Endemic Burkitt's lymphoma (eBL), an aggressive B-cell lymphoma, is the most prevalent childhood cancer in equatorial Africa. Malaria and Epstein-Barr virus (EBV) infections are co-factors in the aetiology of this disease, but how do these pathogens interact to cause eBL? Reporting in PLoS Pathogens, Chêne and co-workers have identified a protein that is produced by the malaria parasite Plasmodium falciparum and that can induce reactivation of EBV from latently infected B cells. Virus reactivation, in turn, might increase the risk of developing eBL.
Infection with EBV during infancy results in a lifelong latent infection of memory B cells, although not all EBV infections result in B-cell tumorigenesis. eBL is restricted to malaria-endemic regions of Africa, and acute malaria infection dramatically increases the levels of circulating EBV. According to earlier research published by the authors, the cysteine-rich inter-domain region 1-α (CIDR1α) of the highly expressed protein P. falciparum erythrocyte membrane protein 1 (PfEMP1) induces proliferation and activation of memory B cells. The latest report details the effects of CIDR1α on the reactivation of latent EBV in B cells.
Chêne et al. showed that red blood cells infected with P. falciparum, which express huge amounts of PfEMP1, and purified CIDR1α both bind to EBV-carrying B cells. Importantly, the binding of CIDR1α to EBV-carrying B cells resulted in a large increase in virus titre that could not be attributed to either increased apoptosis (leading to virus release) or B-cell proliferation. To directly show that CIDR1α stimulates reactivation of EBV from latency to a lytic replication cycle, the authors used a B-cell line that is a reporter for induction of the lytic replication EBV cycle through a fusion of green fluorescent protein (GFP) to an EBV lytic gene. They showed that the addition of CIDR1α results in the upregulation of GFP expression, with a concomitant increase in released EBV genomes that is consistent with reactivation of the EBV lytic replication cycle. CIDR1α had the same effect on EBV-carrying B cells from the tonsils of both healthy donors and those suffering from eBL.
The detection of high antibody titres to EBV lytic proteins is usually a prelude to the onset of eBL. Elucidating the mechanisms underlying the link between exposure to malaria and increased EBV replication represents an important advance in the understanding of eBL carcinogenesis.
ORIGINAL RESEARCH PAPER
Chêne, A. et al. A molecular link between malaria and Epstein-Barr virus reactivation. PloS Pathogens 3, e80 (2007)
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Jones, S. A deadly partnership. Nat Rev Microbiol 5, 568 (2007). https://doi.org/10.1038/nrmicro1724
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DOI: https://doi.org/10.1038/nrmicro1724