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 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.

TLR9 triggering in Burkitt's lymphoma cell lines suppresses the EBV BZLF1 transcription via histone modification

“…This apparently contrasts the recent findings by Chene et al (2007), who showed that P. falciparum CIDR1a might bind to Akata cells in vitro and lead to an increase in the number of cells switching to the viral lytic phase. Nevertheless, the data can be reconciled given that access of hemozoin and CIDR1a to B cells in vivo and the proposed mechanisms of action of the two compounds are distinct.…”

“…Nevertheless, the data can be reconciled given that access of hemozoin and CIDR1a to B cells in vivo and the proposed mechanisms of action of the two compounds are distinct. CIDR1a is expressed at the surface of infected erythrocytes, and direct contact between erythrocytes and B cells is required to show a posited mechanism similar to BCR crosslinking (Chene et al, 2007). In contrast, hemozoin is shed in large amounts after schizont rupture, is not bound to erythrocytes, and thus may disperse more broadly, and be taken up by immune cells in the absence of direct contact with erythrocytes.…”

Oncogenic Mechanisms in Burkitt Lymphoma

“…EBV persists in a latent state in resting memory B cells that circulate in the peripheral blood (Thorley-Lawson 2001). The exposure of B cells to malarial antigens during multiple infectious episodes could reactivate the virus from memory B cells, thereby increasing viral load and the number of EBV-infected cells (Donati et al 2006;Chene et al 2007).…”

Interleukin-6 and Interleukin-10 Gene Promoter Polymorphisms and Risk of Endemic Burkitt Lymphoma

“…7 eBL is hypothesized to be of a multifactorial etiology, encompassing environmental factors, infectious factors (i.e., EBV and malaria infection), immune system disturbances, and potentially, host genetic predisposition. 2,8,9 Although the precise pathogenic mechanisms for eBL have not been fully elucidated, genetic susceptibility has been found to play an important role in the development and progression of BL. 10,11 Polymorphisms in cytokine genes can influence inflammation and immune response to infection and may be related to risk of eBL, 12,13 but they have yet to be well-investigated within the context of epidemiologic studies.…”