Critical role of phospholipase A2 group IID in age-related susceptibility to severe acute respiratory syndrome-CoV infection

J Exp Med. 2015 Oct 19;212(11):1851-68. doi: 10.1084/jem.20150632. Epub 2015 Sep 21.

Abstract

Oxidative stress and chronic low-grade inflammation in the lungs are associated with aging and may contribute to age-related immune dysfunction. To maintain lung homeostasis, chronic inflammation is countered by enhanced expression of proresolving/antiinflammatory factors. Here, we show that age-dependent increases of one such factor in the lungs, a phospholipase A2 (PLA2) group IID (PLA2G2D) with antiinflammatory properties, contributed to worse outcomes in mice infected with severe acute respiratory syndrome-coronavirus (SARS-CoV). Strikingly, infection of mice lacking PLA2G2D expression (Pla2g2d(-/-) mice) converted a uniformly lethal infection to a nonlethal one (>80% survival), subsequent to development of enhanced respiratory DC migration to the draining lymph nodes, augmented antivirus T cell responses, and diminished lung damage. We also observed similar effects in influenza A virus-infected middle-aged Pla2g2d(-/-) mice. Furthermore, oxidative stress, probably via lipid peroxidation, was found to induce PLA2G2D expression in mice and in human monocyte-derived macrophages. Thus, our results suggest that directed inhibition of a single inducible phospholipase, PLA2G2D, in the lungs of older patients with severe respiratory infections is potentially an attractive therapeutic intervention to restore immune function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • CD11c Antigen / analysis
  • Dendritic Cells / physiology
  • Disease Susceptibility*
  • Group II Phospholipases A2 / physiology*
  • Humans
  • Immunity, Innate
  • Lipids / analysis
  • Lung / immunology
  • Mice
  • Mice, Inbred C57BL
  • Oxidative Stress
  • Severe Acute Respiratory Syndrome / etiology*

Substances

  • CD11c Antigen
  • Lipids
  • Group II Phospholipases A2