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

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 beta 2-adrenergic receptor (beta 2-AR), which binds the stress mediators adrenaline and noradrenaline, in modulating host response to mouse cytomegalovirus (MCMV) infection. Mice treated with a beta 2-AR agonist were more susceptible to MCMV infection. By contrast, beta 2-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-gamma production by liver natural killer (NK) cells and stronger resistance to MCMV. However, the control of NK cell IFN-gamma 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 beta 2-AR signaling could be used to increase resistance to infectious diseases.