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Abstract
Epstein–Barr virus (EBV) is a necessary cause of endemic Burkitt lymphoma (eBL), while the role of Plasmodium falciparum in eBL remains uncertain. This study aimed to generate new hypotheses on the interplay between both infections in the development of eBL by investigating the IgG and IgM profiles against several EBV and P. falciparum antigens. Serum samples collected in a childhood study in Malawi (2005–2006) from 442 HIV-seronegative children (271 eBL cases and 171 controls) between 1.4 and 15 years old were tested by quantitative suspension array technology against a newly developed multiplex panel combining 4 EBV antigens [Z Epstein–Barr replication activator protein (ZEBRA), early antigen-diffuse component (EA-D), EBV nuclear antigen 1, and viral capsid antigen p18 subunit (VCA-p18)] and 15 P. falciparum antigens selected for their immunogenicity, role in malaria pathogenesis, and presence in different parasite stages. Principal component analyses, multivariate logistic models, and elastic-net regressions were used. As expected, elevated levels of EBV IgG (especially against the lytic antigens ZEBRA, EA-D, and VCA-p18) were strongly associated with eBL [high vs low tertile odds ratio (OR) = 8.67, 95% confidence interval (CI) = 4.81–15.64]. Higher IgG responses to the merozoite surface protein 3 were observed in children with eBL compared with controls (OR = 1.29, 95% CI = 1.02–1.64), showing an additive interaction with EBV IgGs (OR = 10.6, 95% CI = 5.1–22.2, P = 0.05). Using elastic-net regression models, eBL serological profile was further characterized by lower IgM levels against P. falciparum preerythrocytic-stage antigen CelTOS and EBV lytic antigen VCA-p18 compared with controls. In a secondary analysis, abdominal Burkitt lymphoma had lower IgM to EBV and higher IgG to EA-D levels than cases with head involvement. Overall, this exploratory study confirmed the strong role of EBV in eBL and identified differential IgG and IgM patterns to erythrocytic vs preerythrocytic P. falciparum antigens that suggest a more persistent/chronic malaria exposure and a weaker IgM immune response in children with eBL compared with controls. Future studies should continue exploring how the malaria infection status and the immune response to P. falciparum interact with EBV infection in the development of eBL.
Highlights
Endemic Burkitt lymphoma, a highly aggressive B-cell non-Hodgkin lymphoma, is one of the most prevalent pediatric cancers in areas of sub-Saharan Africa where Plasmodium falciparum transmission is high
Our data support a strong role of Epstein–Barr virus (EBV) in Endemic Burkitt lymphoma (eBL), and a weak effect of malaria, but suggest that both infections might act jointly on eBL, as shown by the additive interaction between elevated IgGs against EBV and merozoite surface protein 3 (MSP-3)
In agreement with this observation, two recent studies have reported that the key determinants of EBV primary infection kinetics in children are the degree of malaria exposure and maternal antibody decay [9, 40]
Summary
Endemic Burkitt lymphoma (eBL), a highly aggressive B-cell non-Hodgkin lymphoma, is one of the most prevalent pediatric cancers in areas of sub-Saharan Africa where Plasmodium falciparum transmission is high. The parasite deregulates the activation-induced deaminase enzyme that is associated with somatic hypermutation and class switch recombination of immunoglobulin genes. This leads to DNA damage and increases the likelihood of c-myc translocations that, when happening in EBV-infected cells, leads to the development of lymphoma [6]. In line with these observations, the International Agency for Research on Cancer categorized P. falciparum infection as a probable carcinogen (group 2A) in relation to the pathogenesis of eBL [7]
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