Functional and microstructural brain abnormalities, fatigue, and cognitive dysfunction after mild COVID-19 (preprint)

Background: Little is known about the underpinning mechanisms of neurological dysfunction in post-COVID syndrome. Methods: We conducted a cross-sectional study of 87 consecutive subjects after a mild infection, with a median of 54 days after diagnosis of COVID-19. We performed structured interviews, neurological examinations, 3T-MRI scans, and neuropsychological assessments. The MRI study included white matter investigation with diffusion tensor images (DTI) and functional connectivity with resting-state functional MRI (RS-fMRI). Results: Subjects self-reported headaches (40%) and memory difficulties (33%). The quantitative analyses confirmed symptoms of fatigue (68% of participants), excessive somnolence (35%), symptoms of anxiety (29%), impaired cognitive flexibility (40%), and language dysfunction (33%). Besides, we observed a correlation between DTI fractional anisotropy (FA) and abnormal attention and cognitive flexibility in the Trail Making Test part B. Elevated levels of fatigue and somnolence associated with higher connectivity of the posterior cingulate cortex (PCC) in the RS-fMRI study of the default mode network. While higher connectivity of the PCC with bilateral angular gyri was associated with higher fatigue levels, the elevated levels of somnolence correlated with higher connectivity between the PCC and both the left thalamus and putamen. Conclusions: COVID-19 is associated with long-term neuropsychiatric symptoms and cerebral functional and microstructural alterations.

Targeting C5aR1 signaling reduced neutrophil extracellular traps and ameliorates COVID-19 pathology (preprint)

Patients with severe COVID-19 develop acute respiratory distress syndrome (ARDS) that may progress to cytokine storm syndrome, organ dysfunction, and death. Considering that complement component 5a (C5a), through its cellular receptor C5aR1, has potent proinflammatory actions, and plays immunopathological roles in inflammatory diseases, we investigated whether C5a/C5aR1 pathway could be involved in COVID-19 pathophysiology. C5a/C5aR1 signaling increased locally in the lung, especially in neutrophils of critically ill COVID-19 patients compared to patients with influenza infection, as well as in the lung tissue of K18-hACE2 Tg mice (Tg mice) infected with SARS-CoV-2. Genetic and pharmacological inhibition of C5aR1 signaling ameliorated lung immunopathology in Tg-infected mice. Mechanistically, we found that C5aR1 signaling drives neutrophil extracellular trap (NET)s-dependent immunopathology. These data confirm the immunopathological role of C5a/C5aR1 signaling in COVID-19 and indicate that antagonist of C5aR1 could be useful for COVID-19 treatment. Keywords: COVID-19, C5aR1, C5a, SARS-CoV-2, Myeloid cells, Neutrophils, NETs

Nebulization of glutathione and N-Acetylcysteine as an adjuvant therapy for COVID-19 onset.

Ever since its emergence, the highly transmissible and debilitating coronavirus disease spread at an incredibly fast rate, causing global devastation in a matter of months. SARS-CoV-2, the novel coronavirus responsible for COVID-19, infects hosts after binding to ACE2 receptors present on cells from many structures pertaining to the respiratory, cardiac, hematological, neurological, renal and gastrointestinal systems. COVID-19, however, appears to trigger a severe cytokine storm syndrome in pulmonary structures, resulting in oxidative stress, exacerbated inflammation and alveolar injury. Due to the recent nature of this disease no treatments have shown complete efficacy and safety. More recently, however, researchers have begun to direct some attention towards GSH and NAC. These natural antioxidants play an essential role in several biological processes in the body, especially the maintenance of the redox equilibrium. In fact, many diseases appear to be strongly related to severe oxidative stress and deficiency of endogenous GSH. The high ratios of ROS over GSH, in particular, appear to reflect severity of symptoms and prolonged hospitalization of COVID-19 patients. This imbalance interferes with the body's ability to detoxify the cellular microenvironment, fold proteins, replenish antioxidant levels, maintain healthy immune responses and even modulate apoptotic events. Oral administration of GSH and NAC is convenient and safe, but they are susceptible to degradation in the digestive tract. Considering this drawback, nebulization of GSH and NAC as an adjuvant therapy may therefore be a viable alternative for the management of the early stages of COVID-19.