Biofilm exopolysaccharides alter sensory-neuron-mediated sickness during lung infection

• Published in: Cell Vol. 187; no. 8; pp. 1874 - 1888.e14
• Main Authors: Granton, Elise, Brown, Luke, Defaye, Manon, Moazen, Parisa, Almblad, Henrik, Randall, Trevor E., Rich, Jacquelyn D., Geppert, Andrew, Abdullah, Nasser S., Hassanabad, Mortaza F., Hiroki, Carlos H., Farias, Raquel, Nguyen, Angela P., Schubert, Courtney, Lou, Yuefei, Andonegui, Graciela, Iftinca, Mircea, Raju, Deepa, Vargas, Mario A., Howell, P. Lynne, Füzesi, Tamás, Bains, Jaideep, Kurrasch, Deborah, Harrison, Joe Jonathan, Altier, Christophe, Yipp, Bryan G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.04.2024
• Subjects: Animals; biofilm infection; Biofilms; corticotropin-releasing hormone; Escherichia coli - physiology; Escherichia coli Infections - metabolism; Escherichia coli Infections - microbiology; Escherichia coli Infections - pathology; Female; host defense; hypothalamus; Hypothermia - metabolism; Hypothermia - pathology; inflammation; Inflammation - metabolism; Inflammation - pathology; Lung - microbiology; Lung - pathology; Male; Mice; neuroimmunity; neuroinflammation; neutrophils; nociception; nociceptor; Nociceptors - metabolism; pain neurons; paraventricular nuclei; pneumonia; Pneumonia - microbiology; Pneumonia - pathology; Polysaccharides, Bacterial - metabolism; Pseudomonas; Pseudomonas aeruginosa - physiology; Pseudomonas Infections - metabolism; Pseudomonas Infections - microbiology; Pseudomonas Infections - pathology; sensory neurons; Sensory Receptor Cells; sickness; stress; stress; nociceptor; corticotropin-releasing hormone; host defense; sickness; nociception; sensory neurons; Pseudomonas; paraventricular nuclei; pain neurons; biofilm infection; pneumonia; neuroinflammation; inflammation; neuroimmunity; neutrophils; hypothalamus
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2024.03.001

Infections of the lung cause observable sickness thought to be secondary to inflammation. Signs of sickness are crucial to alert others via behavioral-immune responses to limit contact with contagious individuals. Gram-negative bacteria produce exopolysaccharide (EPS) that provides microbial protection; however, the impact of EPS on sickness remains uncertain. Using genome-engineered Pseudomonas aeruginosa (P. aeruginosa) strains, we compared EPS-producers versus non-producers and a virulent Escherichia coli (E. coli) lung infection model in male and female mice. EPS-negative P. aeruginosa and virulent E. coli infection caused severe sickness, behavioral alterations, inflammation, and hypothermia mediated by TLR4 detection of the exposed lipopolysaccharide (LPS) in lung TRPV1+ sensory neurons. However, inflammation did not account for sickness. Stimulation of lung nociceptors induced acute stress responses in the paraventricular hypothalamic nuclei by activating corticotropin-releasing hormone neurons responsible for sickness behavior and hypothermia. Thus, EPS-producing biofilm pathogens evade initiating a lung-brain sensory neuronal response that results in sickness. [Display omitted] •Non-biofilm P. aeruginosa induce greater sickness than biofilm-producing strains•Lung TRPV1+ nociceptors detect LPS from non-biofilm bacterial pneumonias via TLR4•Vagal nociceptors in the lung activate acute stress neurocircuits in the hypothalamus•CRH from the PVN of the hypothalamus drives sickness behavior in non-biofilm infections Biofilm production alters sickness during P. aeruginosa pneumonia by masking the ability of TLR4-TRPV1+ lung nociceptors to activate corticotropin-releasing hormone-mediated acute stress pathways in the paraventricular nuclei of the brain.