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

[tetano]

Br J Pharmacol


. 2022 Dec 16.
doi: 10.1111/bph.16013. Online ahead of print.
Neuraminidase is a host-directed approach to regulate neutrophil responses in sepsis and COVID-19


Rodrigo de Oliveira Formiga ^{1 2 3} , Flávia C Amaral ^{1 3} , Camila F Souza ¹ , Daniel A G B Mendes ^{1 3} , Carlos W S Wanderley ⁴ , Cristina B Lorenzini ^{1 3} , Adara A Santos ^{1 3} , Juliana Antônia ¹ , Lucas F Faria ¹ , Caio C Natale ^{1 3} , Nicholas M Paula ^{1 3} , Priscila C S Silva ¹ , Fernanda R Fonseca ⁵ , Luan Aires ^{1 3} , Nicoli Heck ^{1 3} , Márick R Starick ^{1 3} , Celso M Queiroz-Junior ⁶ , Felipe R S Santos ⁷ , Filipe R O de Souza ⁶ , Vivian V Costa ⁶ , Shana P C Barroso ⁸ , Alexandre Morrot ^{9 10} , Johan Van Weyenbergh ¹¹ , Regina Sordi ¹ , Frederico Alisson-Silva ¹² , Fernando Q Cunha ⁴ , Edroaldo L Rocha ^{1 3} , Sylvie Chollet-Martin ¹³ , Maria Margarita Hurtado-Nedelec ¹⁴ , Clémence Martin ^{2 15} , Pierre-Régis Burgel ^{2 15} , Daniel S Mansur ³ , Rosemeri Maurici ⁵ , Matthew S Macauley ¹⁶ , André Báfica ³ , Véronique Witko-Sarsat ² , Fernando Spiller ^{1 3}



Affiliations

• PMID: 36526272
• DOI: 10.1111/bph.16013

Abstract

Background and purpose: Neutrophil overstimulation plays a crucial role in tissue damage during severe infections. As pathogen-derived neuraminidase (NEU) stimulate neutrophils, we investigated whether host NEU can be targeted to regulate neutrophil dysregulation observed in severe infections.
Experimental approach: The effects of NEU inhibitors in 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 was also carried out. The effects of Oseltamivir on sepsis and betacoronavirus-induced acute lung injury were evaluated in murine models.
Key results: Oseltamivir and Zanamivir constrain 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 the matrix metalloproteinase (MMP)-9. Inhibition of MMP-9 prevents LPS-induced NEU activity and neutrophil response. In vivo, treatment with Oseltamivir fine-tunes neutrophil migration and improves infection control and host survival in peritonitis and pneumonia sepsis. NEU1 is also highly expressed in neutrophils from COVID-19 patients and treatment of whole blood samples from these patients with Oseltamivir or Zanamivir reduces 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 NEU1-MMP-9 interplay induces neutrophil overactivation. In vivo, it was shown that NEU may serve as a host-directed target to dampen neutrophil dysfunction during severe infections.

Keywords: COVID-19; Oseltamivir; SARS-CoV-2; Zanamivir, neutrophil; metalloproteinase-9; neuraminidase; sepsis; sialic acid.