title: A molecular link between malaria and Epstein-Barr virus reactivation.
abstract: Although malaria and Epstein-Barr (EBV) infection are recognized cofactors in the genesis of endemic Burkitt lymphoma (BL), their relative contribution is not understood. BL, the most common paediatric cancer in equatorial Africa, is a high-grade B cell lymphoma characterized by c-myc translocation. EBV is a ubiquitous B lymphotropic virus that persists in a latent state after primary infection, and in Africa, most children have sero-converted by 3 y of age. Malaria infection profoundly affects the B cell compartment, inducing polyclonal activation and hyper-gammaglobulinemia. We recently identified the cystein-rich inter-domain region 1alpha (CIDR1alpha) of the Plasmodium falciparum membrane protein 1 as a polyclonal B cell activator that preferentially activates the memory compartment, where EBV is known to persist. Here, we have addressed the mechanisms of interaction between CIDR1alpha and EBV in the context of B cells. We show that CIDR1alpha binds to the EBV-positive B cell line Akata and increases the number of cells switching to the viral lytic cycle as measured by green fluorescent protein (GFP) expression driven by a lytic promoter. The virus production in CIDR1alpha-exposed cultures was directly proportional to the number of GFP-positive Akata cells (lytic EBV) and to the increased expression of the EBV lytic promoter BZLF1. Furthermore, CIDR1alpha stimulated the production of EBV in peripheral blood mononuclear cells derived from healthy donors and children with BL. Our results suggest that P. falciparum antigens such as CIDR1alpha can directly induce EBV reactivation during malaria infection that may increase the risk of BL development for children living in malaria-endemic areas. To our knowledge, this is the first report to show that a microbial protein can drive a latently infected B cell into EBV replication.
authors.affiliation: Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Chêne
authors.forename: Daria
authors.initials: D
authors.lastname: Donati
authors.forename: André Ortlieb
authors.initials: AO
authors.lastname: Guerreiro-Cacais
authors.forename: Victor
authors.initials: V
authors.lastname: Levitsky
authors.forename: Qijun
authors.initials: Q
authors.lastname: Chen
authors.forename: Kerstin I
authors.initials: KI
authors.lastname: Falk
authors.forename: Jackson
authors.initials: J
authors.lastname: Orem
authors.forename: Fred
authors.initials: F
authors.lastname: Kironde
authors.forename: Mats
authors.initials: M
authors.lastname: Wahlgren
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Bejarano
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D004279:DNA, Viral / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020031:Epstein-Barr Virus Infections / Q000150:complications*; D004912:Erythrocytes / Q000469:parasitology; D015967:Gene Expression Regulation, Viral; D004854:Herpesvirus 4, Human / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology; D008288:Malaria / Q000821:virology*; D010963:Plasmodium falciparum / Q000235:genetics* / Q000276:immunology; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012008:Recurrence; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D014775:Virus Activation / Q000235:genetics* / Q000276:immunology; D014779:Virus Replication
chemical_list: D000953:Antigens, Protozoan; C063676:BZLF1 protein, Herpesvirus 4, Human; D004279:DNA, Viral; D004268:DNA-Binding Proteins; D015800:Protozoan Proteins; D015534:Trans-Activators; D014764:Viral Proteins; C085731:erythrocyte membrane protein 1, Plasmodium falciparum