The evaluation commission of the Grants to SARS-CoV-2 and COVID-19 Scientific Research Teams of the BBVA Foundation in Biomedicine, meeting on September 29, 2020, has granted the proposal requested by the research group led by Drs. Ángel Corbí and Miguel A. Vega, at the Margarita Salas Center for Biological Research (CIB-CSIC), for the project “Human macrophage activation in COVID-19: involvement of MAF and MAFB in the cytokine storm triggered upon SARS-CoV-2 infection and identification of novel prognostic biomarkers”.
Severe SARS-CoV-2 infection (COVID-19) causes a defective response of interferons (IFN, anti-viral proteins produced upon infection), as well as an exacerbated production of pro-inflammatory cytokines (known as “cytokine storm), which are associated with acute respiratory distress syndrome and organ failure. Monocytes and macrophages are key cells for pathological events in COVID-19. Macrophages that massively invade the lungs and other organs during COVID-19 are derived from circulating monocytes, and their presence is associated with the severity of the disease. Besides, pathological pulmonary macrophages in COVID-19 exhibit a transcriptome related to MAFB and MAF factors, and recent data suggest that TLR7-initiated signaling contributes to the "cytokine storm" in severe COVID-19.
The Myeloid Cell Biology group at CIB-CSIC has previously demonstrated that the production of pro-inflammatory cytokines by macrophages is regulated by MAFB and MAF, and have defined the TLR7-dependent gene expression profile of MAF+/MAFB+ monocyte-derived macrophages.
Based on these findings, the project proposed and funded in this call from the BBVA Foundation hypothesizes that MAFB and MAF determine the altered production of type I IFN and pro-inflammatory cytokines by macrophages in COVID-19. Likewise, intermediate (INT) and non-classical (NC) monocytes would trigger an amplification loop for the perpetuation of the "cytokine storm" after infection by SARS-CoV-2. The study will integrate cellular, molecular and transcriptomic approaches to identify new therapeutic targets and prognostic biomarkers for COVID-19. Furthermore, and given that intravenous immunoglobulin (IVIg) therapy shows clinical efficacy in patients with severe COVID-19, the therapeutic relevance of the results obtained will be addressed by evaluating the effect of IVIg on macrophage activation MAF+/MAFB+ mediated by SARS-CoV-2 in vitro, and measuring the production of pro-inflammatory factors induced by TLR7 or dependent on MAF/MAFB in plasma of COVID-19 patients treated with IVIg.
CIB researchers María Colmenares, Concepción Nieto, Ángeles Domínguez, Arturo González de la Aleja, Miriam Simón and Cristina Herrero also participate in the project, in collaboration with the Immunology (Dr. Silvia Sánchez-Ramón) and Internal Medicine Departments (Dr. Vicente Estrada) of the Fundación Hospital Clínico San Carlos.
BBVA Foundation Press Release (in Spanish): link.