TNF-mediated alveolar macrophage necroptosis drives disease pathogenesis during respiratory syncytial virus infection

Leonardo Duarte Santos, Krist Helen Antunes, Stéfanie Primon Muraro, Gabriela Fabiano De Souza, Amanda Gonzalez Da Silva, Jaqueline De Souza Felipe, Larissa Cardoso Zanetti, Rafael Sanguinetti Czepielewski, Karen Magnus, Marcelo Scotta, Rita Mattiello, Fabio Maito, Ana Paula Duarte De Souza, Ricardo Weinlich, Marco Aurélio Ramirez Vinolo, Bárbara Nery Porto

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Respiratory syncytial virus (RSV) is the major cause of acute bronchiolitis in infants under 2 years old. Necroptosis has been implicated in the outcomes of respiratory virus infections. We report that RSV infection triggers necroptosis in primary mouse macrophages and human monocytes in a RIPK1-, RIPK3- and MLKL-dependent manner. Moreover, necroptosis pathways are harmful to RSV clearance from alveolar macrophages. Additionally, Ripk3-/- mice were protected from RSV-induced weight loss and presented with reduced viral loads in the lungs. Alveolar macrophage depletion also protected mice from weight loss and decreased lung RSV virus load. Importantly, alveolar macrophage depletion abolished the upregulation of Ripk3 and Mlkl gene expression induced by RSV infection in the lung tissue. Autocrine tumor necrosis factor (TNF)-mediated RSV-triggered macrophage necroptosis and necroptosis pathways were also involved in TNF secretion even when macrophages were committed to cell death, which can worsen lung injury during RSV infection. In line, Tnfr1-/- mice had a marked decrease in Ripk3 and Mlkl gene expression and a sharp reduction in the numbers of necrotic alveolar macrophages in the lungs. Finally, we provide evidence that elevated nasal levels of TNF are associated with disease severity in infants with RSV bronchiolitis. We propose that targeting TNF and/or the necroptotic machinery may be valuable therapeutic approaches to reduce the respiratory morbidity caused by RSV infection in young children.

Original languageEnglish
Article number37642020
JournalEuropean Respiratory Journal
Volume57
Issue number6
DOIs
StatePublished - Jun 1 2021

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