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Structure of the trypanosome transferrin receptor reveals mechanisms of ligand recognition and immune evasion.

ABSTRACT: To maintain prolonged infection of mammals, African trypanosomes have evolved remarkable surface coats and a system of antigenic variation1. Within these coats are receptors for macromolecular nutrients such as transferrin2,3. These must be accessible to their ligands but must not confer susceptibility to immunoglobulin-mediated attack. Trypanosomes have a wide host range and their receptors must also bind ligands from diverse species. To understand how these requirements are achieved, in the context of transferrin uptake, we determined the structure of a Trypanosoma brucei transferrin receptor in complex with human transferrin, showing how this heterodimeric receptor presents a large asymmetric ligand-binding platform. The trypanosome genome contains a family of around 14 transferrin receptors4, which has been proposed to allow binding to transferrin from different mammalian hosts5,6. However, we find that a single receptor can bind transferrin from a broad range of mammals, indicating that receptor variation is unlikely to be necessary for promiscuity of host infection. In contrast, polymorphic sites and N-linked glycans are preferentially found in exposed positions on the receptor surface, not contacting transferrin, suggesting that transferrin receptor diversification is driven by a need for antigenic variation in the receptor to prolong survival in a host.

SUBMITTER: Trevor CE

PROVIDER: S-EPMC6881179 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Structure of the trypanosome transferrin receptor reveals mechanisms of ligand recognition and immune evasion.

Trevor Camilla E CE Gonzalez-Munoz Andrea L AL Macleod Olivia J S OJS Woodcock Peter G PG Rust Steven S Vaughan Tristan J TJ Garman Elspeth F EF Minter Ralph R Carrington Mark M Higgins Matthew K MK

Nature microbiology 20191021 12

To maintain prolonged infection of mammals, African trypanosomes have evolved remarkable surface coats and a system of antigenic variation<sup>1</sup>. Within these coats are receptors for macromolecular nutrients such as transferrin<sup>2,3</sup>. These must be accessible to their ligands but must not confer susceptibility to immunoglobulin-mediated attack. Trypanosomes have a wide host range and their receptors must also bind ligands from diverse species. To understand how these requirements a ...[more]

PMID: 31636418

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Project description:Toxocara canis has extraordinary abilities to survive for many years in the tissues of diverse vertebrate species, as well as to develop to maturity in the intestinal tract of its definitive canid host. Human disease is caused by larval stages invading musculature, brain and the eye, and immune mechanisms appear to be ineffective at eliminating the infection. Survival of T. canis larvae can be attributed to two molecular strategies evolved by the parasite. Firstly, it releases quantities of 'excretory-secretory' products which include lectins, mucins and enzymes that interact with and modulate host immunity. For example, one lectin (CTL-1) is very similar to mammalian lectins, required for tissue inflammation, suggesting that T. canis may interfere with leucocyte extravasation into infected sites. The second strategy is the elaboration of a specialised mucin-rich surface coat; this is loosely attached to the parasite epicuticle in a fashion that permits rapid escape when host antibodies and cells adhere, resulting in an inflammatory reaction around a newly vacated focus. The mucins have been characterised as bearing multiple glycan side-chains, consisting of a blood-group-like trisaccharide with one or two O-methylation modifications. Both the lectins and these trisaccharides are targeted by host antibodies, with anti-lectin antibodies showing particular diagnostic promise. Antibodies to the mono-methylated trisaccharide appear to be T. canis-specific, as this epitope is not found in the closely related Toxocara cati, but all other antigenic determinants are very similar between the two species. This distinction may be important in designing new and more accurate diagnostic tests. Further tools to control toxocariasis could also arise from understanding the molecular cues and steps involved in larval development. In vitro-cultivated larvae express high levels of four mRNAs that are translationally silenced, as the proteins they encode are not detectable in cultured larvae. However, these appear to be produced once the parasite has entered the mammalian host, as they are recognised by specific antibodies in infected patients. Elucidating the function of these genes, or analysing if micro-RNA translational silencing suppresses production of the proteins, may point towards new drug targets for tissue-phase parasites in humans.

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Structure of the trypanosome transferrin receptor reveals mechanisms of ligand recognition and immune evasion.

Publications

Structure of the trypanosome transferrin receptor reveals mechanisms of ligand recognition and immune evasion.

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