The trypanosome lytic factor of human serum, a Trojan horse

The trypanolytic factor of human serum :a trojan horse.African trypanosomes, the prototype of which is Trypanosoma brucei, are protozoan parasites of huge clinical, veterinary and economical importance. They develop in the body fluids of various mammals (including humans) where they face and manipulate many different aspects of the immune system. The extent of this interplay is pivotal to both host and parasite survival, and depending on parasite virulence and host susceptibility, infection duration ranges from some months to several years. At the end, host survival is invariably compromised.Humans and few other primates provide however a striking exception to this fatal outcome. They are indeed fully protected against most trypanosome infections through the presence in their blood of a so-called trypanosome lytic factor (TLF). The TLF is known to circulate mainly in the form of a high density lipoprotein particle characterized by the simultaneous presence of two primate-specific proteins: haptoglobin-related protein (Hpr) and apolipoprotein L-I (apoL-I).We have contributed to delineate the respective roles played by Hpr and apoL-I in the lysis process.ApoL-I was shown to be the exclusive toxin of the TLF. In its absence humans get fully susceptible to any trypanosome infection. The toxin was shown to kill the parasite after endocytosis through the generation of ionic pores in the lysosomal membrane. Those pores dissipate membrane potential and trigger the influx of chloride ions from the cytoplasm into the lysosomal compartment, leading to an eventually fatal uncontrolled osmotic phenomenon. ApoL-I efficient delivery to the parasite relies on Hpr. African trypanosomes indeed fulfil their heme nutritional requirements by receptor-mediated internalization of the complex formed by haptoglobin, an evolutionary conserved acute-phase protein, and hemoglobin, resulting from physiological intravascular hemolysis. This heme uptake by the auxotrophic parasites contributes to both growth rate and resistance against host oxidative burst. In human serum, the trypanosome receptor is unable to discriminate between Hp and the closely related TLF-bound Hpr, explaining TLF efficient endocytosis.As such, the TLF acts as a Trojan horse, killing the parasite from inside the cell after having deceived its vigilance through the high similarity between heme-delivering haptoglobin and toxin-associated Hpr. Doctorat en Sciencesinfo:eu-repo/semantics/nonPublishe

Mutual self-defence: the trypanolytic factor story.

Around 1900 Laveran and Mesnil discovered that African trypanosomes (prototype: Trypanosoma brucei brucei) do not survive in the blood of some primates and humans. The nature of the trypanolytic factor present in these sera has been the focus of a long-standing debate between different groups, but recent developments have allowed the proposal of a coherent model incorporating most seemingly divergent views and providing an interesting example of the complex interplay that continuously occurs between hosts and parasites. Possibly as an adaptation to their natural environment, great African apes and humans have acquired a new member of the apolipoprotein-L family, termed apoL1. This protein is the only one of the family to be secreted in the blood, where it binds to a subset of HDL particles that also contain another human-specific protein, haptoglobin-related protein or Hpr. T. b. brucei possesses a specific surface receptor for the haptoglobin-hemoglobin (Hp-Hb) complex, as a way to capture heme into hemoproteins that contribute to cell growth and resistance to the oxidative stress of the host. As this receptor does not discriminate between Hp and Hpr, Hpr-containing HDL particles of human serum are efficiently taken up by the parasite, leading to the simultaneous internalization of apoL1, Hpr and Hb-derived heme. Once in the lysosome, apoL1 is targeted to the lysosomal membrane, where its colicin-like anionic pore-forming activity triggers an influx of chloride ions from the cytoplasm. Osmotic effect linked to this ionic flux leads to uncontrolled swelling of the lysosome, ultimately causing the death of the parasite. Two T. brucei clones, termed Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense, have managed to resist this lysis mechanism and, therefore, cause sleeping sickness in humans. While the mechanism of this resistance is still not known in the case of T. b. gambiense, the dominant factor responsible for resistance of T. b. rhodesiense has been identified. This protein, named SRA for Serum Resistance-Associated, is a truncated version of the major and variable surface antigen of the parasite, the Variant Surface Glycoprotein or VSG. Presumably due to its defective nature, SRA is not targeted to the plasma membrane as do regular VSGs, but ends up in the late endosomal compartment. In this location SRA is thought to neutralize apoL1 through coiled-coil interactions between alpha-helices. We discuss the potential of these discoveries in terms of fight against the disease.Journal ArticleResearch Support, Non-U.S. Gov'tReviewinfo:eu-repo/semantics/publishe

L'histoire controversée du facteur trypanolytique humain.

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Human innate immunity against African trypanosomes.

