Neuraminidase inhibitors rewire neutrophil functionin vivoin murine sepsis andex vivoin COVID-19

Abstract

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.

Possible Role of P-selectin Adhesion in Long-COVID: A Comparative Analysis of a Long-COVID Case Versus an Asymptomatic Post-COVID Case

“…Endogenous cell NA activity plays a role in shedding of cell surface SiA, plays a key role in activation of both platelets [50] and neutrophils [51]. While SARS-CoV-2 seem to be lacking HE gene [52], samples from COVID-19 patients revealed an overexpression of NEU in infected neutrophils and treatment with NEU inhibitors led to decreased host NEU-mediated shedding of cell SiA and reduced overactivation of neutrophils [53]. The limitation of this discussion is that the possibility of leukocyte-platelet aggregates co-purifying during i-WBC isolation cannot be completely ruled out.…”

The impact of DAMP-mediated inflammation in severe COVID-19 and related disorders

“…(D) Increased levels of neuraminidase 1 (Neu1) enzyme in severe COVID-19 may prevent protective Siglec activation through cleavage of sialic acid (SA) residues on CD24/CD52. Treatment with Neu inhibitors Oseltamivir or Zanamivir reduces SA shedding and neutrophil overactivation in COVID-19 patients [128] . …”

“…sialic acid residues which enhances ROS production and NETosis by inflammatory neutrophils in COVID-19, and these effects can be blocked by the Neu inhibitors oseltamivir or zanamivir ( Figure. 1 D ) [128] . Similarly, the Neu inhibitor peramivir, in combination with an anti-HMGB1 antibody, attenuated immune signaling and improved survival in an influenza-induced pneumonia mouse model [129] .…”

Mammalian Neuraminidases in Immune-Mediated Diseases: Mucins and Beyond

“…NEU3-deficient, S. enterica Typhimurium-infected mice also demonstrated decreases in LPS phosphorylation, intestinal levels of proinflammatory cytokines, and gut infiltration of CD3 + T cells, Gr1 + neutrophils, and F4/80 + monocyte/macrophages, and protected against the development of bacterial colitis. The NEU inhibitor oseltamivir (Tamiflu), originally developed against influenza virus NEU, but also active against NEU1 ( 41 , 237 – 239 ), reduced murine lung neutrophil infiltration, IL-17 and TNF-α levels in BALF and serum, and mortality in both experimental E. coli sepsis and the cecal ligation puncture model of sepsis ( 240 ).…”

“…Because reduced cell surface levels of GD1a also were decreased upon NEU3 overexpression, this ganglioside was suggested to constitute an NDV receptor on host cells. The expression of NEU1, but not NEU3 or NEU4, was increased in upper and lower respiratory tract cells, and in lung infiltrating neutrophils, of SARS-CoV-2-infected patients ( 240 ). Interestingly, two recent reports have documented increased MUC1 protein levels in the airways of SARS-Cov-2-infected patients compared with healthy controls ( 272 , 273 ).…”