Escaping the enemy's bullets: an update on how malaria parasites evade host immune response

Abstract

Malaria continues to cause untold hardship to inhabitants of malaria-endemic regions, causing significant morbidity and mortality that severely impact global health and the economy. Considering the complex life cycle of malaria parasites (MPs) and malaria biology, continued research efforts are ongoing to improve our understanding of the pathogenesis of the diseases. Female Anopheles mosquito injects MPs into its hosts during a blood meal, and MPs invade the host skin and the hepatocytes without causing any serious symptoms. Symptomatic infections occur only during the erythrocytic stage. In most cases, the host's innate immunity (for malaria-naïve individuals) and adaptive immunity (for pre-exposed individuals) mount severe attacks and destroy most MPs. It is increasingly understood that MPs have developed several mechanisms to escape from the host's immune destruction. This review presents recent knowledge on how the host's immune system destroys invading MPs as well as MPs survival or host immune evasion mechanisms. On the invasion of host cells, MPs release molecules that bind to cell surface receptors to reprogram the host in a way to lose the capacity to destroy them. MPs also hide from the host immune cells by inducing the clustering of both infected and uninfected erythrocytes (rosettes), as well as inducing endothelial activation. We hope this review will inspire more research to provide a complete understanding of malaria biology and promote interventions to eradicate the notorious disease.

Keywords: Evasion of host immunity; Host immune response; Malaria; Plasmodium infection; Rosetting.

Fig. 1

Immune system recognition of and responses to liver-stage plasmodial infection: the region II-plus region of CSP and/or the phospholipid scramblase of the sporozoite can, respectively, bind to the heparan sulfate proteoglycans and/or the carbamoyl-phosphate synthetase on a hepatocyte (1 and 2), followed by invagination and entry. In the infected hepatocyte, the plasmodial RNA or DNA can be recognized by MDA5 or another unknown receptor(s) (3a and 3b), which can trigger the adaptor MAVS or other unidentified adaptor(s) (4a and 4b). The adaptors, in turn, trigger IRF3 and IRF7 (5a and 5b) to activate transcription and expression of IFN-α and IFN-β (type I IFNs). Type I IFNs bind to IFNAR on other hepatocytes to induce the expression of more type I IFNs (6a) or bind to the IFNAR on lymphocytes (especially NKT cells) (6b), which expresses IFN-γ (7) for inhibition of sporozoites multiplication (8)

Fig. 2

Immune system recognition of and responses to blood-stage plasmodial infection: merozoite (1), through an unclear mechanism, can be recognized (2) by Vγ9Vδ2 T cells, which can release granulysin (3) and IFN-γ (4). The granulysin can inhibit merozoites (5) but requires cell-to-cell contact. Uninhibited merozoites can invade (6) RBCs to produce iRBCs (7), which expresses the parasite’s proteins on its surface and also releases phosphoantigens (8) into the extracellular environment. These phosphoantigens can also activate (9) Vγ9Vδ2 T cells. iRBCs can burst (10) to release new merozoites and many metabolites, activating other immune cells. Aside from being activated by IFN-γ released by Vγ9Vδ2 T cells (11), monocytes can be activated by GPI, hemozoin, and plasmodial DNA and RNA (12–14). Vγ9Vδ2 T cells can also process (15) and present (16) the parasite’s proteins to monocytes (17) and neutrophils (18). Activated monocytes can differentiate into macrophages (19) or dendritic cells (20) and can also secrete B-cell activation factors (21) for the development of specific antibodies. The antibodies can bind to and opsonize (22) merozoite and iRBCs, and interact (23) with neutrophils to destroy opsonized merozoite and iRBCs. Dendritic cells can process and present antigens via MHC molecules to macrophages (24) and CD8⁺ T cells (25). The activated macrophages can phagocytose and destroy merozoites (26) and iRBCs (27) expressing parasite proteins on their surfaces. Activated CD8⁺ T cells produce cytokines that attack pathogens (28). Merozoites, in some cases, can attack erythroblasts (29), which will process and present the parasite’s antigens via MHC class I molecules to CD8⁺ T cells, which respond as already described. uRBCs = uninfected red blood cells