Humans are naturally resistant to infection by the African trypanosome prototype Trypanosoma brucei brucei, and only two variant clones of this parasite can avoid this innate immunity and cause sleeping sickness. The resistance to T. brucei is due to serum complexes associating apolipoprotein A-1 (apoA1) with two primate-specific proteins, apolipoprotein L-1 (apoL1) and haptoglobin-related protein (Hpr). We discuss recent advances on the respective functions of apoL1 and Hpr in this system. ApoL1 was found to share structural and functional similarities with proteins of the apoptotic Bcl2 family, and to kill trypanosomes through anionic pore formation in the lysosomal membrane of the parasite. In association with hemoglobin (Hb), Hpr was found to promote the binding of the trypanolytic complexes to a haptoglobin (Hp)-Hb receptor of the trypanosome surface, hereby facilitating the internalization of apoL1. Hpr or apoL1 deficiency respectively leads to the reduction or abolishment of human protection against T. brucei.Journal ArticleResearch Support, Non-U.S. Gov'tReviewinfo:eu-repo/semantics/publishe

The function of apolipoproteins L.

The function of the proteins of the apolipoprotein L (apoL) family is largely unknown. These proteins are classically thought to be involved in lipid transport and metabolism, mainly due to the initial discovery that a secreted member of the family, apoL-I, is associated with high-density lipoprotein particles. However, the other members of the family are believed to be intracellular. The recent unravelling of the mechanism by which apoL-I kills African trypanosomes, as well as the increasing evidence for modulation of apoL expression in various pathological processes, provides new insights about the functions of these proteins. ApoLs share structural and functional similarities with proteins of the Bcl-2 family. Based on the activity of apoL-I in trypanosomes and the comparison with Bcl-2 proteins, we propose that apoLs could function as ion channels of intracellular membranes and be involved in mechanisms triggering programmed cell death.Journal ArticleResearch Support, Non-U.S. Gov'tReviewinfo:eu-repo/semantics/publishe

A cross-species transcriptomic comparison to identify novel genetic regulators of BBB maintenance

The blood-brain barrier (BBB) is a dynamic interface between the central nervous system (CNS) and peripheral blood circulation that ensures CNS homeostasis and is formed at the brain endothelial cells (BECs) lining the walls of brain capillaries by interactions between components of the neurovascular unit. In recent years, increasing evidence implicating its role in neurological disorders has led to enhanced efforts to improve our understanding of molecular mechanisms involved in maintaining BBB function. To this end, recent approaches using transcriptomic analyses have identified novel BBB regulators such as DR6 (Tnfrsf21)/TROY (Tnfrsf19), vitronectin (Vtn), Mfsd2a and PAR bZIP transcription factors, albeit inefficiently, relying on making educated guesstimates from large transcriptomic datasets. To meaningfully select candidate genes, we leveraged the conserved role of BBB function across vertebrates, from teleost fish such as zebrafish to mammals such as mice and humans. This comparison provided us with a list of evolutionarily-conserved-BBB-enriched transcripts termed the “core BBB transcriptome.” The presence of previously reported BBB genes such as Cldn5, Slc2a1, Foxf2 validate the core BBB transcriptome. The core BBB transcriptome serves as a guide for further selection of candidate genes to be assessed for their role in maintaining BBB function by reverse genetic approaches in zebrafish and mice.info:eu-repo/semantics/nonPublishe

The molecular arms race between African trypanosomes and humans.

Humans can survive bloodstream infection by African trypanosomes, owing to the activity of serum complexes that have efficient trypanosome-killing ability. The two trypanosome subspecies that are responsible for human sleeping sickness--Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense--can evade this defence mechanism by expressing distinct resistance proteins. In turn, sequence variation in the gene that encodes the trypanosome-killing component in human serum has enabled populations in western Africa to restore resistance to T. b. rhodesiense, at the expense of the high probability of developing kidney sclerosis. These findings highlight the importance of resistance to trypanosomes in human evolution.SCOPUS: re.jinfo:eu-repo/semantics/publishe

La carrera de armamentos moleculares entre los tripanosomas Africanos y los seres humanos

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Human serum lyses Trypanosoma brucei by triggering uncontrolled swelling of the parasite lysosome.

Trypanosoma brucei brucei infects a wide range of mammals, but is unable to infect humans because this subspecies is lysed by normal human serum (NHS). The phenotype of cellular lysis is debated. For some authors the lysosome undergoes osmotic swelling due to massive influx of chloride ions from the cytoplasmic compartment, but others describe multiple small cytoplasmic vacuoles and general swelling of the cellular body. Using population-level imaging of live immobilized trypanosomes throughout the lysis process, we report that specific swelling of the lysosome is a genuine and major characteristic of NHS-mediated lysis and that this phenotype is independent of the strain of trypanosomes and of NHS aging or damaging. Thus, irrespective of experimental conditions NHS reproducibly induced the swelling of the parasite lysosome.Journal ArticleResearch Support, Non-U.S. Gov'tFLWINinfo:eu-repo/semantics/publishe

Traitement expérimental de la trypanosomiase Africaine par le facteur trypanolytique humain combiné à un nanocorps.

Journal ArticleSCOPUS: ar.jinfo:eu-repo/semantics/publishe