Systemic and integrative analysis of T lymphocyte exhaustion mechanisms in patients with COVID-19

• Grant number: 20/07069-0
• Support Opportunities: Regular Research Grants
• Start date: July 01, 2020
• End date: December 31, 2022
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Otávio Cabral Marques
• Grantee: Otávio Cabral Marques
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 18/18886-9 - Systemic and integrative analysis of the immune response to Zika and Dengue viral infections, AP.JP
• Associated scholarship(s): 20/09146-1 - Systemic and integrative analysis of molecular mechanisms associated with immunoregulation in patients with COVID-19, BP.PD

Abstract

The current pandemic of the Coronavirus respiratory disease 2019 (COVID-19) represents a state of international public emergency. The virus causing the disease is called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has been circulating throughout the world, triggering clinical manifestations ranging from asymptomatic cases to severe acute respiratory syndrome and death, especially of individuals with comorbidities (ex: hypertension, asthma, and diabetes). Thus, suggesting the influence of immunological and other host factors in controlling the development of the disease. Meanwhile, patients who develop severe illness may die due to intense immune dysregulation. However, the knowledge about the systemic immunological mechanisms that control the protection against SARS-CoV-2 is still scarce and the systemic aspects of the immune response of T lymphocytes, effector leukocytes and immune system regulators, remain to be characterized. The hypothesis of this project is that a possible predisposition to systemic exhaustion profile of T lymphocytes, i.e. the interaction network of genes/proteins associated with mechanisms of exhaustion, has relevant relationships with different ontogenetic categories dysregulated in COVID-19, influencing the severity of the disease phenotype. Thus, this project aims characterize the mechanisms of exhaustion of the immune response of T lymphocytes from patients infected with SARS-Cov-2, with mild and severe COVID-19. We will carry out a systemic and integrative approach, investigating the transcriptome of T CD4+ lymphocytes, followed by specific functional assays to validate the high-throughput screening (transcriptome analysis). In addition, we will perform a meta-analysis of data previously uploaded to ArrayExpress and GEO (Gene Expression Omnibus) to determine the networks of gene co-expression that systemically regulate the immune response to SARS-CoV-2. This high-throughput approach analysis will allow us to define the immunological signatures, signaling pathways and networks of gene co-expression and the molecular (interactome) and metabolic (metabolome) interactions involved in the immune response against SARS-CoV-2. Then, will promote a translational and multidisciplinary study that can identify biomarkers for the differential diagnosis. This fact will pave the way for the development of new specific therapies that reduce mortality and morbidity induced by the virus. (AU)

Scientific publications

(17)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

MOHAMED, KAWTHAR; RZYMSKI, PIOTR; ISLAM, MD SHAHIDUL; MAKUKU, RANGARIRAI; MUSHTAQ, AYESHA; KHAN, AMJAD; IVANOVSKA, MARIYA; MAKKA, SARA A.; HASHEM, FAREEDA; MARQUEZ, LEANDER; et al. OVID-19 vaccinations: The unknowns, challenges, and hope. Journal of Medical Virology, v. 94, n. 4, DEC 2021. (20/07069-0, 18/18886-9, 20/01688-0)

BORGES, LYSANDRO P.; GUIMARAES, ADRIANA G.; FONSECA, DENNYSON LEANDRO M.; FREIRE, PAULA P.; BARRETO, IKARO D. C.; SOUZA, DANIELA R., V; GURGEL, RICARDO Q.; LOPES, ALINE S. A.; DE REZENDE NETO, JOSE MELQUIADES; DOS SANTOS, KEZIA A.; et al. Cross-sectional analysis of students and school workers reveals a high number of asymptomatic SARS-CoV-2 infections during school reopening in Brazilian cities. HELIYON, v. 8, n. 11, p. 11-pg., 2022-11-07. (20/01688-0, 18/18886-9, 20/09146-1, 20/07069-0)

PRADO, CAROLINE ALIANE DE SOUZA; FONSECA, DENNYSON LEANDRO M.; SINGH, YOUVIKA; FILGUEIRAS, IGOR SALERNO; BAIOCCHI, GABRIELA CRISPIM; PLACA, DESIREE RODRIGUES; MARQUES, ALEXANDRE H. C.; DANTAS-KOMATSU, RAQUEL COSTA SILVA; USUDA, JULIA N.; FREIRE, PAULA PACCIELLI; et al. Integrative systems immunology uncovers molecular networks of the cell cycle that stratify COVID-19 severity. Journal of Medical Virology, v. 95, n. 2, p. 18-pg., 2023-02-01. (20/11710-2, 20/09146-1, 20/16246-2, 20/01688-0, 20/07069-0, 20/07972-1, 18/18886-9)

FONSECA, DENNYSON LEANDRO M.; FILGUEIRAS, IGOR SALERNO; MARQUES, ALEXANDRE H. C.; VOJDANI, ELROY; HALPERT, GILAD; OSTRINSKI, YURI; BAIOCCHI, GABRIELA CRISPIM; PLACA, DESIREE RODRIGUES; FREIRE, PAULA P.; POUR, SHAHAB ZAKI; et al. Severe COVID-19 patients exhibit elevated levels of autoantibodies targeting cardiolipin and platelet glycoprotein with age: a systems biology approach. NPJ AGING, v. 9, n. 1, p. 14-pg., 2023-08-24. (20/11710-2, 20/09146-1, 20/16246-2, 20/01688-0, 20/07069-0, 20/07972-1, 18/18886-9)

