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

Br J Pharmacol. 2023 Jun;180(11):1460-1481. doi: 10.1111/bph.16013. Epub 2023 Jan 13.


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.

Keywords: COVID-19; SARS-CoV-2; metalloproteinase-9; neuraminidase; neutrophil; oseltamivir; sepsis; sialic acid; zanamivir.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COVID-19*
  • Humans
  • Lipopolysaccharides / pharmacology
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Neuraminidase / metabolism
  • Neuraminidase / pharmacology
  • Neutrophils
  • Oseltamivir / adverse effects
  • Reactive Oxygen Species
  • Sepsis* / chemically induced
  • Zanamivir / adverse effects


  • Oseltamivir
  • Zanamivir
  • Neuraminidase
  • Matrix Metalloproteinase 9
  • Reactive Oxygen Species
  • Lipopolysaccharides