Immune evasion of Plasmodium falciparum by RIFIN via inhibitory receptors

Abstract

Malaria is among the most serious infectious diseases affecting humans, accounting for approximately half a million deaths annually1. Plasmodium falciparum is the causative agent of most life-threatening malaria cases. Acquired immunity to malaria is inefficient, even after repeated exposures to P. falciparum2; immune regulatory mechanisms employed by P. falciparum remain largely unclear. Here, we show that P. falciparum uses immune inhibitory receptors for immune evasion. RIFINs, products of a polymorphic multigene family comprising approximately 150–200 genes per parasite genome3, are expressed on the surface of infected erythrocytes. We found that a subset of RIFINs binds to either leucocyte immunoglobulin-like receptor B1 (LILRB1) or leucocyte-associated immunoglobulin-like receptor 1 (LAIR1). LILRB1-binding RIFINs inhibited activation of LILRB1-expressing B cells and NK cells. Furthermore, interactions between LILRB1 and P. falciparum-infected erythrocytes isolated from malaria patients were associated with severe malaria, although an extended study with larger sample sizes is required to confirm the findings. These results suggest that P. falciparum has acquired multiple RIFINs to evade the host immune system by targeting immune inhibitory receptors.

Complete avian malaria parasite genomes reveal features associated with lineage specific evolution in birds and mammals

“…pir genes are present in all Plasmodium species sequenced to date and are the largest multi--gene family within the genus. Their function is unclear, but their protein products are present at the host parasite interface, are implicated in parasite--host interactions (Goel et al 2015;Niang et al 2014) and have been associated with immune evasion (Cunningham et al 2010;Fernandez--Becerra et al 2009;Saito et al 2017). In the P.…”

The MHC class I‐LILRB1 signalling axis as a promising target in cancer therapy

“…The expression of LILRB1 on B cells increases in people who have malaria, which may affect IL‐8, IL‐10 and TNF‐α signalling . Erythrocytes isolated from patients infected by Plasmodium falciparum have increased LILRB1 binding with increasing disease severity, which may lead to heightened immune surveillance . Human MHC class I protein HLA‐G expression in solid tumours predicts poor prognosis.…”

“…Natural Killer cells are cytotoxic lymphocytes. LILRB‐binding ligands can inhibit the activation and cytotoxicity of LILRB1‐expressing NK cells, leading to immune evasion by both tumours and Plasmodium falciparum . The overexpression of LILRB1 inhibits cetuximab‐mediated NK cell antibody‐dependent cellular cytotoxicity (ADCC) in triple‐negative breast cancer (TNBC) patients, and this effect can be restored with an anti‐LILRB1 antibody .…”

NF90 regulation of immune factor expression in response to malaria antigens

“…Proteins such as fms-related tyrosine kinase 3 (FLT3), leukocyte immunoglobulin-like receptor 1 (LILRB1), complement receptor 1 (CR1), tumor necrosis factor (TNF), the acute-phase-regulated monocyte/macrophage membrane receptor CD163, and the inflammatory/inducible chemokines CXCL10, CXCL11, CCL2 and CCL8 are involved in the response to malaria infection [25][26][27][28][29][30] and were selected for further analysis ( Figure 2(a)).…”