Osteoprotegerin (OPG) and its ligands RANKL and TRAIL in falciparum, vivax and knowlesi malaria: correlations with disease severity, and B cell production of OPG.

Osteoprotegerin (OPG) is a soluble decoy receptor for receptor activator of NF-ƙB ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL), and is increasingly recognised as a marker of poor prognosis in a number of diseases. Here we demonstrate that in Malaysian adults with falciparum and vivax malaria, OPG is increased, and its ligands TRAIL and RANKL decreased, in proportion to disease severity. In volunteers experimentally infected with and , RANKL was suppressed, while TRAIL was unexpectedly increased, suggesting binding of OPG to RANKL prior to TRAIL.

Longitudinal changes in iron homeostasis in human experimental and clinical malaria.

Background: The interaction between iron status and malaria is incompletely understood. We evaluated longitudinal changes in iron homeostasis in volunteers enrolled in malaria volunteer infection studies (VIS) and in Malaysian patients with falciparum and vivax malaria.

Methods: We retrieved data and samples from 55 participants (19 female) enrolled in malaria VIS, and 171 patients (45 female) with malaria and 30 healthy controls (13 female) enrolled in clinical studies in Malaysia.

Longitudinal changes in iron homeostasis in human experimental and clinical malaria.

Background: The interaction between iron deficiency and malaria is incompletely understood. We evaluated longitudinal changes in iron homeostasis in volunteers enrolled in malaria volunteer infection studies (VIS) and in Malaysian patients with falciparum and vivax malaria.

Methods: We retrieved samples and associated data from 55 participants enrolled in malaria VIS, and 171 malaria patients and 30 healthy controls enrolled in clinical studies in Malaysia.

Single cell transcriptomics shows that malaria promotes unique regulatory responses across multiple immune cell subsets.

Plasmodium falciparum malaria drives immunoregulatory responses across multiple cell subsets, which protects from immunopathogenesis, but also hampers the development of effective anti-parasitic immunity. Understanding malaria induced tolerogenic responses in specific cell subsets may inform development of strategies to boost protective immunity during drug treatment and vaccination. Here, we analyse the immune landscape with single cell RNA sequencing during P.

Systemic host inflammation induces stage-specific transcriptomic modification and slower maturation in malaria parasites.

Maturation rates of malaria parasites within red blood cells (RBCs) can be influenced by host nutrient status and circadian rhythm; whether host inflammatory responses can also influence maturation remains less clear. Here, we observed that systemic host inflammation induced in mice by an innate immune stimulus, lipopolysaccharide (LPS), or by ongoing acute infection, slowed the progression of a single cohort of parasites from one generation of RBC to the next. Importantly, plasma from LPS-conditioned or acutely infected mice directly inhibited parasite maturation during in vitro culture, which was not rescued by supplementation, suggesting the emergence of inhibitory factors in plasma.

Age-dependent changes in circulating Tfh cells influence development of functional malaria antibodies in children.

T-follicular helper (Tfh) cells are key drivers of antibodies that protect from malaria. However, little is known regarding the host and parasite factors that influence Tfh and functional antibody development. Here, we use samples from a large cross-sectional study of children residing in an area of high malaria transmission in Uganda to characterize Tfh cells and functional antibodies to multiple parasites stages.

Similarly efficacious anti-malarial drugs SJ733 and pyronaridine differ in their ability to remove circulating parasites in mice.

Background: Artemisinin-based combination therapy (ACT) has been a mainstay for malaria prevention and treatment. However, emergence of drug resistance has incentivised development of new drugs. Defining the kinetics with which circulating parasitized red blood cells (pRBC) are lost after drug treatment, referred to as the "parasite clearance curve", has been critical for assessing drug efficacy; yet underlying mechanisms remain partly unresolved.

Th2-like T Follicular Helper Cells Promote Functional Antibody Production during Infection.

CD4 T follicular helper cells (Tfh) are key drivers of antibody development. During malaria in children, the activation of Tfh is restricted to the Th1 subset and not associated with antibody levels. To identify Tfh subsets that are associated with antibody development in malaria, we assess Tfh and antibodies longitudinally in human volunteers with experimental infection.

Loss of complement regulatory proteins on red blood cells in mild malarial anaemia and in Plasmodium falciparum induced blood-stage infection.

Background: Anaemia is a major consequence of malaria, caused by the removal of both infected and uninfected red blood cells (RBCs) from the circulation. Complement activation and reduced expression of complement regulatory proteins (CRPs) on RBCs are an important pathogenic mechanism in severe malarial anaemia in both Plasmodium falciparum and Plasmodium vivax infection. However, little is known about loss of CRPs on RBCs during mild malarial anaemia and in low-density infection.

Plasmodium-specific antibodies block in vivo parasite growth without clearing infected red blood cells.

Plasmodium parasites invade and multiply inside red blood cells (RBC). Through a cycle of maturation, asexual replication, rupture and release of multiple infective merozoites, parasitised RBC (pRBC) can reach very high numbers in vivo, a process that correlates with disease severity in humans and experimental animals. Thus, controlling pRBC numbers can prevent or ameliorate malaria.

Quantification of host-mediated parasite clearance during blood-stage Plasmodium infection and anti-malarial drug treatment in mice.

A major mechanism of host-mediated control of blood-stage Plasmodium infection is thought to be removal of parasitized red blood cells (pRBCs) from circulation by the spleen or phagocytic system. The rate of parasite removal is thought to be further increased by anti-malarial drug treatment, contributing to the effectiveness of drug therapy. It is difficult to directly compare pRBC removal rates in the presence and absence of treatment, since in the absence of treatment the removal rate of parasites is obscured by the extent of ongoing parasite proliferation.

IFN Regulatory Factor 3 Balances Th1 and T Follicular Helper Immunity during Nonlethal Blood-Stage Infection.

Differentiation of CD4 Th cells is critical for immunity to malaria. Several innate immune signaling pathways have been implicated in the detection of blood-stage parasites, yet their influence over Th cell immunity remains unclear. In this study, we used reactive TCR transgenic CD4 T cells, termed PbTII cells, during nonlethal AS and 17XNL infection in mice, to examine Th cell development in vivo.

Single-cell RNA-seq and computational analysis using temporal mixture modelling resolves Th1/Tfh fate bifurcation in malaria.

Differentiation of naïve CD4 T cells into functionally distinct T helper subsets is crucial for the orchestration of immune responses. Due to extensive heterogeneity and multiple overlapping transcriptional programs in differentiating T cell populations, this process has remained a challenge for systematic dissection . By using single-cell transcriptomics and computational analysis using a temporal mixtures of Gaussian processes model, termed GPfates, we reconstructed the developmental trajectories of Th1 and Tfh cells during blood-stage infection in mice.