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. Here 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 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 ofRipk3andMlklgene expression induced by RSV infection in the lung tissue.
Autocrine 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 inRipk3andMlklgene 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 as therapeutic approaches to reduce the respiratory morbidity caused by RSV infection in young children.
Footnotes
This manuscript has recently been accepted for publication in theEuropean Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of theERJonline. Please open or download the PDF to view this article.
Conflict of interest: Dr. Santos reports grants from CAPES, during the conduct of the study.
Conflict of interest: Dr. Antunes has nothing to disclose.
Conflict of interest: Dr. Muraro has nothing to disclose.
Conflict of interest: Dr. De Souza has nothing to disclose.
Conflict of interest: Dr. Da Silva has nothing to disclose.
Conflict of interest: Dr. Zanetti has nothing to disclose.
Conflict of interest: Dr. Czepielewski has nothing to disclose.
Conflict of interest: Dr. Magnus has nothing to disclose.
Conflict of interest: Dr. Scotta has nothing to disclose.
Conflict of interest: Dr. Mattiello has nothing to disclose.
Conflict of interest: Dr. Maito has nothing to disclose.
Conflict of interest: Dr. Weinlich has nothing to disclose.
Conflict of interest: Dr. Vinolo has nothing to disclose.
Conflict of interest: Dr. Porto reports grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), during the conduct of the study.
Conflict of interest: Dr. Duarte de Souza has nothing to disclose.
Conflict of interest: Dr. Felipe has nothing to disclose.
- Received2020年10月7日。
- AcceptedNovember 27, 2020.
- Copyright ©ERS 2020