Liver-Stage Specific Response among Endemic Populations: Diet and Immunity

Abstract

Developing effective anti-malarial vaccine has been a challenge for long. Various factors including complex life cycle of parasite and lack of knowledge of stage specific critical antigens are some of the reasons. Moreover, inadequate understanding of the immune responses vis-à-vis sterile protection induced naturally by Plasmodia infection has further compounded the problem. It has been shown that people living in endemic areas take years to develop protective immunity to blood stage infection. But hardly anyone believes that immunity to liver-stage infection could be developed. Various experimental model studies using attenuated parasite suggest that liver-stage immunity might exist among endemic populations. This could be induced because of the attenuation of parasite in liver by various compounds present in the diet of endemic populations.

Keywords: Plasmodia; chloroquine and chemoprophylaxis; liver-stage immunity; natural habit; sterile protection.

Figure 1

Life cycle of Plasmodium falciparum. The life cycle of parasite P. falciparum starts in human with inoculation of parasite through mosquito. From the site of injection, sporozoite (SPZ) reaches to the liver and infect hepatocytes. The SPZ multiplies and produces thousands of blood stage infective merozoites. These merozoites enter the blood stream and infect the RBCs to start the erythrocytic cycle of parasite. In RBC, they go through different stages of development before they release the merozoites to infect new RBCs. A small percentage of asexual parasite transforms into sexual form, i.e., gametocytes, which finally develop into sporozoites in the mosquitoes.

Figure 2

Malaria incidences based on WHO report analysis. The data show the % of malaria cases (in China, Brazil, India, and Madagascar) during 2006–2012 reported in World Malaria Report. India and Madagascar have comparative high endemicity but varying infectivity whereas China and Brazil having low endemicity but proportionally higher infectivity.

Figure 3

Proposed altered life cycle of Plasmodium following consumption of diet containing anti-malarial compounds. Action of various compounds derived from diet is depicted in the figure. Green colored parasite represents normal life cycle while that of red colored parasite represents defective life cycle because of action of compounds present in diet. Possibilities: SPZ not able to infect the hepatocytes; parasite development is interrupted at initial or late stage in hepatocytes; or merozoites released might not able to infect the RBCs. Certain compounds in diet might attenuate the parasite following infection in RBCs.

Figure 4

Restricting the parasite development to Liver stage and generation of immune responses. RTS,S vaccines targeting the circumsporozoite protein (CSP) of the parasite generates mainly antibody responses against the CSP that acts on the sporozoite to prevent its invasion into hepatocytes. Allicin from the garlic cloves also would act in similar manner (prevention of hepatocyte invasion by spz) by eliminating CSP processing. After invading the hepatocyte sporozoite will undergo further development, and merozoites released infect the RBCs and start degrading Hb. Heme released is polymerized to curtail its toxicity on the parasite. Chloroquine at this stage blocks the heme polymerization and kills the parasite. Thus, chloroquine (or compounds from food having similar action) would restrict the parasite development. Parasitic antigens released from the infected RBCs might generate the humoral and cellular responses to the blood stage parasite and also against the cross stage antigens from liver stage parasite (69).

Figure 5

Generation of CD8 T cell response vs. protection. CD8 T cells are generated following exposure to parasite antigens through natural infection. Depending on the availability and affinity of antigens CD8 T cell clonotypes would have access to MHC/p complexes. Initially MHC/p in excess or with high affinity would preferentially induce the specific T cells. During subsequent antigen exposures other antigens would come into picture while response to previously generated CD8 T cells will be boosted. Gradually over time the desired repertoire of T cells with required frequencies would be generated helping protect the host from the incoming infection.