The spike protein S1 of SARS-CoV-2 promotes Th17 cell-dependent stress-induced depressive-like behaviors in mice.

AIMS: Depressive symptoms often emerge after viral infections. It is not clear what viral component triggers these symptoms. MATERIALS AND METHOD: Mice received the spike protein S1 of SARS-CoV-2 virus intranasally and were subjected to behaviors. KEY FINDINGS: We show that the spike protein S1 of SARS-CoV-2 virus is sufficient to increase despair behaviors and susceptibility to stress-induced learned helplessness in mice without affecting the locomotor activity or without inducing sickness behaviors, confirming that a viral envelop protein is sufficient to modulate behaviors. At the molecular level, hippocampal accumulation of T cells, and F4/80+ macrophages, but not NK cells or B cells was observed in mice receiving intranasal administration of S1 after stress. In addition, to modulate peripheral inflammation, S1 accumulated in various brain resident cells, known to recruit hippocampal pathogenic Th17 cells. Th17 cells were sufficient to increase susceptibility to the learned helplessness after S1 administration, because elimination of Th17 cells blocked the effects of S1 administration. SIGNIFICANCE: These findings reveal the recruitment of Th17 cells to the brain as a new mechanism mediating S1 viral effects in mice.