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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.

SUBMITTER: Brunetti NS

PROVIDER: S-EPMC10390044 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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

Brunetti Natalia S NS Davanzo Gustavo G GG de Moraes Diogo D Ferrari Allan J R AJR Souza Gabriela F GF Muraro Stéfanie Primon SP Knittel Thiago L TL Boldrini Vinicius O VO Monteiro Lauar B LB Virgílio-da-Silva João Victor JV Profeta Gerson S GS Wassano Natália S NS Nunes Santos Luana L Carregari Victor C VC Dias Artur H S AHS Veras Flavio P FP Tavares Lucas A LA Forato Julia J Castro Icaro M S IMS Silva-Costa Lícia C LC Palma André C AC Mansour Eli E Ulaf Raisa G RG Bernardes Ana F AF Nunes Thyago A TA Ribeiro Luciana C LC Agrela Marcus V MV Moretti Maria Luiza ML Buscaratti Lucas I LI Crunfli Fernanda F Ludwig Raissa G RG Gerhardt Jaqueline A JA Munhoz-Alves Natália N Marques Ana Maria AM Sesti-Costa Renata R Amorim Mariene R MR Toledo-Teixeira Daniel A DA Parise Pierina Lorencini PL Martini Matheus Cavalheiro MC Bispos-Dos-Santos Karina K Simeoni Camila L CL Granja Fabiana F Silvestrini Virgínia C VC de Oliveira Eduardo B EB Faca Vitor M VM Carvalho Murilo M Castelucci Bianca G BG Pereira Alexandre B AB Coimbra Laís D LD Dias Marieli M G MMG Rodrigues Patricia B PB Gomes Arilson Bernardo S P ABSP Pereira Fabricio B FB Santos Leonilda M B LMB Bloyet Louis-Marie LM Stumpf Spencer S Pontelli Marjorie C MC Whelan Sean S Sposito Andrei C AC Carvalho Robson F RF Vieira André S AS Vinolo Marco A R MAR Damasio André A Velloso Licio L Figueira Ana Carolina M ACM da Silva Luis L P LLP Cunha Thiago Mattar TM Nakaya Helder I HI Marques-Souza Henrique H Marques Rafael E RE Martins-de-Souza Daniel D Skaf Munir S MS Proenca-Modena Jose Luiz JL Moraes-Vieira Pedro M M PMM Mori Marcelo A MA Farias Alessandro S AS

eLife 20230731

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. ...[more]

PMID: 37523305

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Project description:The endemic human JC polyomavirus (JCPyV) causes progressive multifocal leukoencephalopathy in immune-suppressed patients. The mechanisms of virus infection in vivo are not understood because the major target cells for virus in the brain do not express virus receptors and do not bind virus. We found that JCPyV associates with extracellular vesicles (EVs) and can infect target cells independently of virus receptors. Virus particles were found packaged inside extracellular vesicles and attached to the outer side of vesicles. Anti-JCPyV antisera reduced infection by purified virus but had no effect on infection by EV-associated virus. Treatment of cells with the receptor-destroying enzyme neuraminidase inhibited infection with purified virus but did not inhibit infection by EV-associated virus. Mutant pseudoviruses defective in sialic acid receptor binding could not transduce cells as purified pseudovirions but could do so when associated with EVs. This alternative mechanism of infection likely plays a critical role in the dissemination and spread of JCPyV both to and within the central nervous system.IMPORTANCE JC polyomavirus (JCPyV) is a ubiquitous human pathogen that causes progressive multifocal leukoencephalopathy (PML), a severe and often fatal neurodegenerative disease in immunocompromised or immunomodulated patients. The mechanisms responsible for initiating infection in susceptible cells are not completely known. The major attachment receptor for the virus, lactoseries tetrasaccharide c (LSTc), is paradoxically not expressed on oligodendrocytes or astrocytes in human brain, and virus does not bind to these cells. Because these are the major cell types targeted by the virus in the brain, we hypothesized that alternative mechanisms of infection must be responsible. Here we provide evidence that JCPyV is packaged in extracellular vesicles from infected cells. Infection of target cells by vesicle-associated virus is not dependent on LSTc and is not neutralized by antisera directed against the virus. This is the first demonstration of a polyomavirus using extracellular vesicles as a means of transmission.

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

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

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