Malaria - how this parasitic infection aids and abets EBV-associated Burkitt lymphomagenesis

Abstract

Burkitt lymphoma (BL) is >90% EBV-associated when this pediatric cancer is diagnosed in regions heavily burden by endemic Plasmodium falciparum malaria and thus has been geographically classified as endemic BL. The incidence of endemic BL is 10-fold higher compared to BL diagnosed in non-malarious regions of the world. The other forms of BL have been classified as sporadic BL which contain EBV in ∼30% of cases and immunodeficiency BL which occurs in HIV-infected adults with ∼40% of tumors containing EBV. Within malaria endemic regions, epidemiologic studies replicating Denis Burkitt's seminal observation continue to show differences in endemic BL incidence linked to intensity of malaria transmission. However, the mechanisms by which malaria contributes to B cell tumorigenesis have not been resolved to the point of designing cancer prevention strategies. The focus of this review is to summarize our current knowledge regarding the influence of prolonged, chronic malaria exposure on defects in immunosurveillance that would otherwise control persistent EBV infections. And thus, set the stage for ensuing mechanisms by which malaria could instigate B cell activation and aberrant activation-induced cytidine deaminase expression initiating somatic hypermutation and thereby increasing the likelihood of an Ig/Myc translocation, the hallmark of all BL tumors. Malaria appears to play multiple, sequential and simultaneous roles in endemic BL etiology; the complexity of these interactions are being revealed by applying computational methods to human immunology. Remaining questions yet to be addressed and prevention strategies will also be discussed.

Figure 1. Illustration of the synergistic mechanisms by which Plasmodium falciparum malaria could contribute to impaired EBV immune surveillance and aberrant AID expression within an EBV-infected B cell as a prelude to endemic Burkitt lymphoma oncogenesis

Step 1: EBV establishes latency in B cell whereby viral proteins (LMP1, LMP2, EBNA3C and possibly microRNA) mimic host activation signals and development of naïve memory B cells. Question remains if eBL precursor is derived from EBV-infected B cell established independent of a primary germinal center (GC) reaction and thus retains surface IgM that did not undergo cognate antigen-affinity maturation. Step 2: Recurrent malaria infections induce EBV lytic reactivation, mediated by antigen-independent PfEMP1-IgM interactions, resulting in cyclical episodes of lytic antigen expression and a cascade of EBV latent antigen expression and expansion of the number of EBV-infected B cells. Malaria-derived DNA/hemozoin is a TLR9 ligand that can induce AID expression in the absence of cognate antigen B cell receptor (BCR) crosslinking. Questions remain as to how many malaria infections or the duration of chronic malaria that would provide a threshold of stimulation to induce aberrant AID expression and if there are other malaria-derived mediators of B cell activation. Step 3: Erosion of EBV immune surveillance presents as a gradual degradation of immune responses to EBV lytic and latent antigens over time. NK cell dysfunction may be induced by malaria with a bystander effect of an inability to control secondary EBV infections. EBV lytic and then latent T cell responses become exhausted or tolerized to this persistent viral infection when antigen load is high. This scenario is further hindered by the human infant immune system being inherently less efficient at controlling infectious diseases and less likely to induce long-term effector-memory T cell subsets. Questions remain as to the threshold of EBV antigen-load that results in loss of T cell function and if this can be rendered moot by decreasing malaria exposure alone. Step 4: EBV-infected memory B cells enter ‘second’ germinal center reaction. The EBV-infected B cell encounters its cognate antigen but now in the presence of antigen-specific CD4 follicular helper T cells (the development of which do not occur until children are older, years after their primary exposures to EBV and repeated malaria infections). Combined, these normal B cell signaling pathways induce class-switch recombination (CSR) and somatic hypermutations (SHM) mediated by AID. Questions remain as to the antigen-specificity of the BCR on eBL tumors and if they have undergone proper affinity maturation if they bypassed the GC reaction in Step 1, or if the chronic malaria infection and repeated peaks of parasitemia are more relevant to antigen-independent AID expression as describe in Step 2. In addition, the inflammatory environment present during the GC reaction could influence B cell development and survival. If these events occur in concert it could have a synergistic effect by over amplifying the expression of AID and may also explain the rarity of one EBV-infected B cell becoming an eBL precursor. Step 5: Endemic Burkitt lymphoma (eBL) tumorigenesis. Underlying host mutations have been described for BL tumors; combined with aberrantly high or prolonged AID expression would likely facilitate the risk of a C-myc translocation resulting in oncogenesis. The success of one B cell becoming a BL tumor is all the more likely when immunosurveillance has been impaired as described in Step 3. In summary, malaria appears to play numerous roles in eBL tumorigenesis, with EBV as the promotor and human mutations the underlying landscape.