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An In vitro Model to Study Immune Responses of Human Peripheral Blood Mononuclear Cells to Human Respiratory Syncytial Virus Infection
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An In vitro Model to Study Immune Responses of Human Peripheral Blood Mononuclear Cells to Human Respiratory Syncytial Virus Infection

Published on: December 10, 2013

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

Leonardo Duarte Santos1, Krist Helen Antunes1, Stéfanie Primon Muraro1,2,3

  • 1Laboratory of Clinical and Experimental Immunology, Infant Center, School of Life and Health Science, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil.

The European Respiratory Journal
|December 11, 2020
PubMed

Insights

Respiratory syncytial virus (RSV) infection triggers necroptosis, a form of cell death, in immune cells. This process hinders viral clearance and worsens lung injury, suggesting new therapeutic targets for RSV bronchiolitis.

Area of Science:

  • Immunology
  • Virology
  • Cell Death Research

Background:

  • Respiratory syncytial virus (RSV) is a leading cause of infant bronchiolitis.
  • Necroptosis, a regulated form of necrosis, is increasingly recognized in viral infections.

Purpose of the Study:

  • To investigate the role of necroptosis in RSV infection and its impact on viral clearance and lung injury.
  • To explore the involvement of RIPK1, RIPK3, MLKL, and TNF signaling pathways in RSV-induced necroptosis.

Main Methods:

  • RSV infection of primary mouse macrophages and human monocytes.
  • Analysis of necroptosis markers and gene expression (RIPK1, RIPK3, MLKL).
  • Use of knockout mouse models (Ripk3, Tnfr1) and macrophage depletion strategies.
  • Measurement of viral loads and lung pathology.

Main Results:

  • RSV infection induces RIPK1-, RIPK3-, and MLKL-dependent necroptosis in macrophages and monocytes.
  • Necroptosis impairs RSV clearance by alveolar macrophages.
  • Ripk3 knockout mice and depleted alveolar macrophages showed protection against RSV-induced weight loss and reduced viral loads.
  • TNF signaling via TNFR1 is crucial for RSV-induced necroptosis and subsequent lung injury.
  • Elevated nasal TNF levels correlate with disease severity in infants with RSV bronchiolitis.

Conclusions:

  • RSV infection triggers a detrimental necroptosis pathway in immune cells.
  • Targeting TNF or the necroptotic machinery presents a potential therapeutic strategy for severe RSV bronchiolitis.
  • Understanding necroptosis in RSV infection may lead to novel treatments for respiratory morbidity in young children.

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