Abstract
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.
Highlights
Persistent pathogens have evolved to avoid elimination by the mammalian immune system including mechanisms to evade complement
Self-cells are protected by complement factor H (FH), which binds to components of the negatively charged glycocalyx[4]
It has been shown that C3 convertase (C3bBb) can assemble on the surface of bloodstream forms (BSFs) but the complement cascade did not progress further and there was no recruitment of complement proteins C5b-9 to form a MAC28
Summary
Persistent pathogens have evolved to avoid elimination by the mammalian immune system including mechanisms to evade complement. We identify an African trypanosome receptor for mammalian factor H, a negative regulator of the alternative pathway. 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. FH recruitment by diverse pathogens has been shown to be an effective strategy to inactivate complement in the host, but the molecular basis has only been characterized for three bacteria: Streptococcus pneumoniae, Borrelia burgdorferi and Neisseria meningitidis[9,10,11,12] These recruit FH by mimicry of mammalian host interactions with FH or by increasing activity of FH. Reported cases of the human disease have diminished in the last decade, the animal disease acts both as a reservoir of human infective trypanosomes[20] and continues to reduce livestock production, representing one of the largest constraints on livestock productivity by pastoralists[21]
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