The sympathetic nervous system drives hyperinflammatory responses to Clostridioides difficile infection
Year: 2024
Type: article
Abstract: Clostridioides difficile infection (CDI) is a leading cause of hospital-acquired infections in the United States, known for triggering severe disease by hyperactivation of the host response. In this study, we determine the impact of the sympathetic nervous system (SNS) on CDI disease severity. Mouse models of CDI are administered inhibitors of SNS activity prior to CDI. Chemical sympathectomy or pharmacological inhibition of norepinephrine synthesis greatly reduces mortality and disease severity in the CDI model. Pharmacological blockade or genetic ablation of the alpha 2 adrenergic receptor ameliorates intestinal inflammation, disease severity, and mortality rate. These results underscore the role of the SNS and the alpha 2 adrenergic receptor in CDI pathogenesis and suggest that targeting neural systems could be a promising approach to therapy in severe disease. • Chemical sympathectomy reduces pathology in C. difficile -infected mice • Blocking norepinephrine signaling protects against C. difficile -induced mortality • The impact of α2 adrenergic receptor on mortality is sex dependent and subtype specific • Genetic ablation of Adra2a improves survival in C. difficile- infected mice C. difficile infection (CDI) severity depends on the composition of the host response. Tyus et al. reveal that sympathetic nervous system activity sensitizes the host to severe CDI through alpha 2 adrenergic receptor stimulation. In mouse models, inhibiting the adrenergic axis protects against intestinal damage and inflammation.
Source: Cell Reports Medicine
Authors: David Tyus, Jhansi L. Leslie, Farha Naz, Md Jashim Uddin, Brandon Thompson, William A. Petri
Institutions: University of Virginia Health System, University of Virginia
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,460
OpenAlex ID: W4403130076