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

Abstract

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.

Prognostic and Diagnostic Power of Delta Neutrophil Index and Mean Platelet Component in Febrile Patients with Suspected Sepsis

“…Under septic conditions, the gut microbiota undergoes dysbiosis [49] and increased permeability, leading to platelet activation, severe tissue damage, and ultimately multi-organ failure and death [50]. Similarly, the gut-lung axis (GLA) can significantly impact the lungs during sepsis [51]. Gut microbiota can modulate pulmonary immune responses and diseases through the mesenteric lymphatic system [48,52].…”

The role of sialidase Neu1 in respiratory diseases

“…Abnormally high expression of NEU1 interacted with MMP-9, contributed to neutrophil overactivation from COVID-19 patients with severe infections [ 47 ]. NEU1 inhibitors (oseltamivir and zanamivir) dampened neutrophil dysfunction and improved infection control as well as host survival in pulmonary infection.…”

“…In addition, some patients recovered from COVID-19 didn’t produce detectable neutralizing antibodies [ 51 ], whether this phenotype is associated the immune dysfunction caused by NEU1 deficiency in cellular response, we should learn it more accurately and deeply. Recent studied revealed that host NEU1 interplay with MMP-9 caused neutrophil overactivation by shedding Sia during severe infections including in sepsis and COVID-19 [ 47 ]. The newest report shows that highly glycosylated N protein of SARS-CoV-2 and HCoV-OC43 was regulated by host NEU1.…”

Sialic acid in the regulation of blood cell production, differentiation and turnover

“…Recent literature supports the idea that neutrophils share some of the pathways first described in macrophages and dendritic cells. For instance, activated neutrophils, including both those exposed to LPS and those isolated from individuals with COVID-19, exhibit high NEU1 activity, which improves TLR4 signalling, leading to exuberant ROS production and detrimental neutrophilic inflammation by a MMP-9 dependent pathway [113,114]. NEU1 also improves neutrophil extravasation by desialylation of β2 integrin (CD11b/CD18), allowing for higher affinity interactions with endothelial ICAM-1/ ICAM-2, especially in the lung [115][116][117].…”