MTOR gene variants are associated with severe COVID-19 outcomes: A multicenter study.

BACKGROUND: The worst outcomes linked to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been attributed to the cytokine storm, which contributes significantly to the immunopathogenesis of the disease. The mammalian target of rapamycin (mTOR) pathway is essential for orchestrating innate immune cell defense including cytokine production and is dysregulated in severe Coronavirus Disease 2019 (COVID-19) individuals. The individual genetic background might play a role in the exacerbated immune response. OBJECTIVE: In this study, we aimed to investigate the association between MTOR genetic variants and COVID-19 outcomes. METHODS: This study enrolled groups of individuals with severe (n = 285) and mild (n = 207) COVID-19 from Brazilian states. The MTOR variants, rs1057079 and rs2536, were genotyped. A logistic regression analysis and Kaplan-Meier survival curves were performed. We applied a genotyping risk score to estimate the cumulative contribution of the risk alleles. Tumor necrosis factor (TNF) and interleukin-6 (IL-6) plasma levels were also measured. RESULTS: The T allele of the MTOR rs1057079 variant was associated with a higher likelihood of developing the most severe form of COVID-19. In addition, higher levels of IL-6 and COVID-19 death was linked to the T allele of the rs2536 variant. These variants exhibited a cumulative risk when inherited collectively. CONCLUSIONS: These results show a potential pathogenetic role of MTOR gene variants and may be useful for predicting severe outcomes following COVID-19 infection, resulting in a more effective allocation of health resources.

Evaluation of systemic inflammatory response and lung injury induced by Crotalus durissus cascavella venom.

This study investigated the systemic inflammatory response and mechanism of pulmonary lesions induced by Crotalus durissus cascavella venom in murine in the state of Bahia. In order to investigate T helper Th1, Th2 and Th17 lymphocyte profiles, we measured interleukin (IL) -2, IL-4, IL-6, IL-10, IL-17, tumor necrosis factor (TNF) and interferon gamma (IFN-γ) levels in the peritoneal fluid and macerated lungs of mice and histopathological alterations at the specific time windows of 1h, 3h, 6h, 12h, 24h and 48h after inoculation with Crotalus durissus cascavella venom. The data demonstrated an increase of acute-phase cytokines (IL-6 and TNF) in the first hours after inoculation, with a subsequent increase in IL-10 and IL-4, suggesting immune response modulation for the Th2 profile. The histopathological analysis showed significant morphological alterations, compatible with acute pulmonary lesions, with polymorphonuclear leukocyte (PMN) infiltration, intra-alveolar edema, congestion, hemorrhage and atelectasis. These findings advance our understanding of the dynamics of envenomation and contribute to improve clinical management and antiophidic therapy for individuals exposed to venom.