Fig 1.
Factors that can influence malaria disease severity.
Parasite factors include molecules mediating the invasion of RBCs and modulating host immune responses. Host genetic background can influence parasite invasion of RBCs and host immunity, too. Prior infections, nutritional status, and anti-malaria treatment also contribute to disease severity.
Fig 2.
Many parasite life cycle stages can trigger host immune responses.
Sporozoites are injected into the human skin when an infected mosquito bites a human host. The parasites migrate to the liver, developing into schizonts containing thousands of merozoites. Merozoites are released into the blood and invade RBCs, within which they develop from rings to trophozoites to schizonts. Mature schizonts again release merozoites to infect more RBCs. Some of the merozoites differentiate into male and female gametocytes. When another mosquito takes blood, the male and female gametocytes fertilize to produce zygotes that differentiate into ookinetes and oocysts. Sporozoites within oocysts migrate to the salivary glands of the mosquito. When the mosquito bites another human host, the sporozoites will start a new cycle. iRBCs, parasite nucleic acids, and metabolites can be picked up by DCs and macrophages (Mac) to trigger immune responses through activation of Toll-like (TLR) and other receptors in immune organs such as the spleen or lymph nodes in early infection. Activation of DCs and other antigen-presenting cells will activate T and B cells, leading to antibody production later. Parasite materials such as hemozoin could also induce immune cell exhaustion and immune inhibition later in the infection. Other immune mechanisms are also activated, such as interferon signaling against liver stages and the Toll, Imd, JNK, and STAT pathways to kill mosquito stages. Some images of cells and receptors were adopted from BioRender.
Fig 3.
Major mechanisms of immune evasion in malaria.
(A) Parasite lives within RBCs, avoiding various intracellular killing mechanisms, although parasite proteins expressed on the surface of RBCs can be recognized by the host immune system. (B) Parasite molecules exposed to host immunity are highly polymorphic, allowing survival under strain-specific immunity. (C) Expression of a different copy of a variant antigen gene (var) can also evade immunity against a previously expressed variant. (D) Binding of parasite proteins such as PfEMP1 and PfRIFIN to various host cells can induce immune inhibition and avoid clearance by the spleen. (E) Binding of parasite proteins to molecules in the host complement system blocks complement-mediated lysis and killing of the parasites. (F) Genome-wide transcriptional analyses show down-regulation of host genes in many immune pathways, including B and T cell activations. (G) DC dysfunction with reduced expression of many surface proteins required for T cell activation. (H) Malaria parasite infection also leads to T cell dysfunction and exhaustion with increased expression of T cell exhaustion and senescence markers. (I) Expansion of a group of B cells with reduced B cell receptor signaling was recognized in malaria. The status and functions of the atypical B cell required further investigation. (J) Dysfunction of macrophages and NK cells was also observed in malaria. Dysfunction of erythropoietic island macrophage can also cause anemia. (K) Antibodies from prior exposure or immunization may block the binding of new antibodies generated. (L) Many immune checkpoint pathways are activated in malaria, and blockade of the pathways can reverse immune inhibition, inhibit parasite growth, and enhance host survival in rodent malaria models. Note that many of these elements are overlapping and can be integrated into a broad systematic immune inhibition. Some images of cells and receptors were adopted from BioRender.
Fig 4.
Potential strategies to reverse immune inhibition and enhance vaccination efficacy.
Inhibition of interactions of PD-1/PD-L1 and CTLA-4/CD80 with SMs can block the immune checkpoint inhibition pathways to activate T cells. Additionally, inhibition of MARCH1 using SMs or specific peptides from CD83 may increase levels of CD86 and MHC II expression on DCs, promoting T cell activation. Combining monoclonal antibodies and SMs blocking PD-1/PD-L1 interaction or inhibiting MARCH1 may achieve better results than individually blocking PD-1/PD-L1 or inhibiting MARCH1. Enhancing T cell activities will promote antibody production by B cells, leading to better vaccination efficacy. Some images of cells and receptors were adopted from BioRender.