A Molecular Link between Malaria and Epstein–Barr Virus Reactivation

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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 1α (CIDR1α) 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 CIDR1α and EBV in the context of B cells. We show that CIDR1α 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 CIDR1α-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, CIDR1α 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 CIDR1α 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. Malaria and Epstein–Barr virus (EBV) infections are recognized cofactors in the genesis of endemic Burkitt lymphoma, the most common paediatric cancer in equatorial Africa. EBV is a ubiquitous virus residing in B lymphocytes that establishes a lifelong persistence in the host after primary infection. EBV has two lifestyles: latent infection (non-productive), and lytic replication (productive). Children living in malaria-endemic areas exhibit an elevated viral load, and acute malaria infection increases the levels of circulating EBV. The mechanisms leading to viral reactivation during Plasmodium falciparum malaria infection are not well understood. Cystein-rich inter-domain region 1α (CIDR1α) is a domain of a large protein expressed at the surface of P. falciparum–infected red blood cells. Based on previous findings showing that CIDR1α activates and expands the B cells compartment where EBV persists, we assessed the impact of CIDR1α on viral reactivation. Here, we identify CIDR1α as the first microbial protein able to drive a latently EBV-infected B cell (no virus production) into lytic replication (virus production). Our results suggest that P. falciparum–derived proteins can lead to a direct reactivation of EBV during acute malaria infection, increasing the risk of Burkitt lymphoma development for children living in malaria-endemic areas.