A molecular link between malaria and Epstein-Barr virus reactivation.
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.
Chêne
Arnaud
A
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
Donati
Daria
D
Guerreiro-Cacais
André Ortlieb
AO
Levitsky
Victor
V
Chen
Qijun
Q
Falk
Kerstin I
KI
Orem
Jackson
J
Kironde
Fred
F
Wahlgren
Mats
M
Bejarano
Maria Teresa
MT
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
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