ABSTRACT
Neutrophils overstimulation plays a crucial role in tissue damage during severe infections. Neuraminidase-mediated cleavage of surface sialic acid has been demonstrated to regulate leukocyte responses. Here, we report that antiviral neuraminidase inhibitors constrain host neuraminidase 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 murine models of sepsis. Moreover, Oseltamivir or Zanamivir treatment of whole blood cells from severe COVID-19 patients reduces host NEU-mediated shedding of surface sialic acid and neutrophil overactivation. These findings suggest that neuraminidase inhibitors are host-directed interventions to dampen neutrophil dysfunction in severe infections.
Competing Interest Statement
The authors have declared no competing interest.
- List of Abbreviations
- 4-MU-NANA
- 4-methylumbelliferyl-N-acetyl-α-D-Neuramic Acid
- ALP
- alkaline phosphatase
- ALT
- alanine aminotransferase
- ARRIVE
- Animal Research: Reporting of In Vivo Experiments
- AST
- aspartate aminotransferase
- ATCC
- American Type Culture Collection
- BAL
- bronchoalveolar lavage
- BHI
- brain_heart infusion
- CD
- cluster of differentiation
- CFU
- colony forming units
- CLP
- cecal ligation and puncture
- CM-H2DCFDA
- cell-permeant 2’,7’-dichlorodihydrofluorescein diacetate
- CpNEU
- Clostridium perfringens neuraminidase
- DANA
- 2,3-dehydro-2-deoxy-N-acetylneuraminic acid
- EDTA
- ethylenediamine tetra-acetic acid
- FACS
- fluorescence-activated cell sorting
- FcγR
- Fc gamma receptor
- fMLP
- N-formyl-Met-Leu-Phe
- FVS
- fixable viability stain
- HBSS
- Hanks’ balanced salt solution
- IgG
- immunoglobulin G
- IP
- intraperitoneal pathway
- LPS
- lipopolysaccharide
- MAL-II
- Maackia amurensis lectin II
- MFI
- median fluorescence intensity
- NETs
- neutrophil extracellular traps
- NEU
- neuraminidases
- Neu5Ac2en
- 2-deoxy-2, 3-didehydro-D-N-acetylneuraminic acid
- PBS
- phosphate buffered saline
- PFA
- paraformaldehyde
- PL
- peritoneal lavage
- PMA
- 12-myristate 13-acetate
- PMN
- polymorphonuclear
- PO
- oral pathway
- RBCs
- red blood cells
- ROS
- reactive oxygen species
- SARS-CoV-2
- severe acute respiratory syndrome coronavirus 2
- SC
- subcutaneous pathway
- Sia
- sialic acids
- Siglecs
- sialic acid-binding immunoglobulin-like lectins
- TLR
- toll-like receptor
- COVID-19
- coronavirus disease 2019
- WT
- wild-type