Transport stress induces immune dysregulation and exacerbates Mycobacterium tuberculosis infection in mice

While transport stress (TS) is a well-known factor impacting immune function and infection, its cellular and molecular mechanisms remain elusive. In this study, we investigated the effects of TS on immune responses and its role in exacerbating Mycobacterium tuberculosis (Mtb) infection in mice. Behavioral assessments revealed that TS induced anxiety-like behaviors in mice. Concomitantly, TS disrupted hypothalamic-pituitary-adrenal (HPA) axis homeostasis, altered hormone secretion patterns, and led to dysregulation of stress response genes (Egr1, Fos) and circadian regulators (Dbp, Per3). Single-cell RNA sequencing of the spleen revealed severe immune dysfunction, characterized by inhibition of Th17 differentiation, IL-17 signaling, and antigen presentation. Importantly, TS affects the crosstalk between the HPA axis and the spleen through ligand-receptor interactions, such as Pomc-Oprm1 and Gdf15-Tgfbr2. Furthermore, TS exacerbated the severity of Mtb infection, increased bacterial loads in the lungs and spleen, and attenuated infection-induced upregulation of immune genes (Tnfα, Il12b). Mechanistically, TS impairs adaptive immunity (Th1/Th2 differentiation) while amplifying neurotransmitter-related signaling, ultimately compromising host defenses. These findings highlight TS as a key contributor to neuroendocrine immune dysregulation, leading to increased susceptibility to infection. Addressing stress-related immune dysfunction may be crucial for improving outcomes in tuberculosis and other infectious diseases.