SARS-CoV-2 Uses CD4 to Infect T Helper Lymphocytes

Brunetti, Natália S; Davanzo, Gustavo Gastão; Moraes, Diogo de; Ferrari, Állan J. R.; Souza, Gabriela Fabiano de; Muraro, Stéfanie Primon; Knittel, Thiago L; Boldrini, Vinícius O.; Monteiro, Lauar de Brito; Virgílio-da-Silva, João Victor; Profeta, Gerson S.; Wassano, Natália S.; Santos, Luana Nunes; Carregari, Victor Corasolla; Dias, Artur Hermano Sampaio; Veras, Flávio P.; Tavares, Lucas Alves; Forato, Julia; Castro, Ícaro Maia Santos de; Silva-Costa, Lícia C.; Palma, André C.; Mansour, Eli; Ulaf, Raisa G.; Bernardes, Ana Flávia; Nunes, Thyago A.; Ribeiro, Luciana C.; Agrela, Marcus Vinicius Rodrigues de; Moretti, Maria Luíza; Buscaratti, Lucas I; Crunfli, Fernanda; Ludwig, Raissa G.; Gerhardt, Jaqueline Aline; Munhoz-Alves, Natália; Marques, Ana Maria; Sesti-Costa, Renata; Amorim, Mariene R.; Texeira, Daniel A. T.; Parise, Pierina Lorencini; Martini, Matheus Cavalheiro; Bispo-dos-Santos, Karina; Simeoni, Camila L.; Granja, Fabiana; Silvestrini, Virgínia Campos; Oliveira, Eduardo B.; Faça, Vitor M.; Carvalho, Murilo; Castelucci, Bianca Gazieri; Borin, Alexandre; Coimbra, Laís D.; Dias, Marieli M. G.; Rodrigues, Patrícia Brito; Gomes, Arilson Bernardo SP; Pereira, Fabrício Ramos Silvestre; Santos, Leonilda Maria Barbosa dos; Bloyet, Louis-Marie; Stumpf, Spencer; Pontelli, Marjorie Cornejo; Whelan, Sean P. J.; Spósito, Andrei C.; Carvalho, Robson Francisco; Vieira, André Schwambach; Vinolo, Marco Aurélio Ramirez; Damásio, André; Velloso, Lı́cio A.; Figueira, Ana Carolina Migliorini; Silva, Luis L. P. da; Cunha, Thiago Mattar; Nakaya, Helder I.; Marques-Souza, Henrique; Marques, Rafael Elias; Martins‐de‐Souza, Daniel; Skaf, Munir S.; Proença-Módena, José Luiz; Moraes-Vieira, Pedro M.; Mori, Marcelo A.; Farias, Alessandro S.

doi:10.1101/2020.09.25.20200329

Cited by 35 publications

(49 citation statements)

References 50 publications

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“…There is emerging evidence of cytokine over-production, in particular IL-6 and IL-10, as part of immunopathogenesis within COVID-19; however, drivers of these observed changes are still not fully understood. A recent pre-print report from a Brazilian research group describes infection of CD4+ T cells by SARS-CoV-2, with subsequent high expression of IL-10 by infected cells [ 79 ]. If these data are robust to peer-review and can be replicated elsewhere, this finding may represent one of the contributory factors.…”

Section: Discussionmentioning

confidence: 99%

T cell response to SARS-CoV-2 infection in humans: A systematic review

et al. 2021

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Background Understanding the T cell response to SARS-CoV-2 is critical to vaccine development, epidemiological surveillance and disease control strategies. This systematic review critically evaluates and synthesises the relevant peer-reviewed and pre-print literature published from 01/01/2020-26/06/2020. Methods For this systematic review, keyword-structured literature searches were carried out in MEDLINE, Embase and COVID-19 Primer. Papers were independently screened by two researchers, with arbitration of disagreements by a third researcher. Data were independently extracted into a pre-designed Excel template and studies critically appraised using a modified version of the MetaQAT tool, with resolution of disagreements by consensus. Findings were narratively synthesised. Results 61 articles were included. 55 (90%) studies used observational designs, 50 (82%) involved hospitalised patients with higher acuity illness, and the majority had important limitations. Symptomatic adult COVID-19 cases consistently show peripheral T cell lymphopenia, which positively correlates with increased disease severity, duration of RNA positivity, and non-survival; while asymptomatic and paediatric cases display preserved counts. People with severe or critical disease generally develop more robust, virus-specific T cell responses. T cell memory and effector function has been demonstrated against multiple viral epitopes, and, cross-reactive T cell responses have been demonstrated in unexposed and uninfected adults, but the significance for protection and susceptibility, respectively, remains unclear. Conclusion A complex pattern of T cell response to SARS-CoV-2 infection has been demonstrated, but inferences regarding population level immunity are hampered by significant methodological limitations and heterogeneity between studies, as well as a striking lack of research in asymptomatic or pauci-symptomatic individuals. In contrast to antibody responses, population-level surveillance of the T cell response is unlikely to be feasible in the near term. Focused evaluation in specific sub-groups, including vaccine recipients, should be prioritised.

