SARS-CoV-2 uses CD4 to infect T helper lymphocytes

Natalia S. Brunetti; Gustavo G. Davanzo; Diogo de Moraes; Allan J.R. Ferrari; Gabriela F. Souza; Stéfanie Primon Muraro; Thiago L. Knittel; Vinicius O. Boldrini; Lauar B. Monteiro; João Victor Virgílio-Da-silva; Gerson S. Profeta; Natália S. Wassano; Luana Nunes Santos; Victor C. Carregari; Artur H.S. Dias; Flavio P. Veras; Lucas A. Tavares; Julia Forato; Icaro M.S. Castro; Lícia C. Silva-Costa; André C. Palma; Eli Mansour; Raisa G. Ulaf; Ana F. Bernardes; Thyago A. Nunes; Luciana C. Ribeiro; Marcus V. Agrela; Maria Luiza Moretti; Lucas I. Buscaratti; Fernanda Crunfli; Raissa G. Ludwig; Jaqueline A. Gerhardt; Natália Munhoz-Alves; Ana Maria Marques; Renata Sesti-Costa; Mariene R. Amorim; Daniel A. Toledo-Teixeira; Pierina Lorencini Parise; Matheus Cavalheiro Martini; Karina Bispos-Dos-santos; Camila L. Simeoni; Fabiana Granja; Virgínia C. Silvestrini; Eduardo B. de Oliveira; Vitor M. Faca; Murilo Carvalho; Bianca G. Castelucci; Alexandre B. Pereira; Laís D. Coimbra; Marieli M.G. Dias; Patricia B. Rodrigues; Arilson Bernardo S.P. Gomes; Fabricio B. Pereira; Leonilda M.B. Santos; Louis Marie Bloyet; Spencer Stumpf; Marjorie C. Pontelli; Sean Whelan; Andrei C. Sposito; Robson F. Carvalho; André S. Vieira; Marco A.R. Vinolo; André Damasio; Licio Velloso; Ana Carolina M. Figueira; Luis L.P. da Silva; Thiago Mattar Cunha; Helder I. Nakaya; Henrique Marques-Souza; Rafael E. Marques; Daniel Martins-De-souza; Munir S. Skaf; Jose Luiz Proenca-Modena; Pedro M.M. Moraes-Vieira; Marcelo A. Mori; Alessandro S. Farias

doi:10.7554/eLife.84790

SARS-CoV-2 uses CD4 to infect T helper lymphocytes

Natalia S. Brunetti, Gustavo G. Davanzo, Diogo de Moraes, Allan J.R. Ferrari, Gabriela F. Souza, Stéfanie Primon Muraro, Thiago L. Knittel, Vinicius O. Boldrini, Lauar B. Monteiro, João Victor Virgílio-Da-silva, Gerson S. Profeta, Natália S. Wassano, Luana Nunes Santos, Victor C. Carregari, Artur H.S. Dias, Flavio P. Veras, Lucas A. Tavares, Julia Forato, Icaro M.S. Castro, Lícia C. Silva-CostaAndré C. Palma, Eli Mansour, Raisa G. Ulaf, Ana F. Bernardes, Thyago A. Nunes, Luciana C. Ribeiro, Marcus V. Agrela, Maria Luiza Moretti, Lucas I. Buscaratti, Fernanda Crunfli, Raissa G. Ludwig, Jaqueline A. Gerhardt, Natália Munhoz-Alves, Ana Maria Marques, Renata Sesti-Costa, Mariene R. Amorim, Daniel A. Toledo-Teixeira, Pierina Lorencini Parise, Matheus Cavalheiro Martini, Karina Bispos-Dos-santos, Camila L. Simeoni, Fabiana Granja, Virgínia C. Silvestrini, Eduardo B. de Oliveira, Vitor M. Faca, Murilo Carvalho, Bianca G. Castelucci, Alexandre B. Pereira, Laís D. Coimbra, Marieli M.G. Dias, Patricia B. Rodrigues, Arilson Bernardo S.P. Gomes, Fabricio B. Pereira, Leonilda M.B. Santos, Louis Marie Bloyet, Spencer Stumpf, Marjorie C. Pontelli, Sean Whelan, Andrei C. Sposito, Robson F. Carvalho, André S. Vieira, Marco A.R. Vinolo, André Damasio, Licio Velloso, Ana Carolina M. Figueira, Luis L.P. da Silva, Thiago Mattar Cunha, Helder I. Nakaya, Henrique Marques-Souza, Rafael E. Marques, Daniel Martins-De-souza, Munir S. Skaf, Jose Luiz Proenca-Modena, Pedro M.M. Moraes-Vieira, Marcelo A. Mori^*, Alessandro S. Farias^*

