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. In the present study, several experimental approaches were carried out to evaluate the regulatory role of host neuraminidase (NEU) on the neutrophil response: (1) Lipopolysaccharide (LPS)‐induced NEU activity triggers human neutrophil activation, an effect significantly inhibited by either oseltamivir or zanamivir; (2) mice oral treatment with oseltamivir and inhibition of host NEU fine‐tunes neutrophil migration, improving infection control and survival rates in peritonitis and pneumonia‐induced sepsis; (3) treatment of whole blood from severe COVID‐19 patients with either oseltamivi