Neuraminidase inhibitors rewire neutrophil function in vivo in murine sepsis and ex vivo in COVID-19

• Published in: bioRxiv
• Main Authors: de Oliveira Formiga, Rodrigo, Amaral, Flávia C, Souza, Camila F, Mendes, Daniel A G B, Wanderley, Carlos W S, Lorenzini, Cristina B, Santos, Adara A, Antônia, Juliana, Faria, Lucas F, Natale, Caio C, Paula, Nicholas M, Silva, Priscila C S, Fonseca, Fernanda R, Aires, Luan, Heck, Nicoli, Starick, Márick R, Queiroz-Junior, Celso M, Santos, Felipe R S, de Souza, Filipe R O, Costa, Vivian V, Barroso, Shana P C, Morrot, Alexandre, Van Weyenbergh, Johan, Sordi, Regina, Alisson-Silva, Frederico, Cunha, Fernando Q, Rocha, Edroaldo L, Chollet-Martin, Sylvie, Hurtado-Nedelec, Maria Margarita, Martin, Clémence, Burgel, Pierre-Régis, Mansur, Daniel S, Maurici, Rosemeri, Macauley, Matthew S, Báfica, André, Witko-Sarsat, Véronique, Spiller, Fernando
• Format: Journal Article Paper
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 14.10.2022
• Subjects: Cell culture; Cell surface; Coronaviruses; COVID-19; Exo-a-sialidase; Leukocytes (neutrophilic); Neutrophils; Oseltamivir; Peritonitis; Respiratory tract; Sepsis; Zanamivir
• DOI: 10.1101/2020.11.12.379115

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. , 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. In a severe systemic inflammatory response, such as sepsis and COVID-19, neutrophils play a central role in organ damage. Thus, finding new ways to inhibit the exacerbated response of these cells is greatly needed. Here, we demonstrate that treatment of whole blood with the viral neuraminidase inhibitors Oseltamivir or Zanamivir, inhibits the activity of human neuraminidases as well as the exacerbated response of neutrophils. In experimental models of severe sepsis, oseltamivir decreased neutrophil activation and increased the survival rate of mice. Moreover, Oseltamivir or Zanamivir treatment of whole blood cells from severe COVID-19 patients rewire neutrophil function.