Dynamics of Radiation attenuated sporozoites induced Liver stage specific CD8 Memory T cells following Infectious Sporozoite Challenge that ensue long lived protection against Plasmodium berghei infection

Abstract

Developing effective anti-malarial vaccine has been a challenge. Radiation attenuated newlinesporozoite (RAS) vaccine induces sterile protection against Plasmodium liver-stage (LS)infection, but the protection lasts 6-9 months in rodents. Interestingly, we have shown that the intermittent infectious sporozoite challenge within few weeks post last boost immunization enhances the sterile protection up to 18 months. While the loss of protection within 6 months was correlated with a sharp decline of CD8+ memory T cells in liver, the intermittent challenge newlineappeared to rescue the loss of T cell responses. Here, an interval of 6 months or longer between the last boost immunization and the challenge is associated with the loss of protection. In this thesis work, we wanted to understand how the delayed challenge might impair the liver-stage specific CD8+ memory T cell responses. The C57BL/6 mice were vaccinated with multiple doses of Plasmodium berghei RAS (Pb-RAS). Two weeks later, they were challenged with 10K infectious P. berghei sporozoites. (1) We observed that CD8+ memory T cells were maintained in RAS vaccinated mice irrespective of their status of challenge, although the frequencies of the memory T cells were higher in the challenged group. The expression of anti-apoptotic factor Bcl-2 was reflected in newlinethe status of CD8+ memory T cells in liver. (2) Upon evaluating the effector function of T cells, we found that RAS-mice w/o challenge showed significantly declined cytotoxic (CD107a+) CD8+ T cell response in liver after six months of RAS vaccination, while it was maintained in challenged mice. Although the IFN-and#61543;+ CD8+ T cells were maintained in both the groups, the overall frequencies of T cells were significantly higher in the challenged mice. More importantly, challenged mice showed CD8+ T cells expressing higher IFN-and#61543; compared to RAS vaccinated mice (w/o challenged). (3) We further measured the homing potential of the CD8+ T cells in terms of chemokine receptor expression of CXCR3 and CXCR6. We did not find much diff