The Role of TLR-4 on the Mapkinases Signaling Pathways of Inflammatory Responses against Recombinant BCG Malaria Vaccine Candidate

Abstract

Malaria, a life-threatening disease caused by Plasmodium parasites, which have developed resistance to all anti-malaria drugs on the background resistance of the mosquito vector to insecticides, necessitates a more intense search for an effective vaccine. A recombinant BCG (rBCG) vaccine candidate expressing the merozoite surface protein 1C (MSP-1C) of Plasmodium falciparum was developed in our laboratory, which generated robust innate and adaptive immune responses that pointed to the likelihood of the role of Toll-like receptor-4 (TLR-4). This study analysed the role TLR-4 attachment of the rBCG to macrophages in eliciting the observed immune responses. Mice (n = 6 per group) were immunised with PBS-T80, parent BCG, or rBCG in the presence or absence of a TLR-4 inhibitor; TAK-242, and the effects of TLR-4 on the expression of c-Jun N-terminal kinases 1 and 2 (JNK1/2) and extracellular signal–regulated kinases 1 and 2 (ERK1/2), which are involved in the signalling pathway, were analysed through western blot on macrophages harvested from the mice peritoneum. The results obtained showed a significant increase in the expression of the MAPKinases in the group immunised with rBCG compared to BCG and PBS-T80 immunised groups. There was significant inhibition of the JNK1/2 and ERK1/2 expression in the presence of TAK-242, signifying, for the first time, the role of TLR-4 in the phosphorylation of both JNK1/2 and ERK1/2 in the immune response against the vaccine candidate expressing the MSP-1C of P. falciparum. This study highlighted the role of TLR-4 in the phosphorylation of ERK1/2 and JNK1/2 in the immune response against recombinant BCG malaria vaccine candidate.