FRANCA, TABATA TAKAHASHI; AL-SBIEI, ASHRAF; BASHIR, GHADA; MOHAMED, YASSIR AWAD; SALGADO, RANIERI COELHO; BARREIROS, LUCILA AKUNE; DA SILVA NAPOLEAO, SARAH MARIA; WEBER, CRISTINA WORM; SEVERO FERREIRA, JANAIRA FERNANDES; ARANDA, CAROLINA SANCHEZ; et al. CD40L modulates transcriptional signatures of neutrophils in the bone marrow associated with development and trafficking. JCI INSIGHT, v. 6, n. 16, AUG 23 2021. (16/22158-3, 20/01688-0, 18/18886-9, 17/04187-9, 20/07069-0)

MOLL, GUIDO; LUECHT, CHRISTIAN; GYAMFI, MICHAEL ADU; DA FONSECA, DENNYSON L. M.; WANG, PINCHAO; ZHAO, HONGFAN; GONG, ZEXIAN; CHEN, LEI; ASHRAF, MUHAMAD IMTIAZ; HEIDECKE, HARALD; et al. Autoantibodies from patients with kidney allograft vasculopathy stimulate a proinflammatory switch in endothelial cells and monocytes mediated via GPCR-directed PAR1-TNF-α signaling. FRONTIERS IN IMMUNOLOGY, v. 14, p. 15-pg., 2023-10-30. (18/18886-9, 20/07069-0, 20/01688-0)

GUIMARAES, GABRIELA RAPOZO; MAKLOUF, GIOVANNA RESK; TEIXEIRA, CRISTIANE ESTEVES; SANTOS, LEANDRO DE OLIVEIRA; TESSAROLLO, NAYARA GUSMAO; DE TOLEDO, NAYARA EVELIN; SERAIN, ALESSANDRA FREITAS; DE LANNA, CRISTOVAO ANTUNES; PRETTI, MARCO ANTONIO; DA CRUZ, JESSICA GONCALVES VIEIRA; et al. Single-cell resolution characterization of myeloid-derived cell states with implication in cancer outcome. NATURE COMMUNICATIONS, v. 15, n. 1, p. 23-pg., 2024-07-07. (18/18886-9, 20/07069-0, 20/01688-0, 23/07806-2)

CABRAL-MARQUES, OTAVIO; MOLL, GUIDO; CATAR, RUSAN; PREUSS, BEATE; BANKAMP, LUKAS; PECHER, ANN-CHRISTIN; HENES, JOERG; KLEIN, REINHILD; KAMALANATHAN, A. S.; AKBARZADEH, REZA; et al. Autoantibodies targeting G protein-coupled receptors: An evolving history in autoimmunity. Report of the 4th international symposium. AUTOIMMUNITY REVIEWS, v. 22, n. 5, p. 14-pg., 2023-03-14. (18/18886-9, 20/16246-2, 20/01688-0, 20/07069-0, 20/07972-1, 20/05146-7, 19/14526-0)

FREIRE, PAULA P.; MARQUES, ALEXANDRE H. C.; BAIOCCHI, GABRIELA C.; SCHIMKE, LENA F.; FONSECA, DENNYSON L. M.; SALGADO, RANIERI C.; FILGUEIRAS, IGOR S.; NAPOLEAO, SARAH M. S.; PLACA, DESIREE R.; AKASHI, KAREN T.; et al. The relationship between cytokine and neutrophil gene network distinguishes SARS-CoV-2-infected patients by sex and age. JCI INSIGHT, v. 6, n. 10, MAY 24 2021. (20/09146-1, 20/01688-0, 17/05264-7, 13/50343-1, 20/07069-0, 20/07972-1)

SOTZNY, FRANZISKA; FILGUEIRAS, IGOR SALERNO; KEDOR, CLAUDIA; FREITAG, HELMA; WITTKE, KIRSTEN; BAUER, SANDRA; SEPULVEDA, NUNO; MATHIAS DA FONSECA, DENNYSON LEANDRO; BAIOCCHI, GABRIELA CRISPIM; MARQUES, ALEXANDRE H. C.; et al. Dysregulated autoantibodies targeting vaso- and immunoregulatory receptors in Post COVID Syndrome correlate with symptom severity. FRONTIERS IN IMMUNOLOGY, v. 13, p. 17-pg., 2022-09-27. (20/16246-2, 20/01688-0, 20/07069-0, 18/18886-9, 20/11710-2, 20/07972-1)