^*Corresponding author for this work

Pharmacology

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

13 Scopus citations

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the agent of a major global outbreak of respiratory tract disease known as Coronavirus Disease 2019 (COVID-19). SARS-CoV-2 infects mainly lungs and may cause several immune-related complications, such as lymphocytopenia and cytokine storm, which are associated with the severity of the disease and predict mortality. The mechanism by which SARS-CoV-2 infection may result in immune system dysfunction is still not fully understood. Here, we show that SARS-CoV-2 infects human CD4+ T helper cells, but not CD8+ T cells, and is present in blood and bronchoalveolar lavage T helper cells of severe COVID-19 patients. We demonstrated that SARS-CoV-2 spike glycoprotein (S) directly binds to the CD4 molecule, which in turn mediates the entry of SARS- CoV-2 in T helper cells. This leads to impaired CD4 T cell function and may cause cell death. SARS-CoV-2-infected T helper cells express higher levels of IL-10, which is associated with viral persistence and disease severity. Thus, CD4-mediated SARS-CoV-2 infection of T helper cells may contribute to a poor immune response in COVID-19 patients.

Original language	English (US)
Journal	eLife
Volume	12
DOIs	https://doi.org/10.7554/eLife.84790
State	Published - Jul 31 2023

Funding

We acknowledge the technical support of Elzira E Saviani, Paulo A Baldasso, and Mariana Ozello Baratti. We thank Dr. Leda Castilho (UFRJ) for providing sCoV-2 recombinant protein, Dr. Edson Luiz Durigon (USP) for providing viral strains, and Dr. Hernandes F de Carvalho (UNICAMP) for providing valuable reagents for immunofluorescence. We also thank the National Institute of Science and Technology of Photonics Applied to Cell Biology (INFABIC) for aid with confocal microscopy. We also thank Antonio Borges, Fabiano Montoro, and LNNano/CNPEM for the use of the electron microscopy facility (TEM-C2-26912, TEM-C2-26935). We acknowledge the Spectroscopy and Calorimetry Laboratory of the Brazilian Biosciences National Laboratory (LNBio), CNPEM, Campinas, Brazil, for the support in fluorescence anisotropy assays. This work was supported by grants from FAEPEX-UNICAMP (#2295/20, #2458/20, #2266/20 and #2274/20), São Paulo Research Foundation (FAPESP) (#2021/08354-2, #2019/16116-4, #2019/06372-3, #2020/04583-4, #2013/08293-7, #2020/04579-7, #2015/15626-8, #2018/14933-2, #2020/04746-0, #2019/00098-7, #2020/04919-2, #2017/01184-9, #2019/14465-1, #2020/04558-0, #2016/00194-8), the National Institute of Science and Technology in Neuroimmunomodulation (INCT-NIM) (#465489/2014-1) and FINEP (#01.20.0003.00). ASF and MAM. were supported by CNPq productivity awards (#306248/2017-4 and #310287/2018-9). AJRF, GGD, NSB, LBM, FC, VCC, AB, TLK, GSP, and RGL were supported by FAPESP fellowships (#2019/17007-4, #2016/18031-8, #2019/22398-2, #2019/13552-8, #2019/05155-9, #2019/06459-1, #2019/04726-2, #2017/23920-9, #2016/24163-4, #2016/23328-0). VOB and LNS were supported by FAEPEX fellowship (#2295/20 and #2319/20). DM was supported by CAPES fellowship.

