Mechanisms for Host Immune Evasion Mediated by Plasmodium falciparum-Infected Erythrocyte Surface Antigens

Abstract

Plasmodium falciparum infection causes the most severe form of malaria. It has been hypothesized that P. falciparum directly suppresses host immune responses because sufficient acquired immunity is often not induced even by repeated P. falciparum infections in malaria-endemic areas. It is known that many kinds of P. falciparum-derived proteins are expressed on the surface of P. falciparum-infected erythrocytes (IEs), and these proteins have long been thought to be a key to the elucidation of the host immune evasion mechanisms. Our recent studies have revealed that the P. falciparum-derived erythrocyte surface antigen, RIFIN, the largest multiple gene family protein in the P. falciparum genome, suppresses host immune cell activation through direct interaction with human inhibitory immune receptors. In this review, we will discuss the molecular mechanisms for host immune evasion by P. falciparum-infected erythrocyte surface antigens. In addition, we will discuss the recently identified host immune response to P. falciparum using specialized antibodies that target host-P. falciparum-derived molecule interactions.

Keywords: Plasmodium falciparum; RIFIN; immune evasion; inhibitory immune receptors; receptor-containing antibodies; variant surface antigens.

Figure 1

The genomic location of inhibitory immune receptors and the structure of VSAs. (A) The genomic location of inhibitory immune receptors. Inhibitory immune receptors are located in the leukocyte receptor complex (LRC) region on human chromosome 19q13.4 in tandem. LRC region contains a number of immunoglobulin-like receptors such as leukocyte immunoglobulin like receptors (LILRs) and leukocyte associated immunoglobulin-like receptors (LAIRs). Each of these receptors forms a multiple gene family, and LILR family consists of five inhibitory receptors (LILRB1-5), five activating receptors (LILRA1, 2, 4-6) and one secretory form (LILRA3). It is thought that activating receptors have evolved from inhibitory receptors to overcome pathogens because some inhibitory receptors such as LILRB1 and LAIR1 are exploited by pathogens in their immune evasion mechanisms.. (B) The structure of VSAs. PfEMP-1 proteins are divided into groups (A-C) based on chromosomal location and the direction of transcription. The extracellular region of PfEMP1 is composed of the combination of a Duffy binding-like domain (DBLα-ζ) and a cysteine-rich interdomain region (CIDRα-δ) depending on the organization and the length. This figure shows the typical structure of group (A-C) PfEMP-1. The larger PfEMP1 proteins have additional DBL domains between DBL and CIDR domains. PfEMP-1 can bind to molecules such as CD36, intercellular adhesion molecule-1 (ICAM-1), and endothelial protein C receptor (EPCR) via its CIDR and DBL domains. RIFIN is divided into type A and type B RIFIN, and type A RIFIN contains a 25 amino acid sequence inserted at the N-terminus (Indel) that is not present in type B RIFINs. RIFIN interacts with immune receptors via its variable region (V2).

Figure 2

The signaling pathways mediated by inhibitory immune receptors. The phosphorylation of immunoreceptor tyrosine-based inhibition motifs (ITIMs) in the intracellular domain is induced by the binding of ligands to the extracellular domain of inhibitory immune receptors including LILRB1, LILRB2, and LAIR1. Phosphorylation of ITIMs induces phosphatases such as SHP-1 and SHP-2, resulting in immunosuppressive effects such as decreased cytokine production via various intracellular signaling pathways.

Figure 3

The immunosuppressive functions of RIFINs towards host immunity and the host immune response against RIFINs. Some RIFINs bind to the human inhibitory immune receptors and induce the inhibitory signal to the host immune system, and it is suggested that LILRB1-binding RIFINs may contribute to the severity of malaria. The host conversely induces normal antibodies against RIFINs and specialized antibodies that contain a portion of the immune receptors to block the RIFIN-receptor interaction and broadly recognize IEs expressing LAIR1 or LILRB1-binding RIFINs and promote the elimination of these IEs.