title: Complement and Antibody-mediated Enhancement of Red Blood Cell Invasion and Growth of Malaria Parasites.
abstract: Plasmodium falciparum malaria is a deadly pathogen. The invasion of red blood cells (RBCs) by merozoites is a target for vaccine development. Although anti-merozoite antibodies can block invasion in vitro, there is no efficacy in vivo. To explain this discrepancy we hypothesized that complement activation could enhance RBC invasion by binding to the complement receptor 1 (CR1). Here we show that a monoclonal antibody directed against the merozoite and human polyclonal IgG from merozoite vaccine recipients enhanced RBC invasion in a complement-dependent manner and that soluble CR1 inhibited this enhancement. Sialic acid-independent strains, that presumably are able to bind to CR1 via a native ligand, showed less complement-dependent enhancement of RBC invasion than sialic acid-dependent strains that do not utilize native CR1 ligands. Confocal fluorescent microscopy revealed that complement-dependent invasion resulted in aggregation of CR1 at the RBC surface in contact with the merozoite. Finally, total anti-P. berghei IgG enhanced parasite growth and C3 deficiency decreased parasite growth in mice. These results demonstrate, contrary to current views, that complement activation in conjunction with antibodies can paradoxically aid parasites invade RBCs and should be considered in future design and testing of merozoite vaccines.
authors.affiliation: Department of Microbiology and Immunology, Pennsylvania State University, College of Medicine, 500 University Drive, Hershey, PA 17033, United States.
authors.forename: Sergei
authors.initials: S
authors.lastname: Biryukov
authors.affiliation: Walter Reed Army Institute of Research, Division of Malaria Vaccine Development, Silver Spring, MD 20910, United States.
authors.forename: Evelina
authors.initials: E
authors.lastname: Angov
authors.affiliation: Department of Microbiology and Immunology, Pennsylvania State University, College of Medicine, 500 University Drive, Hershey, PA 17033, United States; Department of Medicine, Division of Infectious Diseases and Epidemiology, Pennsylvania State University, College of Medicine, 500 University Drive, Hershey, PA 17033, United States.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Landmesser
authors.affiliation: Walter Reed Army Institute of Research, Division of Malaria Vaccine Development, Silver Spring, MD 20910, United States.
authors.forename: Michele D
authors.initials: MD
authors.lastname: Spring
authors.affiliation: PATH Malaria Vaccine Initiative, Washington, DC 20001, United States.
authors.forename: Christian F
authors.initials: CF
authors.lastname: Ockenhouse
authors.affiliation: Department of Microbiology and Immunology, Pennsylvania State University, College of Medicine, 500 University Drive, Hershey, PA 17033, United States; Department of Medicine, Division of Infectious Diseases and Epidemiology, Pennsylvania State University, College of Medicine, 500 University Drive, Hershey, PA 17033, United States. Electronic address: jstoute@psu.edu.
authors.forename: José A
authors.initials: JA
authors.lastname: Stoute
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D004912:Erythrocytes / Q000166:cytology / Q000378:metabolism / Q000469:parasitology; D005434:Flow Cytometry; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D008288:Malaria / Q000469:parasitology; D052940:Merozoites / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D018512:Parasitemia / Q000469:parasitology / Q000473:pathology / Q000662:veterinary; D010963:Plasmodium falciparum / Q000254:growth & development / Q000378:metabolism / Q000472:pathogenicity*; D015800:Protozoan Proteins / Q000276:immunology / Q000378:metabolism; D016052:Protozoan Vaccines / Q000276:immunology; D011940:Receptor Aggregation; D011951:Receptors, Complement / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D015800:Protozoan Proteins; D016052:Protozoan Vaccines; D011951:Receptors, Complement
keywords: CR1; Complement; Malaria; Merozoites; Red blood cells