title: Recombinant PfEMP1 peptide inhibits and reverses cytoadherence of clinical Plasmodium falciparum isolates in vivo.
abstract: The parasite ligand Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) and host endothelial receptors represent potential targets for antiadhesive therapy for cytoadherence. In the present study, the major host receptor CD36 was targeted in vitro and in vivo with a recombinant peptide, PpMC-179, corresponding to the minimal CD36-binding domain from the cysteine-rich interdomain region 1 (CIDR1) within the MCvar1 PfEMP1. The in vitro inhibitory effect of PpMC-179 on human dermal microvascular endothelial cells (HDMECs) expressing multiple relevant adhesion molecules was investigated using a parallel-plate flow chamber. Pretreatment of endothelial monolayers with PpMC-179 (2 microM) inhibited the adhesion of infected erythrocytes (IRBCs) from all clinical isolates tested by 84.4% on resting and 62.8% on tumor necrosis factor alpha (TNF-alpha)-stimulated monolayers. Adhesion to stimulated cells was further inhibited (90.4%) when PpMC-179 was administered with an inhibitory anti-intercellular adhesion molecule 1 (ICAM-1) monoclonal antibody 84H10 (5 microg/mL). To determine the in vivo effectiveness of PpMC-179, we used a human/severe combined immunodeficiency (SCID) mouse chimeric model that allowed direct visualization of cytoadherence on intact human microvasculature. In unstimulated skin grafts, PpMC-179 inhibited adhesion by 86.3% and by 84.6% in TNF-alpha-stimulated skin grafts. More importantly, PpMC-179 administration resulted in the detachment of already adherent IRBCs by 80.7% and 83.3% on resting and stimulated skin grafts, respectively. The antiadhesive effect of PpMC-179 was rapid and sustained in vivo for at least 30 minutes. Our data indicate that targeting cytoadhesion in vivo is feasible and may offer a rapid antimalarial therapy.
authors.affiliation: Immunology Research Group, University of Calgary, AB, Canada.
authors.forename: Bryan G
authors.initials: BG
authors.lastname: Yipp
authors.forename: Dror I
authors.initials: DI
authors.lastname: Baruch
authors.forename: Ciaran
authors.initials: C
authors.lastname: Brady
authors.forename: Allan G
authors.initials: AG
authors.lastname: Murray
authors.forename: Sornchai
authors.initials: S
authors.lastname: Looareesuwan
authors.forename: Paul
authors.initials: P
authors.lastname: Kubes
authors.forename: May
authors.initials: M
authors.lastname: Ho
mesh_terms: D000268:Adhesiveness / Q000187:drug effects; D000818:Animals; D004730:Endothelium, Vascular / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008833:Microcirculation; D018715:Microscopy, Video; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000472:pathogenicity; D015800:Protozoan Proteins / Q000302:isolation & purification / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000302:isolation & purification / Q000494:pharmacology
chemical_list: D015800:Protozoan Proteins; D011994:Recombinant Proteins; C085731:erythrocyte membrane protein 1, Plasmodium falciparum