Neuraminidase is a host-directed approach to regulate neutrophil responses in sepsis and COVID-19.

BACKGROUND AND PURPOSE: Neutrophil overstimulation plays a crucial role in tissue damage during severe infections. Because pathogen-derived neuraminidase (NEU) stimulates neutrophils, we investigated whether host NEU can be targeted to regulate the neutrophil dysregulation observed in severe infections. EXPERIMENTAL APPROACH: The effects of NEU inhibitors on lipopolysaccharide (LPS)-stimulated neutrophils from healthy donors or COVID-19 patients were determined by evaluating the shedding of surface sialic acids, cell activation, and reactive oxygen species (ROS) production. Re-analysis of single-cell RNA sequencing of respiratory tract samples from COVID-19 patients also was carried out. The effects of oseltamivir on sepsis and betacoronavirus-induced acute lung injury were evaluated in murine models. KEY RESULTS: Oseltamivir and zanamivir constrained host NEU activity, surface sialic acid release, cell activation, and ROS production by LPS-activated human neutrophils. Mechanistically, LPS increased the interaction of NEU1 with matrix metalloproteinase 9 (MMP-9). Inhibition of MMP-9 prevented LPS-induced NEU activity and neutrophil response. In vivo, treatment with oseltamivir fine-tuned neutrophil migration and improved infection control as well as host survival in peritonitis and pneumonia sepsis. NEU1 also is highly expressed in neutrophils from COVID-19 patients, and treatment of whole-blood samples from these patients with either oseltamivir or zanamivir reduced neutrophil overactivation. Oseltamivir treatment of intranasally infected mice with the mouse hepatitis coronavirus 3 (MHV-3) decreased lung neutrophil infiltration, viral load, and tissue damage. CONCLUSION AND IMPLICATIONS: These findings suggest that interplay of NEU1-MMP-9 induces neutrophil overactivation. In vivo, NEU may serve as a host-directed target to dampen neutrophil dysfunction during severe infections.

Effects of physical training on functional, clinical, morphological, behavioural and psychosocial outcomes in post-COVID-19 infection: COVID-19 and REhabilitation study (CORE-study)-a study protocol for a randomised controlled clinical trial.

BACKGROUND: The COVID-19 pandemic remains ongoing, with a significant number of survivors who have experienced moderate to severe clinical conditions and who have suffered losses of great magnitude, especially in functional capacity, triggering limitations to daily autonomy and quality of life. Among the possibilities of intervention for disease rehabilitation, physical exercise training stands out, which can benefit several health outcomes and favours the adoption of healthier behaviours. Therefore, the aim of the study will be to analyse the effects of physical training on the functional, clinical, morphological, behavioural and psychosocial status in adults and the elderly following COVID-19 infection. METHODS: A randomised controlled clinical trial is to be conducted in parallel, with the experimental group undergoing an intervention involving a multicomponent physical rehabilitation programme, carried out at the Sports Center in partnership with the Academic Hospital of the Federal University of Santa Catarina, in Florianópolis, Brazil. Participants will be adults and the elderly, of both sexes, in a post-COVID-19-infection state, who were hospitalised during the infection. The intervention will have a total duration of 24 weeks and will include a multicomponent physical training programme, which will have gradual progression in frequency, duration and intensity over time. Regarding the outcomes, before, at the 12th and after 24 weeks of intervention, functional (primary outcome = functional index of aerobic capacity), clinical, morphological, behavioural and psychosocial outcomes will be assessed. DISCUSSION: This study will contribute to a greater understanding of the safety, adherence and benefits of physical training in the rehabilitation of post-COVID-19 patients. The results of this study will be disseminated through presentations at congresses, workshops, peer-reviewed publications and local and international conferences, especially with a view to proposing a post-COVID-19 rehabilitation care protocol. TRIAL REGISTRATION: ReBEC, RBR-10y6jhrs . Registered on 22 February 2022. 2015.