title: Ancient human sialic acid variant restricts an emerging zoonotic malaria parasite.
abstract: Plasmodium knowlesi is a zoonotic parasite transmitted from macaques causing malaria in humans in Southeast Asia. Plasmodium parasites bind to red blood cell (RBC) surface receptors, many of which are sialylated. While macaques synthesize the sialic acid variant N-glycolylneuraminic acid (Neu5Gc), humans cannot because of a mutation in the enzyme CMAH that converts N-acetylneuraminic acid (Neu5Ac) to Neu5Gc. Here we reconstitute CMAH in human RBCs for the reintroduction of Neu5Gc, which results in enhancement of P. knowlesi invasion. We show that two P. knowlesi invasion ligands, PkDBPβ and PkDBPγ, bind specifically to Neu5Gc-containing receptors. A human-adapted P. knowlesi line invades human RBCs independently of Neu5Gc, with duplication of the sialic acid-independent invasion ligand, PkDBPα and loss of PkDBPγ. Our results suggest that absence of Neu5Gc on human RBCs limits P. knowlesi invasion, but that parasites may evolve to invade human RBCs through the use of sialic acid-independent pathways.
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: Selasi
authors.initials: S
authors.lastname: Dankwa
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: Caeul
authors.initials: C
authors.lastname: Lim
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: Amy K
authors.initials: AK
authors.lastname: Bei
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: Rays H Y
authors.initials: RH
authors.lastname: Jiang
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Abshire
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.|Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Saurabh D
authors.initials: SD
authors.lastname: Patel
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Goldberg
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: Yovany
authors.initials: Y
authors.lastname: Moreno
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: Maya
authors.initials: M
authors.lastname: Kono
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Jacquin C
authors.initials: JC
authors.lastname: Niles
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: Manoj T
authors.initials: MT
authors.lastname: Duraisingh
mesh_terms: D000818:Animals; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology; D018503:Genome, Protozoan; D057809:HEK293 Cells; D006801:Humans; D008288:Malaria / Q000517:prevention & control*; D006899:Mixed Function Oxygenases / Q000235:genetics; D019158:N-Acetylneuraminic Acid / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D009438:Neuraminic Acids / Q000737:chemistry / Q000378:metabolism; D016790:Plasmodium knowlesi / Q000235:genetics / Q000472:pathogenicity*; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics; D015047:Zoonoses / Q000469:parasitology* / Q000517:prevention & control / Q000635:transmission
chemical_list: D009438:Neuraminic Acids; D015800:Protozoan Proteins; C032592:N-glycolylneuraminic acid; D006899:Mixed Function Oxygenases; C074383:CMPacetylneuraminate monooxygenase; D019158:N-Acetylneuraminic Acid