CABRAL-MARQUES, OTAVIO; HALPERT, GILAD; SCHIMKE, LENA F.; OSTRINSKI, YURI; VOJDANI, ARISTO; BAIOCCHI, GABRIELA CRISPIM; FREIRE, PAULA PACCIELLI; FILGUEIRAS, IGOR SALERNO; ZYSKIND, ISRAEL; LATTIN, MIRIAM T.; et al. Autoantibodies targeting GPCRs and RAS-related molecules associate with COVID-19 severity. NATURE COMMUNICATIONS, v. 13, n. 1, p. 12-pg., 2022-03-09. (20/07069-0, 18/18886-9, 20/16246-2, 20/11710-2, 20/07972-1, 20/09146-1, 20/01688-0)

COUTO, PEDRO S.; AL-ARAWE, NADA; FILGUEIRAS, IGOR S.; FONSECA, DENNYSON L. M.; HINTERSEHER, IRENE; CATAR, RUSAN A.; CHINNADURAI, RAGHAVAN; BERSENEV, ALEXEY; CABRAL-MARQUES, OTAVIO; MOLL, GUIDO; et al. Systematic review and meta-analysis of cell therapy for COVID-19: global clinical trial landscape, published safety/efficacy outcomes, cell product manufacturing and clinical delivery. FRONTIERS IN IMMUNOLOGY, v. 14, p. 24-pg., 2023-06-21. (18/18886-9, 20/16246-2, 20/01688-0, 20/07069-0)

PLACA, DESIREE RODRIGUES; FONSECA, DENNYSON LEANDRO M.; MARQUES, ALEXANDRE H. C.; ZAKI POUR, SHAHAB; USUDA, JULIA NAKANISHI; BAIOCCHI, GABRIELA CRISPIM; PRADO, CAROLINE ALIANE DE SOUZA; SALGADO, RANIERI COELHO; FILGUEIRAS, IGOR SALERNO; FREIRE, PAULA PACCIELLI; et al. Immunological signatures unveiled by integrative systems vaccinology characterization of dengue vaccination trials and natural infection. FRONTIERS IN IMMUNOLOGY, v. 15, p. 17-pg., 2024-02-20. (20/16246-2, 20/07069-0, 20/09146-1, 20/01688-0, 18/18886-9, 20/07972-1, 20/11710-2, 21/03675-5)

SALGADO, RANIERI COELHO; FONSECA, DENNYSON LEANDRO M.; MARQUES, ALEXANDRE H. C.; DA SILVA NAPOLEAO, SARAH MARIA; FRANCA, TABATA TAKAHASHI; AKASHI, KAREN TIEMI; DE SOUZA PRADO, CAROLINE ALIANE; BAIOCCHI, GABRIELA CRISPIM; PLACA, DESIREE RODRIGUES; JANSEN-MARQUES, GABRIEL; et al. The network interplay of interferon and Toll-like receptor signaling pathways in the anti-Candida immune response. SCIENTIFIC REPORTS, v. 11, n. 1, OCT 13 2021. (20/01688-0, 18/18886-9, 20/07069-0)

FONSECA, DENNYSON LEANDRO M.; JAEPEL, MAJ; GYAMFI, MICHAEL ADU; FILGUEIRAS, IGOR SALERNO; BAIOCHI, GABRIELA CRISPIM; OSTRINSKI, YURI; HALPERT, GILAD; LAVI, YAEL BUBLIL; VOJDANI, ELROY; SILVA-SOUSA, THAYNA; et al. Dysregulated autoantibodies targeting AGTR1 are associated with the accumulation of COVID-19 symptoms. NPJ SYSTEMS BIOLOGY AND APPLICATIONS, v. 11, n. 1, p. 13-pg., 2025-01-13. (20/16246-2, 19/27139-5, 18/18886-9, 20/01688-0, 23/13356-0, 20/07972-1, 23/12268-0, 23/07806-2, 23/06086-6, 20/09146-1, 20/07069-0)

WANG, PINCHAO; WU, DASHAN; GONG, ZEXIAN; ADU-GYAMFI, MICHAEL; KAMHIEH-MILZ, JULIAN; DA FONSECA, DENNYSON LEANDRO MATHIAS; SUERUECUE, GUELISTAN; ASHRAF, MUHAMMAD I.; HEIDECKE, HARALD; SIKORSKA, DOROTA; et al. Stimulation of endothelin-1 production by autoantibodies present in patients with scleroderma renal crisis. Clinical Immunology, v. 273, p. 10-pg., 2025-02-20. (20/07069-0, 20/01688-0, 18/18886-9)

DANTAS-KOMATSU, RAQUEL COSTA SILVA; CRUZ, MARINA SAMPAIO; FREIRE, PAULA PACCIELLI; DINIZ, ROSIANE VIANA ZUZA; BORTOLIN, RAUL HERNANDES; CABRAL-MARQUES, OTAVIO; SOUZA, KAMILLA BATISTA DA SILVA; HIRATA, MARIO HIROYUKI; HIRATA, ROSARIO DOMINGUEZ CRESPO; REIS, BRUNA ZAVARIZE; et al. The let-7b-5p, miR-326, and miR-125a-3p are associated with left ventricular systolic dysfunction in post-myocardial infarction. FRONTIERS IN CARDIOVASCULAR MEDICINE, v. 10, p. 11-pg., 2023-05-12. (20/09146-1, 18/18886-9, 20/01688-0, 20/07069-0)