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PreprintCited by 0Complement system in diseasesTrypanosoma species research and implicationsInvertebrate Immune Response Mechanisms

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Molecular mechanism of complement inhibition by the trypanosome receptor ISG65

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Cook, Alexander D., Carrington, Mark, Higgins, Matthew K.·2024·eLife
DOI 10.7554/elife.88960.2

Preprint — published as 10.7554/elife.88960.3 · Paper page

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Abstract

Abstract African trypanosomes replicate within infected mammals where they are exposed to the complement system. This system centres around complement C3, which is present in a soluble form in serum but becomes covalently deposited onto the surfaces of pathogens after proteolytic cleavage to C3b. Membrane-associated C3b triggers different complement-mediated effectors which promote pathogen clearance. To counter complement-mediated clearance, African trypanosomes have a cell surface receptor, ISG65, which binds to C3b and which decreases the rate of trypanosome clearance in an infection model. However, the mechanism by which ISG65 reduces C3b function has not been determined. We reveal through cryogenic electron microscopy that ISG65 has two distinct binding sites for C3b, only one of which is available in C3 and C3d. We show that ISG65 does not block the formation of C3b or the function of the C3 convertase which catalyses the surface deposition of C3b. However, we show that ISG65 forms a specific conjugate with C3b, perhaps acting as a decoy. ISG65 also occludes the binding sites for complement receptors 2 and 3, which may disrupt recruitment of immune cells, including B cells, phagocytes and granulocytes. This suggests that ISG65 protects trypanosomes by combining multiple approaches to dampen the complement cascade.

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Metadata

Authors
Cook, A. D., Carrington, M., & Higgins, M. K.
Affiliations
  • University of Oxford (GB)
  • University of Cambridge (GB)
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2024-04-05
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.88960.2
OpenAlex
W4393977472
Cited by
0
References
2
Type
posted content
Language
en
Open access
Licence
Locations
eLife (acceptedVersion, cc-by)
Funders
Wellcome Trust (217138/Z/19/Z)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
  • Health Sciences › Medicine › Epidemiology › Trypanosoma species research and implications
  • Life Sciences › Immunology and Microbiology › Immunology › Invertebrate Immune Response Mechanisms
Keywords
African trypanosomes, complement inhibition, C3b, complement C3, C3 convertase, cell surface receptors, decoy receptor, CR2, complement receptor 3, host-pathogen interaction, cryo-electron microscopy

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