Nanobody-mediated macromolecular crowding induces membrane fission and remodeling in the African trypanosome

Hempelmann, A.; Hartleb, Laura; Straaten, Monique van; Hashemi, Hossein; Zeelen, J.P.; Bongers, Kevin; Papavasiliou, F. Nina; Engstler, Markus; Stebbins, C. Erec; Jones, Nicholas Blurton

doi:10.1016/j.celrep.2021.109923

Cited by 13 publications

(10 citation statements)

References 51 publications

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“…Pulmonary parasites cluster together in nests and release EVs that may participate in cell–cell communication 22 which, to our knowledge, has not yet been documented in an in vivo setting. Similar ultrastructural studies in infected skin 11 could not reveal the relatively frequent EV release as beads on a string observed in the lungs and in vitro 22 , 47 . Recurrently these EVs were observed at the boundary of the flagellum and the cell body, and frequently, originating at the entry of the flagellar pocket.…”

Section: Discussionmentioning

confidence: 66%

Impact of pulmonary African trypanosomes on the immunology and function of the lung

et al. 2022

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Approximately 20% of sleeping sickness patients exhibit respiratory complications, however, with a largely unknown role of the parasite. Here we show that tsetse fly-transmitted Trypanosoma brucei parasites rapidly and permanently colonize the lungs and occupy the extravascular spaces surrounding the blood vessels of the alveoli and bronchi. They are present as nests of multiplying parasites exhibiting close interactions with collagen and active secretion of extracellular vesicles. The local immune response shows a substantial increase of monocytes, macrophages, dendritic cells and γδ and activated αβ T cells and a later influx of neutrophils. Interestingly, parasite presence results in a significant reduction of B cells, eosinophils and natural killer cells. T. brucei infected mice show no infection-associated pulmonary dysfunction, mirroring the limited pulmonary clinical complications during sleeping sickness. However, the substantial reduction of the various immune cells may render individuals more susceptible to opportunistic infections, as evident by a co-infection experiment with respiratory syncytial virus. Collectively, these observations provide insights into a largely overlooked target organ, and may trigger new diagnostic and supportive therapeutic approaches for sleeping sickness.

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Section: Discussionmentioning

confidence: 66%

Impact of pulmonary African trypanosomes on the immunology and function of the lung

et al. 2022

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“…To better understand the distinctions between IgFold- and AlphaFold-predicted nanobody structures, we highlight two examples from the benchmark. First, we compared the structures predicted by both methods for the benchmark target 7AQZ 43 (Fig. 2 f).…”

Section: Resultsmentioning

confidence: 99%

Fast, accurate antibody structure prediction from deep learning on massive set of natural antibodies

et al. 2023

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Antibodies have the capacity to bind a diverse set of antigens, and they have become critical therapeutics and diagnostic molecules. The binding of antibodies is facilitated by a set of six hypervariable loops that are diversified through genetic recombination and mutation. Even with recent advances, accurate structural prediction of these loops remains a challenge. Here, we present IgFold, a fast deep learning method for antibody structure prediction. IgFold consists of a pre-trained language model trained on 558 million natural antibody sequences followed by graph networks that directly predict backbone atom coordinates. IgFold predicts structures of similar or better quality than alternative methods (including AlphaFold) in significantly less time (under 25 s). Accurate structure prediction on this timescale makes possible avenues of investigation that were previously infeasible. As a demonstration of IgFold’s capabilities, we predicted structures for 1.4 million paired antibody sequences, providing structural insights to 500-fold more antibodies than have experimentally determined structures.

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“…Twenty years later this parallel can be extended to include comparisons between B5-OspC and VSG-antibody complexes. A recent report describes the structures of three llama-derived single-domain antibodies (nanobodies or VHHs), including one with potent activity against living parasites, including arresting trypanosome motility and promoting membrane blebs ( 86 ). Reminiscent of the B5-OspC structure, the authors found that the three nanobodies engage VSG at a right angle near the base of the molecule rather than the head, where they had predicted.…”

Section: Discussionmentioning

confidence: 99%

Structural Elucidation of a Protective B Cell Epitope on Outer Surface Protein C (OspC) of the Lyme Disease Spirochete, Borreliella burgdorferi

Rudolph

Davis

Haque

et al. 2023

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Nanobody-mediated macromolecular crowding induces membrane fission and remodeling in the African trypanosome

Cited by 13 publications

References 51 publications

Impact of pulmonary African trypanosomes on the immunology and function of the lung

Impact of pulmonary African trypanosomes on the immunology and function of the lung

Fast, accurate antibody structure prediction from deep learning on massive set of natural antibodies

Structural Elucidation of a Protective B Cell Epitope on Outer Surface Protein C (OspC) of the Lyme Disease Spirochete, Borreliella burgdorferi

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