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Войти в исследования Neuraminidase is a host-directed approach to regulate neutrophil responses in sepsis and COVID-19.
Обработка статьи · этапы, ошибки и управление
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История · было → стало
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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
Аннотация
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.