Local cellular and humoral immunity to Bordetella pertussis

THESIS 7483The development of whole cell vaccine (Pw) and acellular pertussis vaccines (Pa) has had a huge impact on the incidence of whooping cough worldwide. The traditional Pw had high protective efficacy, but were associated with a number of adverse reactions, ranging from mild erythemea to seizures, resulting in a reduction in vaccine acceptance. Therefore new generation Pa were developed, which have slightly lower protective efficacies but are associated with fewer side effects. Innate immune mechanisms play an essential role in the control o f B. pertussis early in infection. However, complete elimination of the pathogen and prevention from re-infection is dependent on the activation of the adaptive immune response. Despite numerous studies on the immune response induced by infection and vaccination, the mechanism of immunity against B. pertussis are still not fully understood. The aim of this study was to examine the mechanisms of cellular and humoral immunity to B. pertussis infection in a m urine model. It was found that cells infiltrating into the lungs after infection with B. pertussis, in particular macrophages and natural killer (NK) cells, play a crucial role, not only in innate immunity to B. pertussis but also in the regulation of the adaptive immune response. NK cells were shown to be important inducers of IFN- ? early in infection with B. pertussis. Depletion of NK cells from mice resulted in a more protracted infection and dissemination of the bacteria to the liver and blood, suggesting that NK cell derived IFN- ? controls the early stages of infection of B. pertussis and plays a role in confining bacteria to the lungs. Depletion of NK cells also affected the development of the adaptive immune response. Immunocompetent mice developed Thl and IgG2a antibody responses about 3 weeks after infection with B. pertussis, however, this response was reduced and IL-5 and IgGl production enhanced in N K-depleted mice, suggesting that NK cells may promote the induction of Thl cells. Macrophages were also found to have a critical role in protection against B. pertussis infection. The anti-bacterial function of macrophages was greatly enhanced by IFN- ? possibly produced by NK cells in the early stages of infection with B. pertussis and this enhanced bactericidal activity appears to be partly dependent on nitric oxide production. Macrophage depletion studies revealed a role for macrophages in confining the bacteria to the lung during B. pertussis infection. In the absence of either macrophages or IFN- ? to activate the macrophages, bacteria disseminate to the liver and blood. Depletion of macrophages in mice immunized with pertussis vaccines resulted in a reduction in the antigen specific T cell responses after infection and was associated with a delay in B. pertussis clearing from the lungs, indicating a role for macrophages in the regulation of adaptive immunity. Using a murine respiratory challenge model it was demonstrated that immunization, like natural infection, induces Th1 cells which is enhanced after infection with B. pertussis and confers a high level of protection. In contrast. Pa induced a Th2-type response, which was suppressed after infection. Infection of mice immunized with Pa results in poorer bacterial clearance indicating that superior protection is associated with the induction of a Thl response. In addition the suppression in the Pa-induced response is dependent on FHA, through the induction of regulatory T cells. Although infection of immune cells had inhibitory effects on the T cell response induced by Pa, the antibody response, in particular IgA was enhanced after infection. Parenterally delivered pertussis vaccines do not induce local production of IgA in the lung, however an anamnestic IgA response was detected shortly after B. pertussis infection of immunized mice, suggesting a role for IgA in the clearance of B. pertussis from the lung. Despite the success in pertussis vaccination, acceptance rates are still lower than that of other vaccines, such as polio and tetanus, and more widespread use of Pa is curtailed by their high cost. The use of bacterial vectors, such as BCG as carriers of pertussis antigens provide a low cost alternative and has the potential to provide protection with a single dose. However, the present study demonstrated that BCG expressing a single I protective antigen, pertussis toxin (PT) induced T cells, but poor antibody responses and was not protective in a murine respiratory challenge model. Future developments in pertussis vaccines are dependent on the identification of safe and effective pertussis vaccines that stimulate cellular and hum oral immunity and that can be readily produced at low cost in developing countries