Search

Neutrophil overstimulation plays a crucial role in tissue damage during severe infections. As pathogen-derived neuraminidase (NEU) stimulate neutrophils, we investigated whether host NEU can be targeted to regulate neutrophil dysregulation observed in severe infections.The effects of NEU inhibitors in 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 was also carried out. The effects of Oseltamivir on sepsis and betacoronavirus-induced acute lung injury were evaluated in murine models.Oseltamivir and Zanamivir constrain 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 the matrix metalloproteinase (MMP)-9. Inhibition of MMP-9 prevents LPS-induced NEU activity and neutrophil response. In vivo, treatment with Oseltamivir fine-tunes neutrophil migration and improves infection control and host survival in peritonitis and pneumonia sepsis. NEU1 is also highly expressed in neutrophils from COVID-19 patients and treatment of whole blood samples from these patients with Oseltamivir or Zanamivir reduces 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.These findings suggest that NEU1-MMP-9 interplay induces neutrophil overactivation. In vivo, it was shown that NEU may serve as a host-directed target to dampen neutrophil dysfunction during severe infections.

Neutrophil overstimulation plays a crucial role in tissue damage during severe infections. Neuraminidase (NEU)-mediated cleavage of surface sialic acid has been demonstrated to regulate leukocyte responses. Here, we report that antiviral NEU inhibitors constrain host NEU activity, surface sialic acid release, ROS production, and NETs released by microbial-activated human neutrophils.In vivo, treatment with Oseltamivir results in infection control and host survival in peritonitis and pneumonia models of sepsis. Single-cell RNA sequencing re-analysis of publicly data sets of respiratory tract samples from critical COVID-19 patients revealed an overexpression of NEU1 in infiltrated neutrophils. Moreover, Oseltamivir or Zanamivir treatment of whole blood cells from severe COVID-19 patients reduces host NEU-mediated shedding of cell surface sialic acid and neutrophil overactivation. These findings suggest that neuraminidase inhibitors can serve as host-directed interventions to dampen neutrophil dysfunction in severe infections.At a GlanceIn a severe systemic inflammatory response, such as sepsis and COVID-19, neutrophils play a central role in organ damage. Thus, finding new ways to inhibit the exacerbated response of these cells is greatly needed. Here, we demonstrate thatin vitrotreatment of whole blood with the viral neuraminidase inhibitors Oseltamivir or Zanamivir, inhibits the activity of human neuraminidases as well as the exacerbated response of neutrophils. In experimental models of severe sepsis, oseltamivir decreased neutrophil activation and increased the survival rate of mice. Moreover, Oseltamivir or Zanamivirex vivotreatment of whole blood cells from severe COVID-19 patients rewire neutrophil function.