Taming the SARS-CoV-2-mediated proinflammatory response with BromAc®

Geovane Marques Ferreira; Felipe Alves Clarindo; Ágata Lopes Ribeiro; Letícia Gomes-de-Pontes; Luciana Debortoli de Carvalho; Olindo Assis Martins-Filho; Flávio Guimarães da Fonseca; Mauro Martins Teixeira; Adriano de Paula Sabino; Mathew Suji Eapen; David L Morris; Sarah J Valle; Jordana Grazziela Alves Coelho-Dos-Reis

doi:10.3389/fimmu.2023.1308477

Taming the SARS-CoV-2-mediated proinflammatory response with BromAc^®

Front Immunol. 2023 Dec 13:14:1308477. doi: 10.3389/fimmu.2023.1308477. eCollection 2023.

Authors

Geovane Marques Ferreira¹, Felipe Alves Clarindo¹, Ágata Lopes Ribeiro¹, Letícia Gomes-de-Pontes¹, Luciana Debortoli de Carvalho², Olindo Assis Martins-Filho³, Flávio Guimarães da Fonseca^{1

4}, Mauro Martins Teixeira⁵, Adriano de Paula Sabino⁶, Mathew Suji Eapen⁷, David L Morris^{7

8

9}, Sarah J Valle^{7

8

10}, Jordana Grazziela Alves Coelho-Dos-Reis^{1

5}

Affiliations

¹ Laboratório de Virologia Básica e Aplicada (LVBA), Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
² Departamento de Biologia e Biotecnologia de Microrganismos, Universidade Estadual de Santa Cruz (UESC), Ilhéus, Brazil.
³ Grupo Integrado de Pesquisas em Biomarcadores, Rene Rachou Institute, Oswaldo Cruz Foundation, Belo Horizonte, Brazil.
⁴ Centro de Tecnologia em Vacinas (CT-Vacinas), Parque Tecnológico de Belo Horizonte, Belo Horizonte, Brazil.
⁵ CT Terapias Avançadas e Inovadoras (CT-Terapias), Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
⁶ Laboratório de Hematologia Clínica, Experimental e Molecular, Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
⁷ Research & Development Department, Mucpharm Pty Ltd, Sydney, NSW, Australia.
⁸ St George and Sutherland Hospital Clinical School, University of New South Wales, Sydney, NSW, Australia.
⁹ Department of Surgery, St George Hospital, Sydney, NSW, Australia.
¹⁰ Intensive Care Unit, St George Hospital, Sydney, NSW, Australia.

Abstract

Introduction: In the present study, the impact of BromAc®, a specific combination of bromelain and acetylcysteine, on the SARS-CoV-2-specific inflammatory response was evaluated.

Methods: An in vitro stimulation system was standardized using blood samples from 9 healthy donors, luminex assays and flow cytometry were performed.

Results and discussion: BromAc® demonstrated robust anti-inflammatory activity in human peripheral blood cells upon SARS-CoV-2 viral stimuli, reducing the cytokine storm, composed of chemokines, growth factors, and proinflammatory and regulatory cytokines produced after short-term in vitro culture with the inactivated virus (iSARS-CoV-2). A combined reduction in vascular endothelial growth factor (VEGF) induced by SARS-CoV-2, in addition to steady-state levels of platelet recruitment-associated growth factor-PDGFbb, was observed, indicating that BromAc® may be important to reduce thromboembolism in COVID-19. The immunophenotypic analysis of the impact of BromAc® on leukocytes upon viral stimuli showed that BromAc® was able to downmodulate the populations of CD16+ neutrophils and CD14+ monocytes observed after stimulation with iSARS-CoV-2. Conversely, BromAc® treatment increased steady-state HLA-DR expression in CD14+ monocytes and preserved this activation marker in this subset upon iSARS-CoV-2 stimuli, indicating improved monocyte activation upon BromAc® treatment. Additionally, BromAc® downmodulated the iSARS-CoV-2-induced production of TNF-a by the CD19+ B-cells. System biology approaches, utilizing comprehensive correlation matrices and networks, showed distinct patterns of connectivity in groups treated with BromAc®, suggesting loss of connections promoted by the compound and by iSARS-CoV-2 stimuli. Negative correlations amongst proinflammatory axis and other soluble and cellular factors were observed in the iSARS-CoV-2 group treated with BromAc® as compared to the untreated group, demonstrating that BromAc® disengages proinflammatory responses and their interactions with other soluble factors and the axis orchestrated by SARS-CoV-2.

Conclusion: These results give new insights into the mechanisms for the robust anti-inflammatory effect of BromAc® in the steady state and SARS-CoV-2-specific immune leukocyte responses, indicating its potential as a therapeutic strategy for COVID-19.

Keywords: BromAc; COVID-19; anti-inflammatory; cytokine storm; immunomodulatory; therapeutic strategy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Inflammatory Agents / pharmacology
COVID-19*
Humans
SARS-CoV-2*
Vascular Endothelial Growth Factor A

Substances

bromelain and acetylcysteine drug combination
Vascular Endothelial Growth Factor A
Anti-Inflammatory Agents

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by Fundação de Amparo à Pesquisa de Minas Gerais (FAPEMIG, APQ-01499-21), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq MCTI/CNPQ/Universal), EMBRAPII (Process # 30275) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). FF, OM, MT, and JC-d-R received PQ fellowships from CNPq. This work was also funded by extramural resources from Mucpharm Pty Ltd (AU). OF participated in the fellow program supported by the Universidade do Estado do Amazonas (PROVISIT N° 005/2023-PROPESP/UEA).