Detection of host pathways universally inhibited after Plasmodium yoelii infection for immune intervention

Abstract

Malaria is a disease with diverse symptoms depending on host immune status and pathogenicity of Plasmodium parasites. The continuous parasite growth within a host suggests mechanisms of immune evasion by the parasite and/or immune inhibition in response to infection. To identify pathways commonly inhibited after malaria infection, we infected C57BL/6 mice with four Plasmodium yoelii strains causing different disease phenotypes and 24 progeny of a genetic cross. mRNAs from mouse spleens day 1 and/or day 4 post infection (p.i.) were hybridized to a mouse microarray to identify activated or inhibited pathways, upstream regulators, and host genes playing an important role in malaria infection. Strong interferon responses were observed after infection with the N67 strain, whereas initial inhibition and later activation of hematopoietic pathways were found after infection with 17XNL parasite, showing unique responses to individual parasite strains. Inhibitions of pathways such as Th1 activation, dendritic cell (DC) maturation, and NFAT immune regulation were observed in mice infected with all the parasite strains day 4 p.i., suggesting universally inhibited immune pathways. As a proof of principle, treatment of N67-infected mice with antibodies against T cell receptors OX40 or CD28 to activate the inhibited pathways enhanced host survival. Controlled activation of these pathways may provide important strategies for better disease management and for developing an effective vaccine.

The E3 ubiquitin ligase MARCH1 regulates antimalaria immunity through interferon signaling and T cell activation

“…Many negative regulators of IFN-I response were found, likely due to sampling mRNA relatively late (day 4 pi) after malaria infection. In order to search for potential receptors in IFN-I signaling, here we performed Ts-eQTL analysis using new mRNA samples collected from spleen tissues during early infection (24 h pi) (28) and again identified a large number of gene clusters based on GPLSs (Dataset S1A). Among the clusters were those containing Toll-like receptors (TLR2, 3, 4, 7, 8, 9, 11, 12, and 13) and DDX58 (RIG-I), suggesting activation of various innate immune responses.…”

Host-Malaria Parasite Interactions and Impacts on Mutual Evolution

“…For example, the authors noted that the expression of five genetically regulated human leukocyte antigen (HLA) class II loci was negatively correlated with parasite load and molecules such as IL18R1, TLR4, TLR5, IFNGR1, and IFNGR2, suggesting impairment of antigen processing and immune signaling. Impairment of antigen processing and T cell activation, including suppression of various MHCII genes, were also observed in C57BL/6 mice infected with different P. yoelii strains and progeny of a P. yoelii genetic cross (Xia et al, 2018). In a dual transcriptome analyses of the host and parasite genes in samples from 46 malaria-infected Gambian children, Lee et al (2018) performed multivariate analyses and showed association of disease severity with increased expression of granulopoiesis and IFN-γ related genes as well as inadequate suppression of IFN-I signaling (Lee et al, 2018).…”

“…Malaria parasites trigger an immune response the moment when they enter a host. To survive in this hostile environment, the parasite displays a range of strategies to evade host killing mechanisms, including variations in antigen epitopes targeted by host immune machinery and interference or suppression of specific arms of the host immune response (Recker et al, 2011;Yam and Preiser, 2017;Larsen et al, 2018;Xia et al, 2018). One of the consequences of these host-parasite interactions is increased genetic diversity at genes encoding proteins under host immune selection ( Figure 3A), leading to genetic signatures of diversifying selection in the parasite genome.…”

Parasite-Related Genetic and Epigenetic Aspects and Host Factors Influencing Plasmodium falciparum Invasion of Erythrocytes

“…Most pathogens adopt two strategies for modifying their surface protein expression to bypass detection by a host's immune system: changing some antigens' expression in an “on-off” fashion and by expressing different forms of a particular antigen (Deitsch et al, 2009). Most P. falciparum strain has sequence differences and variable expression levels regarding exposed antigens to avoid antibody recognition (Schofield and Mueller, 2006; Wu et al, 2014; Xia et al, 2018). These mechanisms enable a parasite's immune evasion and the emergence of clinical immunity, manifest by the absence of clinical symptoms.…”

“…These mechanisms enable a parasite's immune evasion and the emergence of clinical immunity, manifest by the absence of clinical symptoms. A parasite's chronic exposure to a host facilitates its adaptation mechanisms, decreasing parasitaemia, changing its invasion phenotype and modulating erythrocyte invasion ligand expression, making itself invisible to a host's immune system (Schofield and Mueller, 2006; Persson et al, 2008; Xia et al, 2018); immune evasion is therefore crucial for parasite survival, establishing chronic infection and transmission.…”