title: Blood Stage Malaria Disrupts Humoral Immunity to the Pre-erythrocytic Stage Circumsporozoite Protein.
abstract: Many current malaria vaccines target the pre-erythrocytic stage of infection in the liver. However, in malaria-endemic regions, increased blood stage exposure is associated with decreased vaccine efficacy, thereby challenging current vaccine efforts. We hypothesized that pre-erythrocytic humoral immunity is directly disrupted by blood stage infection. To investigate this possibility, we used Plasmodium-antigen tetramers to analyze B cells after infection with either late liver stage arresting parasites or wild-type parasites that progress to the blood stage. Our data demonstrate that immunoglobulin G (IgG) antibodies against the pre-erythrocytic antigen, circumsporozoite protein (CSP), are generated only in response to the attenuated, but not the wild-type, infection. Further analyses revealed that blood stage malaria inhibits CSP-specific germinal center B cell differentiation and modulates chemokine expression. This results in aberrant memory formation and the loss of a rapid secondary B cell response. These data highlight how immunization with attenuated parasites may drive optimal immunity to malaria.
authors.affiliation: Department of Immunology, University of Washington School of Medicine, 750 Republican Street, Seattle, WA 98109, USA.
authors.forename: Gladys J
authors.initials: GJ
authors.lastname: Keitany
authors.affiliation: Department of Immunology, University of Washington School of Medicine, 750 Republican Street, Seattle, WA 98109, USA.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Kim
authors.affiliation: Department of Immunology, University of Washington School of Medicine, 750 Republican Street, Seattle, WA 98109, USA.
authors.forename: Akshay T
authors.initials: AT
authors.lastname: Krishnamurty
authors.affiliation: Department of Immunology, University of Washington School of Medicine, 750 Republican Street, Seattle, WA 98109, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Hondowicz
authors.affiliation: Department of Immunology, University of Washington School of Medicine, 750 Republican Street, Seattle, WA 98109, USA.
authors.forename: William O
authors.initials: WO
authors.lastname: Hahn
authors.affiliation: Center for Infectious Disease Research, 307 Westlake Avenue North, No. 500, Seattle, WA 98109, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Dambrauskas
authors.affiliation: Center for Infectious Disease Research, 307 Westlake Avenue North, No. 500, Seattle, WA 98109, USA.
authors.forename: D Noah
authors.initials: DN
authors.lastname: Sather
authors.affiliation: Center for Infectious Disease Research, 307 Westlake Avenue North, No. 500, Seattle, WA 98109, USA.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Vaughan
authors.affiliation: Center for Infectious Disease Research, 307 Westlake Avenue North, No. 500, Seattle, WA 98109, USA.
authors.forename: Stefan H I
authors.initials: SHI
authors.lastname: Kappe
authors.affiliation: Department of Immunology, University of Washington School of Medicine, 750 Republican Street, Seattle, WA 98109, USA. Electronic address: mpepper@uw.edu.
authors.forename: Marion
authors.initials: M
authors.lastname: Pepper
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000469:parasitology; D004912:Erythrocytes / Q000276:immunology / Q000469:parasitology; D006801:Humans; D056724:Immunity, Humoral; D007074:Immunoglobulin G / Q000276:immunology; D008099:Liver / Q000276:immunology / Q000469:parasitology; D017780:Malaria Vaccines / Q000276:immunology* / Q000627:therapeutic use; D016778:Malaria, Falciparum / Q000235:genetics / Q000276:immunology* / Q000469:parasitology; D010963:Plasmodium falciparum / Q000276:immunology* / Q000472:pathogenicity; D014611:Vaccination
chemical_list: D000953:Antigens, Protozoan; D007074:Immunoglobulin G; D017780:Malaria Vaccines
keywords: antibodies; antigen specific B cells; attenuated parasites; humoral immunity; malaria; memory B cells; plasmodium; vaccines