Keywords

COVID-19
T cells
human
immunology
inflammation
virus infection

ASJC Scopus subject areas

General Neuroscience
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology

UN SDGs

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

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10.7554/eLife.84790

Cite this

Brunetti, N. S., Davanzo, G. G., de Moraes, D., Ferrari, A. J. R., Souza, G. F., Muraro, S. P., Knittel, T. L., Boldrini, V. O., Monteiro, L. B., Virgílio-Da-silva, J. V., Profeta, G. S., Wassano, N. S., Santos, L. N., Carregari, V. C., Dias, A. H. S., Veras, F. P., Tavares, L. A., Forato, J., Castro, I. M. S., ... Farias, A. S. (2023). SARS-CoV-2 uses CD4 to infect T helper lymphocytes. eLife, 12. https://doi.org/10.7554/eLife.84790

@article{8823ea08d85f497b8145492f8581cb29,

title = "SARS-CoV-2 uses CD4 to infect T helper lymphocytes",

abstract = "The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the agent of a major global outbreak of respiratory tract disease known as Coronavirus Disease 2019 (COVID-19). SARS-CoV-2 infects mainly lungs and may cause several immune-related complications, such as lymphocytopenia and cytokine storm, which are associated with the severity of the disease and predict mortality. The mechanism by which SARS-CoV-2 infection may result in immune system dysfunction is still not fully understood. Here, we show that SARS-CoV-2 infects human CD4+ T helper cells, but not CD8+ T cells, and is present in blood and bronchoalveolar lavage T helper cells of severe COVID-19 patients. We demonstrated that SARS-CoV-2 spike glycoprotein (S) directly binds to the CD4 molecule, which in turn mediates the entry of SARS- CoV-2 in T helper cells. This leads to impaired CD4 T cell function and may cause cell death. SARS-CoV-2-infected T helper cells express higher levels of IL-10, which is associated with viral persistence and disease severity. Thus, CD4-mediated SARS-CoV-2 infection of T helper cells may contribute to a poor immune response in COVID-19 patients.",

keywords = "COVID-19, T cells, human, immunology, inflammation, virus infection",

author = "Brunetti, {Natalia S.} and Davanzo, {Gustavo G.} and {de Moraes}, Diogo and Ferrari, {Allan J.R.} and Souza, {Gabriela F.} and Muraro, {St{\'e}fanie Primon} and Knittel, {Thiago L.} and Boldrini, {Vinicius O.} and Monteiro, {Lauar B.} and Virg{\'i}lio-Da-silva, {Jo{\~a}o Victor} and Profeta, {Gerson S.} and Wassano, {Nat{\'a}lia S.} and Santos, {Luana Nunes} and Carregari, {Victor C.} and Dias, {Artur H.S.} and Veras, {Flavio P.} and Tavares, {Lucas A.} and Julia Forato and Castro, {Icaro M.S.} and Silva-Costa, {L{\'i}cia C.} and Palma, {Andr{\'e} C.} and Eli Mansour and Ulaf, {Raisa G.} and Bernardes, {Ana F.} and Nunes, {Thyago A.} and Ribeiro, {Luciana C.} and Agrela, {Marcus V.} and Moretti, {Maria Luiza} and Buscaratti, {Lucas I.} and Fernanda Crunfli and Ludwig, {Raissa G.} and Gerhardt, {Jaqueline A.} and Nat{\'a}lia Munhoz-Alves and Marques, {Ana Maria} and Renata Sesti-Costa and Amorim, {Mariene R.} and Toledo-Teixeira, {Daniel A.} and Parise, {Pierina Lorencini} and Martini, {Matheus Cavalheiro} and Karina Bispos-Dos-santos and Simeoni, {Camila L.} and Fabiana Granja and Silvestrini, {Virg{\'i}nia C.} and {de Oliveira}, {Eduardo B.} and Faca, {Vitor M.} and Murilo Carvalho and Castelucci, {Bianca G.} and Pereira, {Alexandre B.} and Coimbra, {La{\'i}s D.} and Dias, {Marieli M.G.} and Rodrigues, {Patricia B.} and Gomes, {Arilson Bernardo S.P.} and Pereira, {Fabricio B.} and Santos, {Leonilda M.B.} and Bloyet, {Louis Marie} and Spencer Stumpf and Pontelli, {Marjorie C.} and Sean Whelan and Sposito, {Andrei C.} and Carvalho, {Robson F.} and Vieira, {Andr{\'e} S.} and Vinolo, {Marco A.R.} and Andr{\'e} Damasio and Licio Velloso and Figueira, {Ana Carolina M.} and {da Silva}, {Luis L.P.} and Cunha, {Thiago Mattar} and Nakaya, {Helder I.} and Henrique Marques-Souza and Marques, {Rafael E.} and Daniel Martins-De-souza and Skaf, {Munir S.} and Proenca-Modena, {Jose Luiz} and Moraes-Vieira, {Pedro M.M.} and Mori, {Marcelo A.} and Farias, {Alessandro S.}",

