Recent levels of pertussis, caused by the bacterial pathogen Bordetella pertussis, are at their highest in the U.S. since the 1950s. In typical pertussis disease, respiratory symptoms are followed by episodes of severe and persistent paroxysmal coughing. In infants, the disease can progress to serious pulmonary complications, often requiring hospital intensive care, and fatal outcomes are possible. However, we still have a poor understanding of the pathogenesis of pertussis and there are no consistently effective therapeutic interventions for infants suffering from this potentially deadly bacterial infection. In mouse models of pertussis, several parallels with human pertussis disease reflect the age- dependent outcomes of infection, such as hyperleukocytosis and organ pathologies seen in infant but not adult mice. Infant mice suffer a lethal disseminating infection while adult mice restrict infection to the respiratory tract and recover. A likely contributing factor to the relative susceptibility of infants versus adults to severe pertussis (and to various other infections) is the different and developing immune system of infants compared to that of adults. This includes limited Th1-polarizing cytokine responses, primarily interferon gamma (IFNg), to most stimuli in infants. Interestingly, adult mice lacking either the IFNg receptor (IFNgR) or natural killer (NK) cells (major early producers of IFNg) fail to restrict B. pertussis infection to the respiratory tract and suffer a lethal disseminating infection, similar to the infection seen in infant wild type mice. Our preliminary data indicate poor IFNg responses to B. pertussis infection in infant mice in contrast to robust IFNg responses in adult mice, a relative deficit of NK cells in the lungs and spleens of infant mice, and poor expression of cytokines that activate NK cells to produce IFNg. Therefore, we hypothesize that deficient NK cell and IFNg levels and/or responses in infant mice contribute significantly to their susceptibility to lethal disseminating B. pertussis infection. To test these hypotheses, the aims of this proposal are (i) to investigate the contribution of NK cell and IFNg deficiencies to the susceptibility of infants to lethal disseminating B. pertussis infection, and (ii) to determine whether deficiency in production of NK cell-activating cytokines (resulting in lower IFNg production) in infants is due to deficiency in macrophage activation in response to B. pertussis. We will use a combination of mouse infection, adoptive cell transfer and cell culture studies to test these hypotheses and begin to investigate mechanisms, and we will take advantage of genetically altered mice to facilitate these studies. Identification of host targets for development of novel therapeutics for infants suffering from debilitating and sometimes fatal pertussis will have a major public health impact on this disease.
Pertussis is a serious disease that is re-emerging in epidemics despite widespread vaccination, and the number of reported cases in the U.S. in recent years is the highest since the early 1950s. Young infants are at risk of severe and sometimes fatal pertussis disease, yet there is no consistently effective treatment for these infants. In this project we plan to study how the lack of certain immune responses to Bordetella pertussis infection contributes to this serious disease in infants, with a view to identification of potential new treatments that may help to save the lives of infants suffering from pertussis.
