Major Histocompatibility Complex and Malaria: Focus on Plasmodium vivax Infection

Abstract

The importance of host and parasite genetic factors in malaria resistance or susceptibility has been investigated since the middle of the last century. Nowadays, of all diseases that affect man, malaria still plays one of the highest levels of selective pressure on human genome. Susceptibility to malaria depends on exposure profile, epidemiological characteristics, and several components of the innate and adaptive immune system that influences the quality of the immune response generated during the Plasmodium lifecycle in the vertebrate host. But it is well known that the parasite's enormous capacity of genetic variation in conjunction with the host genetics polymorphism is also associated with a wide spectrum of susceptibility degrees to complicated or severe forms of the disease. In this scenario, variations in genes of the major histocompatibility complex (MHC) associated with host resistance or susceptibility to malaria have been identified and used as markers in host-pathogen interaction studies, mainly those evaluating the impact on the immune response, acquisition of resistance, or increased susceptibility to infection or vulnerability to disease. However, due to the intense selective pressure, number of cases, and mortality rates, the majority of the reported associations reported concerned Plasmodium falciparum malaria. Studies on the MHC polymorphism and its association with Plasmodium vivax, which is the most widespread Plasmodium and the most prevalent species outside the African continent, are less frequent but equally important. Despite punctual contributions, there are accumulated evidences of human genetic control in P. vivax infection and disease. Herein, we review the current knowledge in the field of MHC and derived molecules (HLA Class I, Class II, TNF-α, LTA, BAT1, and CTL4) regarding P. vivax malaria. We discuss particularly the results of P. vivax studies on HLA class I and II polymorphisms in relation to host susceptibility, naturally acquired immune response against specific antigens and the implication of this knowledge to overcome the parasite immune evasion. Finally, the potential impact of such polymorphisms on the development of vaccine candidate antigens against P. vivax will be studied.

Keywords: HLA; MHC; P.vivax; malaria; vaccine.

Figure 1

Plasmodium vivax lifecycle in human host: P. vivax is transmitted to humans by the bite of an infected female of the Anopheles mosquito, releasing the salivary fluid carrying sporozoites into the tissues or directly into the bloodstream. From the tissues, the motile sporozoites can penetrate small blood vessels. In hepatic sinusoids, they penetrate through Kupffer cells into Space of Disse and invade hepatocytes to begin the exo-erythrocytic or liver-stage cycle. The sporozoite differentiates into mature liver-stage schizont with thousands of uninucleated merozoites surrounded by a parasitophorous membrane. The hepatocyte containing mature liver schizonts ruptures releasing merosomes. These merosomes are transported into the general blood circulation and break, releasing merozoites which invade young red blood cells (reticulocytes), beginning the erythrocytic or blood-stage cycle. P. vivax has dormant liver hypnozoite stages, which can reactivate and lead to blood-stage relapses. Within the erythrocyte, the merozoite differentiates in erythrocytic trophozoite. When fully mature, the infected erythrocyte ruptures, releasing the merozoites, which then invade new erythrocytes, initiating the entire intraerythrocytic-stage cycle, rupture, and reinvasion. Alternatively, some merozoites can develop gametocytes. During blood feeding, female mosquito of a susceptible Anopheles species can ingest the gametocytes, beginning the sexual stage of the life cycle. In the midgut of the mosquito, gametocytes escape from erythrocytes and become sexually stimulated. The male gamete fuses with the female, forming a diploid zygote. Therefore, the zygote is transformed into an invasive parasite stage ookinete. The ookinete traverses the midgut wall by passing through epithelial cells and comes to rest adjacent to the basal lamina where it transforms into an oocyst that undergoes multiple nuclear divisions producing several thousand sporozoites. At maturity, the oocyst breaks open and the sporozoites are released into the hemocele of the mosquito, migrating and penetrating the salivary glands. In the salivary glands, the sporozoites become infectious to humans, completing the life cycle.

Figure 2

Schematic representation of the human Chromosome 6 including the main MHC genes (69).