Chlamydia abortus (Cab), the causative agent of chlamydiosis or ovine enzootic abortion and stillbirth, poses a zoonotic risk to pregnant women. Zoonotic infections are frequently asymptomatic leading to development of flu-like symptoms in both children and adults and abortion or stillbirth in pregnant women. Current live attenuated 1B vaccines cause disease in vaccinated animals and inactivated vaccines are only marginally protective. In order to design an effective vaccine, it is necessary to understand the nature of the immune response that can lead to protection. It has been suggested that the magnitude and quality of the immune response elicited by a protective vaccine would be similar to that observed in convalescent, immune individuals that have recovered from a natural infection. We propose such a vaccine will have a subunit design and stimulate strong and robust cell-mediated immune responses via the production of IFN-? (and IL-17) by CD4+, CD8+ and ?? T cells. We have constructed a recombinant Vibrio cholerae ghost (rVCG)-based vaccine expressing the highly conserved Cab polymorphic membrane protein 18D (Pmp18D), which in preliminary studies generated substantial genital tract immunity. The goal of this project is to utilize the live 1B, rVCG subunit vaccine and live Cab infection to investigate the mechanisms of vaccine- and infection-induced immunity. We hypothesize that Cab infection causes disease/pathology by suppressing host immunity. We will compare the magnitude and quality of vaccine- and infection-induced immunity following immunization with the rVCG-based Pmp18D and live attenuated 1B vaccines, and live Chlamydia infection. Aim 1 will investigate measures of functional cellular and humoral immunity elicited in mice following immunization and infection. We will examine several measures of functional cellular immunity (levels of Th1/Th2 cytokine production; T cell proliferation/frequency) and humoral immunity (Ab levels, frequency of Ab secreting cells [ASC]; immunological memory) after immunization or infection with live Chlamydia. Aim 2 will elucidate the contributions of CD4+, CD8+ and ?? T cells, and antibody (Ab) in protective immunity after immunization or infection and investigate the expression dynamics of TLR/NLRs and adaptor molecule signaling during infection and vaccination.

R01AI126897

2016-07-26

2021-06-30