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Section: Discussionmentioning

confidence: 99%

T cell response to SARS-CoV-2 infection in humans: A systematic review

et al. 2021

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“…Consistently, recent histopathological case studies from post-mortem COVID-19 patient tissues have reported the reactivity of SARS-CoV2 spike protein antibody in tracheal submucosa lymphocytes and alveolar macrophages [ 30 ], with observations of the splenic and lymph node regions of severe COVID patients have shown significant lymphocytic apoptosis, and SARS-CoV2 nucleoprotein reactivity along with IL-6 upregulation in ACE2 positive macrophages [ 31 ]. A recent study has confirmed SARS-CoV2 can directly infect and replicate in CD4 T helper cells via viral infection tests of isolated healthy human peripheral blood samples, and by confirming presence of SARS-CoV2 RNA in COVID patients [ 32 ]. However, these studies have not confirmed the expression of LFA-1 or Mac-1 in the SARS-CoV2-infected cells.…”

Section: Discussionmentioning

confidence: 99%

Structural assessment of SARS-CoV2 accessory protein ORF7a predicts LFA-1 and Mac-1 binding potential

Nizamudeen

Karthik

et al. 2021

Bioscience Reports

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ORF7a is an accessory protein common to SARS-CoV1 and the recently discovered SARS-CoV2, which is causing the COVID-19 pandemic. The ORF7a protein has a structural homology with ICAM-1 which binds to the T lymphocyte integrin receptor LFA-1. As COVID-19 has a strong immune component as part of the disease, we sought to determine whether SARS-CoV2 would have a similar structural interaction with LFA-1. Using molecular docking simulations, we found that SARS-CoV2 ORF7a has the key structural determinants required to bind LFA-1 but also the related leukocyte integrin Mac-1, which is also known to be expressed by macrophages. Our study shows that SARS-CoV2 ORF7a protein has a conserved Ig immunoglobulin-like fold containing an integrin binding site that provides a mechanistic hypothesis for SARS-CoV2’s interaction with the human immune system. This suggests that experimental investigation of ORF7a-mediated effects on immune cells such as T lymphocytes and macrophages (leukocytes) could help understand the disease further and develop effective treatments.

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“…It has been recently proposed that SARS-CoV-2 may be able to infect TH cells by the interaction between S protein and CD4 [ 119 ]. SARS-CoV-2 infected TH cells secrete higher levels of IL-10 and lower proinflammatory cytokines e.g., IFN-γ and IL-17, which is more pronounced in severe cases than in moderate cases or in healthy individuals.…”

Section: Immune Response To Sars-cov-2mentioning

confidence: 99%

SARS–CoV-2 Immuno-Pathogenesis and Potential for Diverse Vaccines and Therapies: Opportunities and Challenges

McGill

Kahlil

Dutta

et al. 2021

Infectious Disease Reports

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Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a novel coronavirus that emerged from Wuhan, China in late 2019 causing coronavirus disease-19 (COVID-19). SARS-CoV-2 infection begins by attaching to angiotensin-converting enzyme 2 receptor (ACE2) via the spike glycoprotein, followed by cleavage by TMPRSS2, revealing the viral fusion domain. Other presumptive receptors for SARS-CoV-2 attachment include CD147, neuropilin-1 (NRP1), and Myeloid C-lectin like receptor (CLR), each of which might play a role in the systemic viral spread. The pathology of SARS-CoV-2 infection ranges from asymptomatic to severe acute respiratory distress syndrome, often displaying a cytokine storm syndrome, which can be life-threatening. Despite progress made, the detailed mechanisms underlying SARS-CoV-2 interaction with the host immune system remain unclear and are an area of very active research. The process’s key players include viral non-structural proteins and open reading frame products, which have been implicated in immune antagonism. The dysregulation of the innate immune system results in reduced adaptive immune responses characterized by rapidly diminishing antibody titers. Several treatment options for COVID-19 are emerging, with immunotherapies, peptide therapies, and nucleic acid vaccines showing promise. This review discusses the advances in the immunopathology of SARS-CoV-2, vaccines and therapies under investigation to counter the effects of this virus, as well as viral variants.

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SARS-CoV-2 Uses CD4 to Infect T Helper Lymphocytes

Cited by 35 publications

References 50 publications

T cell response to SARS-CoV-2 infection in humans: A systematic review

T cell response to SARS-CoV-2 infection in humans: A systematic review

Structural assessment of SARS-CoV2 accessory protein ORF7a predicts LFA-1 and Mac-1 binding potential

SARS–CoV-2 Immuno-Pathogenesis and Potential for Diverse Vaccines and Therapies: Opportunities and Challenges

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