Psychological stress increases susceptibility to Staphylococcus aureus infection by the action of TGFβ to suppress immune acting fibroblasts [scRNA-Seq]

Psychological stress results in increased susceptibility to infection yet the mechanisms responsible for this major healthcare burden are incompletely understood. In mice, stress induced by restraint increases infection by Staphylococcus aureus while adrenalectomy or chemical inhibition of adrenergic signaling blocks this response. Single-cell transcriptomics and lipidomic profiling of the skin after stress reveal fibroblasts undergoing adipogenesis are the major cell type responding to stress. Fibroblasts are critical to the increase in infection as adrenaline inhibits fibroblast Camp expression and bacterial killing, and stress did not increase infection in mice that lack Camp in fibroblasts. The suppression of the antimicrobial function of Camp in fibroblasts occurs due to activation of TGFβ signaling and is critical to the capacity of stress to increase susceptibility to infection since treatment of mice with a neutralizing TGFβ antibody or a TGFβ receptor inhibitor restores expression of Camp and alleviates increased susceptibility to infection. These data show that susceptibility to infection after psychological stress is due to a brain-skin axis that induces TGFβ and subsequently inhibits host defense by immune acting fibroblasts in the dermis. This identifies TGFβ as an unexpected target that can ameliorate increased bacterial infections associated with stress. scRNA-seq of infected mouse skin in the presence or absence of restraint stress with or without TGFβ receptor inhibitor (SB-431542)