVID-19. sc-RNA seq analysis identifies seven heterogeneous clusters of monocytes and nine Treg clusters featuring distinct molecular signatures in association with COVID-19 severity. Asymptomatic patients contain the most abundant clusters of monocytes and Tregs expressing high CD74 or IFN-responsive genes. In contrast, the patients recovered from a severe disease have shown two dominant inflammatory monocyte clusters featuring S100 family genes: one monocyte cluster of S100A8 & A9 coupled with high HLA-I and another cluster of S100A4 & A6 with high HLA-II genes, a specific non-classical monocyte cluster with distinct IFITM family genes, as well as a unique TGF-β high Treg Cluster. The outpatients and seronegative controls share most of the monocyte and Treg clusters patterns with high expression of HLA genes. Surprisingly, while presumably short-lived monocytes appear to have sustained alterations over 4 months, the decreased frequencies of long-lived Tregs (high HLA-DRA and S100A6) in the outpatients restore over the tested convalescent time (≥ 4 months). Collectively, our study identifies sustained and dynamically altered monocytes and Treg clusters with distinct molecular signatures after recovery, associated with COVID-19 severity.

AB - Over two years into the COVID-19 pandemic, the human immune response to SARS-CoV-2 during the active disease phase has been extensively studied. However, the long-term impact after recovery, which is critical to advance our understanding SARS-CoV-2 and COVID-19-associated long-term complications, remains largely unknown. Herein, we characterized single-cell profiles of circulating immune cells in the peripheral blood of 100 patients, including convalescent COVID-19 and sero-negative controls. Flow cytometry analyses revealed reduced frequencies of both short-lived monocytes and long-lived regulatory T (Treg) cells within the patients who have recovered from severe COVID-19. sc-RNA seq analysis identifies seven heterogeneous clusters of monocytes and nine Treg clusters featuring distinct molecular signatures in association with COVID-19 severity. Asymptomatic patients contain the most abundant clusters of monocytes and Tregs expressing high CD74 or IFN-responsive genes. In contrast, the patients recovered from a severe disease have shown two dominant inflammatory monocyte clusters featuring S100 family genes: one monocyte cluster of S100A8 & A9 coupled with high HLA-I and another cluster of S100A4 & A6 with high HLA-II genes, a specific non-classical monocyte cluster with distinct IFITM family genes, as well as a unique TGF-β high Treg Cluster. The outpatients and seronegative controls share most of the monocyte and Treg clusters patterns with high expression of HLA genes. Surprisingly, while presumably short-lived monocytes appear to have sustained alterations over 4 months, the decreased frequencies of long-lived Tregs (high HLA-DRA and S100A6) in the outpatients restore over the tested convalescent time (≥ 4 months). Collectively, our study identifies sustained and dynamically altered monocytes and Treg clusters with distinct molecular signatures after recovery, associated with COVID-19 severity.

KW - COVID-19

KW - Monocytes

KW - Sustained immunity

KW - Tregs

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DO - 10.1016/j.clim.2023.109634

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SN - 1521-6616

VL - 252

JO - Clinical Immunology

JF - Clinical Immunology

M1 - 109634

ER -

Unique molecular signatures sustained in circulating monocytes and regulatory T cells in convalescent COVID-19 patients

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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