Studies on the immunological mechanisms leading to protection or pathology during malaria infection

Abstract

The fight against malaria has proven a challenging one. Despite decades of research and a multitude of immunization strategies we still have not been able to produce a safe and efficacious vaccine. Nevertheless, trials with the most advanced vaccine to date, RTS,S, have demonstrated that small, incremental iterations such as the use of ideal adjuvants, could significantly bolster the effectiveness of promising candidates. We explored two novel mechanisms of inducing immunological responses against severe malaria. The first one is based on sub-unit vaccination and studies the potential use of thermogel polymers as adjuvants. The second one uses vaccination with a live attenuated C. albicans strain and tests whether trained immunity can protect against lethal malaria challenge. While we demonstrated that the used thermogel polymers as adjuvants were capable of protecting BALB/cJ mice from lethal PyYM challenge, comparison of parasitemia curves and antibody titers revealed that this protection was lower than that induced when using Freund’s adjuvant. While a broad association between antibody titers and survival was observed in our model, we did not find correlation between survival and antibody-mediated mechanisms such as opsonic phagocytosis or inhibition of invasion in vitro. The attenuated C albicans strain R24 has been previously shown to induce protective innate immune responses against heterologous bacterial and fungal challenges. Using R24 as a live attenuated vaccine we established that while vaccination with R24 appeared ineffective against PyYM challenge, it protected C57BL/6J from experimental cerebral malaria (ECM) induced by P. berhei ANKA. Moreover we were able to determine that protection against ECM was due to reduced cross-presentation by endothelial cells in the brain while the number of sequestered iRBC and parasite-specific CD8+T cells remained the same.