Interleukin-1 receptor signaling is required to overcome the effects of pertussis toxin and for efficient infection-or vaccination-induced immunity against bordetella pertussis

Interleukin-1 receptor-deficient (IL-1R^-/-) mice are healthy despite being colonized by commensal microbes but are defective in defenses against specific pathogens, suggesting that IL-1R-mediated effects contribute to immune responses against specific pathogenic mechanisms. To better define the role of IL-1R in immunity to respiratory infections, we challenged IL-1R ^-/- mice with Bordetella pertussis and Bordetella parapertussis, the causative agents of whooping cough. Following inoculation with B. pertussis, but not B. parapertussis, IL-1R^-/- mice showed elevated bacterial numbers and more extensive inflammatory pathology than wild-type mice. Acellular B. pertussis vaccines were not efficiently protective against B. pertussis in IL-1R^-/- mice. B. pertussisstimulated dendritic cells from IL-1R ^-/- mice produced higher levels of tumor necrosis factor alpha (TNF-γ) and IL-6 than wild-type cells. Moreover, elevated levels of gamma interferon (IFN-α) and TNF-γ but lower levels of IL-10 were detected during B. pertussis infection in IL-1R^-/- mice. Since B. parapertussis did not cause severe disease in IL-1R^-/- mice, we hypothesized that the extreme requirement for IL-1R involves pertussis toxin (Ptx), which is expressed only by B. pertussis. An isogenic Ptx-deficient B. pertussis strain had only a modest phenotype in wild-type mice but was completely defective in causing lethal disease in IL-1R^-/- mice, indicating that the particular virulence of B. pertussis in these mice requires Ptx. Ptx contributes to IL-1 induction by B. pertussis, which is involved in IL-10 induction through IL-1R signaling. IL-10 treatment reduced B. pertussis numbers in IL-1R^-/- mice, suggesting that the lower IL-10 responses partially account for the uncontrolled inflammation and bacterial growth in these mice.