note = "Publisher Copyright: {\textcopyright} Brunetti, Davanzo, de Moraes et al.",

year = "2023",

month = jul,

day = "31",

doi = "10.7554/eLife.84790",

language = "English (US)",

volume = "12",

journal = "eLife",

issn = "2050-084X",

publisher = "eLife Sciences Publications Ltd",

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Brunetti, NS, Davanzo, GG, de Moraes, D, Ferrari, AJR, Souza, GF, Muraro, SP, Knittel, TL, Boldrini, VO, Monteiro, LB, Virgílio-Da-silva, JV, Profeta, GS, Wassano, NS, Santos, LN, Carregari, VC, Dias, AHS, Veras, FP, Tavares, LA, Forato, J, Castro, IMS, Silva-Costa, LC, Palma, AC, Mansour, E, Ulaf, RG, Bernardes, AF, Nunes, TA, Ribeiro, LC, Agrela, MV, Moretti, ML, Buscaratti, LI, Crunfli, F, Ludwig, RG, Gerhardt, JA, Munhoz-Alves, N, Marques, AM, Sesti-Costa, R, Amorim, MR, Toledo-Teixeira, DA, Parise, PL, Martini, MC, Bispos-Dos-santos, K, Simeoni, CL, Granja, F, Silvestrini, VC, de Oliveira, EB, Faca, VM, Carvalho, M, Castelucci, BG, Pereira, AB, Coimbra, LD, Dias, MMG, Rodrigues, PB, Gomes, ABSP, Pereira, FB, Santos, LMB, Bloyet, LM, Stumpf, S, Pontelli, MC, Whelan, S, Sposito, AC, Carvalho, RF, Vieira, AS, Vinolo, MAR, Damasio, A, Velloso, L, Figueira, ACM, da Silva, LLP, Cunha, TM, Nakaya, HI, Marques-Souza, H, Marques, RE, Martins-De-souza, D, Skaf, MS, Proenca-Modena, JL, Moraes-Vieira, PMM, Mori, MA & Farias, AS 2023, 'SARS-CoV-2 uses CD4 to infect T helper lymphocytes', eLife, vol. 12. https://doi.org/10.7554/eLife.84790

TY - JOUR

T1 - SARS-CoV-2 uses CD4 to infect T helper lymphocytes

AU - Brunetti, Natalia S.

AU - Davanzo, Gustavo G.

AU - de Moraes, Diogo

AU - Ferrari, Allan J.R.

AU - Souza, Gabriela F.

AU - Muraro, Stéfanie Primon

AU - Knittel, Thiago L.

AU - Boldrini, Vinicius O.

AU - Monteiro, Lauar B.

AU - Virgílio-Da-silva, João Victor

AU - Profeta, Gerson S.

AU - Wassano, Natália S.

AU - Santos, Luana Nunes

AU - Carregari, Victor C.

AU - Dias, Artur H.S.

AU - Veras, Flavio P.

AU - Tavares, Lucas A.

AU - Forato, Julia

AU - Castro, Icaro M.S.

AU - Silva-Costa, Lícia C.

AU - Palma, André C.

AU - Mansour, Eli

AU - Ulaf, Raisa G.

AU - Bernardes, Ana F.

AU - Nunes, Thyago A.

AU - Ribeiro, Luciana C.

AU - Agrela, Marcus V.

AU - Moretti, Maria Luiza

AU - Buscaratti, Lucas I.

AU - Crunfli, Fernanda

AU - Ludwig, Raissa G.

AU - Gerhardt, Jaqueline A.

AU - Munhoz-Alves, Natália

AU - Marques, Ana Maria

AU - Sesti-Costa, Renata

AU - Amorim, Mariene R.

AU - Toledo-Teixeira, Daniel A.

