Translational study on the role of specialised pro-resolving lipid mediators in the tolerance against CARS-CoV-2 infection

Abstract

The COVID-19 outbreak has reached pandemic levels and has been causing an unprecedent number of deaths worldwide. The high disease transmissibility and the absence of vaccines or therapies, in combination with the high demand for ventilators in order to keep patients alive, yielded a tragic scenario in which the consequence is the collapse of the health systems in addition to several deaths around the globe. The first published clinical studies on COVID-19 that were recently published clearly showed that either type-1 or -2 diabetes are one of the most important risk factors for death as a consequence of SARS-CoV-2 infection. For these reasons, the in depth understanding of the mechanisms underlying the high susceptibility of diabetic patients to this viral infection is essential and urgent. The first studies investigating the pathological features of COVID-19 in the lungs, have suggested an impairment in the resolution of the inflammatory process. This resolutive step of the inflammatory process is mainly mediated by the specialized pro-resolving mediators (SPMs), which are oxidized lipid metabolites. The SPMs are found in lower levels in obese or diabetic patients as well as in murine models of diabetes. It has been suggested that this SPMs deficiency is the main cause by which diabetic patients exhibit impaired capacity to resolve inflammatory processes. We hypothesized that the reduced levels of SPMs in diabetic patients, and thus their impaired resolutive capacity, importantly contributes to the higher vulnerability of these patients to the inflammatory process caused by SARS-CoV-2 infection in the lungs. To address this problem, we designed an experimental strategy based on the following goals: (1) identify SPMs that are reduced in the plasma of diabetic patients and negatively correlates with inflammatory and disease markers; (2) identify through in vitro studies, the SPMs that effectively mitigates the epithelial damage caused by SARS-CoV-2 infection; (3) evaluate the protective effect of SPMs against SARS-CoV-2 infection in a murine model of type-2 diabetes. (AU)