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