AU - Parise, Pierina Lorencini

AU - Martini, Matheus Cavalheiro

AU - Bispos-Dos-santos, Karina

AU - Simeoni, Camila L.

AU - Granja, Fabiana

AU - Silvestrini, Virgínia C.

AU - de Oliveira, Eduardo B.

AU - Faca, Vitor M.

AU - Carvalho, Murilo

AU - Castelucci, Bianca G.

AU - Pereira, Alexandre B.

AU - Coimbra, Laís D.

AU - Dias, Marieli M.G.

AU - Rodrigues, Patricia B.

AU - Gomes, Arilson Bernardo S.P.

AU - Pereira, Fabricio B.

AU - Santos, Leonilda M.B.

AU - Bloyet, Louis Marie

AU - Stumpf, Spencer

AU - Pontelli, Marjorie C.

AU - Whelan, Sean

AU - Sposito, Andrei C.

AU - Carvalho, Robson F.

AU - Vieira, André S.

AU - Vinolo, Marco A.R.

AU - Damasio, André

AU - Velloso, Licio

AU - Figueira, Ana Carolina M.

AU - da Silva, Luis L.P.

AU - Cunha, Thiago Mattar

AU - Nakaya, Helder I.

AU - Marques-Souza, Henrique

AU - Marques, Rafael E.

AU - Martins-De-souza, Daniel

AU - Skaf, Munir S.

AU - Proenca-Modena, Jose Luiz

AU - Moraes-Vieira, Pedro M.M.

AU - Mori, Marcelo A.

AU - Farias, Alessandro S.

PY - 2023/7/31

Y1 - 2023/7/31

N2 - The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the agent of a major global outbreak of respiratory tract disease known as Coronavirus Disease 2019 (COVID-19). SARS-CoV-2 infects mainly lungs and may cause several immune-related complications, such as lymphocytopenia and cytokine storm, which are associated with the severity of the disease and predict mortality. The mechanism by which SARS-CoV-2 infection may result in immune system dysfunction is still not fully understood. Here, we show that SARS-CoV-2 infects human CD4+ T helper cells, but not CD8+ T cells, and is present in blood and bronchoalveolar lavage T helper cells of severe COVID-19 patients. We demonstrated that SARS-CoV-2 spike glycoprotein (S) directly binds to the CD4 molecule, which in turn mediates the entry of SARS- CoV-2 in T helper cells. This leads to impaired CD4 T cell function and may cause cell death. SARS-CoV-2-infected T helper cells express higher levels of IL-10, which is associated with viral persistence and disease severity. Thus, CD4-mediated SARS-CoV-2 infection of T helper cells may contribute to a poor immune response in COVID-19 patients.

AB - The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the agent of a major global outbreak of respiratory tract disease known as Coronavirus Disease 2019 (COVID-19). SARS-CoV-2 infects mainly lungs and may cause several immune-related complications, such as lymphocytopenia and cytokine storm, which are associated with the severity of the disease and predict mortality. The mechanism by which SARS-CoV-2 infection may result in immune system dysfunction is still not fully understood. Here, we show that SARS-CoV-2 infects human CD4+ T helper cells, but not CD8+ T cells, and is present in blood and bronchoalveolar lavage T helper cells of severe COVID-19 patients. We demonstrated that SARS-CoV-2 spike glycoprotein (S) directly binds to the CD4 molecule, which in turn mediates the entry of SARS- CoV-2 in T helper cells. This leads to impaired CD4 T cell function and may cause cell death. SARS-CoV-2-infected T helper cells express higher levels of IL-10, which is associated with viral persistence and disease severity. Thus, CD4-mediated SARS-CoV-2 infection of T helper cells may contribute to a poor immune response in COVID-19 patients.

KW - COVID-19

KW - T cells

KW - human

KW - immunology

KW - inflammation

KW - virus infection

UR - http://www.scopus.com/inward/record.url?scp=85166395233&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85166395233&partnerID=8YFLogxK

U2 - 10.7554/eLife.84790

DO - 10.7554/eLife.84790

M3 - Article

C2 - 37523305

AN - SCOPUS:85166395233

SN - 2050-084X

VL - 12

JO - eLife

JF - eLife

ER -

SARS-CoV-2 uses CD4 to infect T helper lymphocytes

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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