Age-Related Deficits in Natural Killer Cell-Derived Interferon-Gamma Production Contribute to Severe Bordetella pertussis in Infant Mice”.

Abstract

Many respiratory infections are injurious in infants; however, the etiology of age-associated susceptibility is unknown. One such bacterial pathogen is Bordetella pertussis. In healthy adults, B. pertussis infection typically occurs within the lungs; however, systemic dissemination in infants can cause severe disease. In mouse models, NK cell- and IFN-?-deficient adult mice suffer disseminated lethal infection resembling the infant condition. Accordingly, we hypothesized that infants exhibit age-related deficits in NK cell frequency, maturation, and responsiveness to B. pertussis, associated with low IFN-? levels. To evaluate this hypothesis, we characterized an age-dependent mouse model of pertussis and further delineated the mechanisms underlying age-dependent susceptibility. Analogous to human disease, increasing age in mice is associated with declining susceptibility. Infant mice develop the most severe aspects of B. pertussis infection, including bacterial loads, disseminated infection, leukocytosis, and lethality. Moreover, this increase in protection directly correlated with an increase in innate NK cell-derived IFN-γ production and type 1 cytokines during infection. Postnatal day 7 infant mice had fewer pulmonary NK cells than adult mice during infection. Unlike NK cells from adult mice, Infant NK cells express high levels of CD27, which suggests an immature state with limited effector functions, most notably an inability to produce IFN-?. In addition, the infant's lung showed no up-regulation of IFN-?-inducing cytokine IL-12p70. Adoptive transfer of adult NK cells into infants, or treatment with exogenous IFN-?, significantly reduced bacterial dissemination. These data indicate that the lack of NK cell-produced IFN-? significantly contributes to infant fulminant pertussis. Future studies can explore how age impacts the capacity to produce IL-12/IFN-? during development and how intrinsic age-related differences in NK cell responses could impact early protection during B. pertussis infection.