Does EBV alter the pathogenesis of malaria?

Abstract

Plasmodium falciparum infections have been implicated in immune deficiencies resulting in ineffective control of Epstein-Barr virus, thereby increasing the risk of endemic Burkitt lymphoma in children. However, the impact of Epstein-Barr virus infections on the development of immunity to P. falciparum has not been studied in depth. In this review, we examine novel findings from animal co-infection models and human immuno-epidemiologic studies to speculate on the impact of acute gammaherpesvirus co-infection on malarial disease severity. Children are often concurrently or sequentially infected with multiple pathogens, and this has implications for understanding the development of protective immunity as well as in the evaluation of vaccine efficacy.

Keywords: animal models; co-infection; epidemiologic studies; immunity.

Figure 1

The life cycle of Epstein–Barr virus. EBV is thought to be able to infect B cells directly as lytic virions or epithelial cells during oral transmission. However, one theory suggests that EBV may initially infect B cells even before infecting epithelial cells because X-linked agammaglobulinemia patients are not infected with EBV. EBV efficiently infects naïve B cells that express both CD21 and CD35. However, activated B cells only express CD21, but no or limited CD35 which explains why a significant number of B cells become refractory to EBV infection.

Figure 2

Model of EBV interference with antimalarial immunity. EBV-infected B cells secrete immunosuppressive cytokines (shown in box). The same cytokines are also secreted by EBV-infected pDC, mDC and monocytes – which increases their overall abundance. This immunomodulating cytokine milieu then down-regulates IFN-γ being produced by EBV-specific CD4+ and CD8+ T cells (hashed lines around IFN-γ) – which then in turn prevents monocytes from performing phagocytosis of Plasmodium-infected RBCs or free merozoites and also prevents follicular T cells from providing help to B cells to make antibodies. EBV is represented by the black pentagons. Parasitized red blood cells are represented by red outlined purple circles. Points of interaction are represented by solid lines and inhibition by the dashed lines. BAFF, B-cell-activating factor; BlyS, B lymphocyte stimulator; IDO, indoleamine 2,3 dioxygenase; IFN, interferon; IL, interleukin; iRBCs, malaria-infected red blood cells; mDC, myeloid dendritic cells; pDC, plasmacytoid dendritic cells; TGF, transforming growth factor.