A receptor for the complement regulator factor H increases transmission of trypanosomes to tsetse flies

Persistent pathogens have evolved to avoid elimination by the mammalian immune system including mechanisms to evade complement. Infections with African trypanosomes can persist for years and cause human and animal disease throughout sub-Saharan Africa. It is not known how trypanosomes limit the action of the alternative complement pathway. Here we identify an African trypanosome receptor for mammalian factor H, a negative regulator of the alternative pathway. Structural studies show how the receptor binds ligand, leaving inhibitory domains of factor H free to inactivate complement C3b deposited on the trypanosome surface. Receptor expression is highest in developmental stages transmitted to the tsetse fly vector and those exposed to blood meals in the tsetse gut. Receptor gene deletion reduced tsetse infection, identifying this receptor as a virulence factor for transmission. This demonstrates how a pathogen evolved a molecular mechanism to increase transmission to an insect vector by exploitation of a mammalian complement regulator.

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Policy information about availability of data All manuscripts must include a data availability statement. This statement should provide the following information, where applicable: -Accession codes, unique identifiers, or web links for publicly available datasets -A list of figures that have associated raw data -A description of any restrictions on data availability Mark Carrington Matthew K. Higgins Jan 31, 2020 Data collection and processing software used are described in the methods section and are commercially available or openly accessible.
Data analysis was performed as described in the methods section using commercially available or openly accessible software and code (see Supplementary Data 1). GraphPad Prism version 7 was used to generate graphs, PyMOL for crystallographic structures, and Affinity Photo and Designer to generate figures.
Crystallographic data has been deposited into the Protein Data Bank (PDB) with accession number 6XZ6. The code in this work is deposited on GitHub and details can be found in Supplementary Data 1. All underlying source and raw data can be found in the Source Data file. All other data are available from the authors at request.

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Life sciences study design
All studies must disclose on these points even when the disclosure is negative. Sample sizes for animal and insect model experiments were chosen to yield statistically significant results and are stated in the figure legends or methods section.
No data were excluded from the analysis.
Experimental findings were repeated when stated in the figure legends or methods section. All repeats were successful and described in this work.
Organisms were sorted randomly and independently prior to allocation to and investigation within experimental groups.
Investigators were blinded to the samples when counting and assessing parasitaemia.
The factor H receptor monoclonal antibody and antiserum was generated as described in the methods section. The paraflagellar rod loading control was a kind gift of Keith Gull (Kohl, L., Sherwin, T. & Gull, K. J. Eukaryot. Microbiol. 46, 105-109 (1999)). All secondary antibodies are commercially available from Jackson Laboratories.
All antibodies were validated within this work using the conditions outlined.
Results independent of isolate identity.
Mycoplasma does not contaminate trypanosome cultures.
No commonly misidentified cell lines were used in this work.