title: Recruitment of Factor H as a Novel Complement Evasion Strategy for Blood-Stage Plasmodium falciparum Infection.
abstract: The human complement system is the frontline defense mechanism against invading pathogens. The coexistence of humans and microbes throughout evolution has produced ingenious molecular mechanisms by which microorganisms escape complement attack. A common evasion strategy used by diverse pathogens is the hijacking of soluble human complement regulators to their surfaces to afford protection from complement activation. One such host regulator is factor H (FH), which acts as a negative regulator of complement to protect host tissues from aberrant complement activation. In this report, we show that Plasmodium falciparum merozoites, the invasive form of the malaria parasites, actively recruit FH and its alternative spliced form FH-like protein 1 when exposed to human serum. We have mapped the binding site in FH that recognizes merozoites and identified Pf92, a member of the six-cysteine family of Plasmodium surface proteins, as its direct interaction partner. When bound to merozoites, FH retains cofactor activity, a key function that allows it to downregulate the alternative pathway of complement. In P. falciparum parasites that lack Pf92, we observed changes in the pattern of C3b cleavage that are consistent with decreased regulation of complement activation. These results also show that recruitment of FH affords P. falciparum merozoites protection from complement-mediated lysis. Our study provides new insights on mechanisms of immune evasion of malaria parasites and highlights the important function of surface coat proteins in the interplay between complement regulation and successful infection of the host.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3052, Australia;
authors.forename: Alexander T
authors.initials: AT
authors.lastname: Kennedy
authors.affiliation: Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, 89081 Ulm, Germany;
authors.forename: Christoph Q
authors.initials: CQ
authors.lastname: Schmidt
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia;
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Thompson
authors.affiliation: Burnet Institute, Melbourne, Victoria 3004, Australia;
authors.forename: Greta E
authors.initials: GE
authors.lastname: Weiss
authors.affiliation: Burnet Institute, Melbourne, Victoria 3004, Australia;
authors.forename: Tana
authors.identifier: http://orcid.org/0000-0001-5324-8876
authors.initials: T
authors.lastname: Taechalertpaisarn
authors.affiliation: Burnet Institute, Melbourne, Victoria 3004, Australia; Department of Immunology, Monash University, Victoria 3004, Australia;
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gilson
authors.affiliation: School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FF, United Kingdom; School of Chemistry, University of Edinburgh, Edinburgh EH9 3FJ, United Kingdom; and.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Barlow
authors.affiliation: Burnet Institute, Melbourne, Victoria 3004, Australia; Department of Immunology, Monash University, Victoria 3004, Australia; Department of Microbiology and Immunology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Brendan S
authors.initials: BS
authors.lastname: Crabb
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3052, Australia;
authors.forename: Alan F
authors.initials: AF
authors.lastname: Cowman
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3052, Australia; tham@wehi.edu.au.
authors.forename: Wai-Hong
authors.identifier: http://orcid.org/0000-0001-7950-8699
authors.initials: WH
authors.lastname: Tham
mesh_terms: D015153:Blotting, Western; D003167:Complement Activation / Q000276:immunology*; D017242:Complement Factor H / Q000276:immunology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D057131:Immune Evasion / Q000276:immunology*; D047468:Immunoprecipitation; D016778:Malaria, Falciparum / Q000276:immunology*; D052940:Merozoites / Q000276:immunology
chemical_list: D017242:Complement Factor H