Host-Parasite Interactions in Human Malaria: Clinical Implications of Basic Research

Abstract

The malaria parasite, Plasmodium, is one of the oldest parasites documented to infect humans and has proven particularly hard to eradicate. One of the major hurdles in designing an effective subunit vaccine against the malaria parasite is the insufficient understanding of host-parasite interactions within the human host during infections. The success of the parasite lies in its ability to evade the human immune system and recruit host responses as physiological cues to regulate its life cycle, leading to rapid acclimatization of the parasite to its immediate host environment. Hence understanding the environmental niche of the parasite is crucial in developing strategies to combat this deadly infectious disease. It has been increasingly recognized that interactions between parasite proteins and host factors are essential to establishing infection and virulence at every stage of the parasite life cycle. This review reassesses all of these interactions and discusses their clinical importance in designing therapeutic approaches such as design of novel vaccines. The interactions have been followed from the initial stages of introduction of the parasite under the human dermis until asexual and sexual blood stages which are essential for transmission of malaria. We further classify the interactions as "direct" or "indirect" depending upon their demonstrated ability to mediate direct physical interactions of the parasite with host factors or their indirect manipulation of the host immune system since both forms of interactions are known to have a crucial role during infections. We also discuss the many ways in which this understanding has been taken to the field and the success of these strategies in controlling human malaria.

Keywords: Plasmodium; cytokines; direct interaction; host–parasite interaction; indirect interaction; invasion; malaria; protein.

FIGURE 1

First line of interaction: Skin and liver Hepatocyte Invasion. During initial stages of Plasmodium-host interaction, the mosquito vector (female Anopheles) injects 20–200 sporozoites under the dermis from where it travels into circulation via lymph nodes. These sporozoites enter the liver sinusoidal space by using fenestrations in tissue capillaries. To invade the human hepatocyte, the sporozoite needs to interact with surface lining of heparan sulfate proteoglycans (HSPG). The sporozoite surface proteins- circumsporozoite protein (CSP) and thrombospondin-related adhesive protein (TRAP) help in invasion of liver cells by interacting with surface heparan sulfate molecules. During the cell transversal, parasite encoded transversal proteins viz: SPECT-1, SPECT-2, CelTOS facilitate sporozoite invasion of hepatocytes. Once sporozoite enter the hepatocyte it undergoes schizogonic proliferation and eventually the rupture of hepatic schizonts yeild several blood stage merozoites.

FIGURE 2

Interactions in the Blood Stages: Invasion. Subsequent to eruption of hepatic schizonts, several merozoites are released into the blood stream. Merozoites are well-defined pear shaped blood stage form of the parasite which have characteristic conserved organelles known as rhoptries and micronemes (Step 1) Merozoite initially attaches to the RBC surface which is followed by its (Step 2) reorientation and formation of a moving junction on RBC surface through its apical end. The moving junction acts as a connector between parasite and host cytoskeleton. During this process various molecular interactions take place. Band 3 gets phosphorylated leading to a decrease in its affinity for membrane cytoskeletal elements ankyrin and spectrin, resulting in modulation of host cytoskeleton and formation of parasitophorous vacuole within which the invading merozoite resides. Rhoptry neck protein (RON2) interacts with the hydrophobic pocket of Apical membrane antigen 1 (AMA1) triggering the formation of moving junction. The parasite ligands EBA-175, EBA-140 and EBL-1 are members of the DBL-EBP family and bind to glycophorins via DBL domain. PfRh5 is a ligand for the host receptor Basigin. PfRH5 binds to via its protein core instead of the glycans. (Step 3). This is followed by export of parasite encoded proteins into the RBC compartment that allow invasion to occur. (Step 4) Finally the merozoite is inside the RBCs and resides within the parasitophorous vacuole (PV) throughout the blood stages.

FIGURE 3

Remodeling of erythrocyte membrane. When merozoites enter the RBC, they are encapsulated within a parasitophorous vacuole (PV) within which they grow, replicate, and communicate with its extracellular environment. In order to do so, the parasite establishes an intricate membranous network in the infected RBC cytosol, known as the Maurer’s clefts and tubulovesicular network (TVN), which resembles the eukaryotic secretory pathway. In infected RBCs, RESA interacts with spectrin protein of the membrane cytoskeleton while Plasmodium falciparum knob-associated His-rich protein (KAHRP) interacts with spectrin under the infected RBC plasma membrane. PfEMP1 proteins that are responsible for cytoadhesion and immune evasion Host proteins 4.1R and spectrin helps in the placement of PfEMP 1 from Maurer’s cleft, are presented at knobs for which KAHRP is known to be crucial. PfEMP3 also binds to spectrin causing deformity in RBC membrane.