O fenótipo metabólico determina a gravidade da infecção por coronavírus: o papel da via PAF/PAFR

Abstract

Severe COVID-19 is characterized by a dysregulated immunoinflammatory state. This severity is marked by lung injury with the occurrence of severe acute respiratory syndrome (SARS), coagulopathy, and metabolic and multi-organ dysfunction. The cytokine storm is a common event in this syndrome, frequently involving the production of inflammatory mediators such as IL-1β, CCL2, IL-6, and TNF. Metabolomic and lipidomic analyses have revealed substantial alterations in blood samples from COVID-19 patients during both acute and long-term phases. In this context, platelet-activating factor (PAF) emerges as a critical player, acting its receptor (PAFR) to induce events such as platelet activation and aggregation, increased vascular permeability and leukocyte transmigration, production of reactive oxygen species, pro-inflammatory cytokines, hepatic gluconeogenesis, mobilization, and remodeling of adipose tissue. Thus, this study aimed to understand the involvement of the PAF/PAFR pathway in the inflammatory and metabolic repercussions of coronavirus infection in both animal models and humans. This research utilized a SARS model induced by the murine betacoronavirus MHV-3, which mimics, in several aspects, the pulmonary and multisystemic syndrome associated with severe COVID-19 cases. Mice were infected intranasally with 30 µL of MHV-3 at an inoculum of 10³. During the course of coronavirus infection (1–5 dpi), an increase in Pafr gene expression in the lung was observed, along with transient glycemic alterations, a progressive increase in cholesterol, reduction in adipose mass and adipokine production, an increase in liver weight, and elevated expression of Hif1α. Compared to infected wild-type (WT) mice, Pafr-/- mice exhibited an exacerbated inflammatory response and worsened clinical signs, as well as greater tissue damage, without affecting lethality or viral titers in the lungs and liver. The next step was to evaluate whether metabolic alterations resulting from coronavirus infection could be associated with the clinical deterioration observed in Pafr-/- mice. The results demonstrated that MHV-3 infection induced hypoglycemia, reduction of adipose pads, alterations in adipokine production, elevated triglycerides and cholesterol, poor performance in glucose tolerance tests (GTT), increased resting energy expenditure, and elevated expression of Hif1α in the lungs and liver. These changes were more pronounced in Pafr-/- mice. Pafr-/- mice also displayed higher production of TNF, a cytokine critically involved in the worsening of COVID-19. Interestingly, mice deficient in the inflammatory TNF receptor (Tnfr1-/-) were protected from the clinical, inflammatory, and metabolic effects of MHV-3 infection. Similar results were obtained through pharmacological treatment of WT and Pafr-/- mice with the TNF inhibitor etanercept. Treatment with etanercept in Pafr-/- mice improved clinical scores, delayed lethality, and reduced adipose tissue loss. Conversely, Hif1α-/- mice exhibited more pronounced metabolic disturbances, including greater adipose tissue mobilization, hypoglycemia, and reduced liver mass compared to WT controls. Finally, allele frequencies of SNPs in genes related to PAFR and metabolic pathways were analyzed in COVID-19 patients. The data revealed associations between these SNPs, polymorphisms in PTAFR, and the hospitalization phenotype. In conclusion, the PAF/PAFR axis plays a significant role in promoting the inflammatory and metabolic alterations associated with coronavirus infection through mechanisms dependent on TNF and HIF1-α.