Reduction of Pertussis Inflammatory Pathology by Therapeutic Treatment With Sphingosine-1-Phosphate Receptor Ligands by a Pertussis Toxin-Insensitive Mechanism.
Recent data have demonstrated the potential of sphingosine 1-phosphate (S1P) receptor (S1PR) agonism in the treatment of infectious diseases. A previous study used a murine model of Bordetella pertussis infection to demonstrate that treatment with the S1PR agonist AAL-R reduces pulmonary inflammation during infection. In the current study, we showed that this effect is mediated via the S1PR1 on LysM+ (myeloid) cells. Signaling via this receptor results in reduced lung inflammation and cellular recruitment as well as reduced morbidity and mortality in a neonatal mouse model of disease. Despite the fact that S1PRs are pertussis toxin-sensitive G protein-coupled receptors, the effects of AAL-R were pertussis toxin insensitive in our model. Furthermore, our data demonstrate that S1PR agonist administration may be effective at therapeutic time points. These results indicate a role for S1P signaling in B. pertussis-mediated pathology and highlight the possibility of host-targeted therapy for pertussis.
Department of Microbiology and Immunology.
Ciaran
C
Skerry
Department of Microbiology and Immunology.
Karen
K
Scanlon
Department of Microbiology and Immunology.
Jeremy
J
Ardanuy
Department of Physiology, University of Maryland Medical School, Baltimore.
Drew
D
Roberts
Department of Physiology, University of Maryland Medical School, Baltimore.
Li
L
Zhang
Departments of Chemical Physiology and Immunology, The Scripps Research Institute, La Jolla, California.
Hugh
H
Rosen
Department of Microbiology and Immunology.
Nicholas H
NH
Carbonetti
D000818:Animals; D000831:Animals, Newborn; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D004195:Disease Models, Animal; D007249:Inflammation / Q000188:drug therapy* / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000378:metabolism; D037342:Pertussis Toxin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D013110:Sphingosine / Q000008:administration & dosage* / Q000031:analogs & derivatives; D000081025:Sphingosine-1-Phosphate Receptors; D014917:Whooping Cough / Q000188:drug therapy* / Q000473:pathology
D000893:Anti-Inflammatory Agents; D049349:Receptors, Lysosphingolipid; C556330:S1pr1 protein, mouse; D000081025:Sphingosine-1-Phosphate Receptors; D037342:Pertussis Toxin; D013110:Sphingosine
AAL-R; Bordetella; CYM-5442; host-directed therapy; sphingosine 1-phosphate