β2-adrenergic signals downregulate the innate immune response and reduce host resistance to viral infection

J Exp Med. 2020 Apr 6;217(4):e20190554. doi: 10.1084/jem.20190554.

Abstract

In humans, psychological stress has been associated with a higher risk of infectious illness. However, the mechanisms by which the stress pathway interferes with host response to pathogens remain unclear. We demonstrate here a role for the β2-adrenergic receptor (β2-AR), which binds the stress mediators adrenaline and noradrenaline, in modulating host response to mouse cytomegalovirus (MCMV) infection. Mice treated with a β2-AR agonist were more susceptible to MCMV infection. By contrast, β2-AR deficiency resulted in a better clearance of the virus, less tissue damage, and greater resistance to MCMV. Mechanistically, we found a correlation between higher levels of IFN-γ production by liver natural killer (NK) cells and stronger resistance to MCMV. However, the control of NK cell IFN-γ production was not cell intrinsic, revealing a cell-extrinsic downregulation of the antiviral NK cell response by adrenergic neuroendocrine signals. This pathway reduces host immune defense, suggesting that the blockade of the β2-AR signaling could be used to increase resistance to infectious diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytomegalovirus Infections / immunology*
  • Down-Regulation / immunology*
  • Epinephrine / immunology
  • Immunity, Innate / immunology*
  • Interferon-gamma / immunology
  • Killer Cells, Natural / immunology
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred C57BL
  • Muromegalovirus / immunology
  • Norepinephrine / immunology
  • Receptors, Adrenergic, beta-2 / immunology*
  • Signal Transduction / immunology*

Substances

  • Receptors, Adrenergic, beta-2
  • Interferon-gamma
  • Norepinephrine
  • Epinephrine