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. 2017 Oct 26:8:1284.
doi: 10.3389/fimmu.2017.01284. eCollection 2017.

Assessment of the Combined Effect of Epstein-Barr Virus and Plasmodium falciparum Infections on Endemic Burkitt Lymphoma Using a Multiplex Serological Approach

Ruth Aguilar  1 , Delphine Casabonne  2   3 , Cristina O'Callaghan-Gordo  2   4   5 , Marta Vidal  1 , Joseph J Campo  1 , Nora Mutalima  6   7 , Evelina Angov  8 , Sheetij Dutta  8 , Deepak Gaur  9   10 , Chetan E Chitnis  9 , Virander Chauhan  9 , Angelika Michel  11 , Silvia de Sanjosé  2   3 , Tim Waterboer  11 , Manolis Kogevinas  2   4   5   12 , Rob Newton  13   14 , Carlota Dobaño  1
Affiliations

Assessment of the Combined Effect of Epstein-Barr Virus and Plasmodium falciparum Infections on Endemic Burkitt Lymphoma Using a Multiplex Serological Approach

Ruth Aguilar et al. Front Immunol. .

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.

Keywords: Africa; Epstein–Barr virus; IgG; IgM; Plasmodium falciparum; children; endemic Burkitt lymphoma; multiplex.

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Figures

Figure 1
Figure 1
Flowchart of endemic Burkitt lymphoma (eBL) cases and controls included in the study.
Figure 2
Figure 2
Pairwise correlations between logged antibody levels of both pathogens.
Figure 3
Figure 3
Odds ratios (ORs) for endemic Burkitt lymphoma in relation to IgG and IgM levels against single Epstein–Barr virus (EBV) and Plasmodium falciparum antigens and against EBV PCA components.
Figure 4
Figure 4
Selecting important Epstein–Barr virus (EBV) and Plasmodium falciparum antigen-specific antibodies for endemic Burkitt lymphoma using elastic-net penalized regression models.
Figure 5
Figure 5
Additive interactions for endemic Burkitt lymphoma between “Epstein–Barr virus (EBV) IgG pattern” and IgG to merozoite surface protein 3 antigen.
Figure 6
Figure 6
Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for endemic Burkitt lymphoma in relation to IgG and IgM levels against Epstein–Barr virus (EBV) antigens by tumor location.
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