1. Introduction

Epstein-Barr Virus (EBV) known as human herpesvirus 4 (HHV-4) is an oncogenic virus that belongs to the herpesvirus family. It is a ubiquitous virus that infects 95% of the world’s adult population at an early age establishing long-term persistent infection [1, 2]. The virus has two life cycles, namely, the lytic replication that is important for the spread of the virus whereas latency facilitates the episomal persistence of the viral genome [1,3,4]. Sometimes, under psychological and physiological stress, EBV reactivates. During pregnancy, which is assumed to be an immunosuppressed state, nearly 35% of latent EBV infection becomes reactivated [5]. Maternal EBV reactivation has been associated with adverse offspring development, including severe symmetrical fetal growth restriction, lower birth weight, and leukemia [6]. EBV infection in children usually don’t cause symptoms but in adolescents and young adults, it may cause infectious mononucleosis, with symptoms like fatigue, malaise, pharyngitis, fever, abdominal discomfort, lymphadenopathy and headache. Some patients may develop complications such as autoimmune diseases, splenic rupture and neurological complications [7].

In sub-Saharan Africa, Epstein-Barr virus (EBV) and Plasmodium falciparum have similar geographical distribution [8-10]. The co-infection with these two infectious agents has been proven to be more dangerous than each infection separately [11]. Various epidemiological studies have long established an etiology link between Epstein-Barr virus (EBV), Plasmodium, and endemic Burkitt Lymphoma (eBL). Endemic Burkitt Lymphoma is the most common paediatric malignant tumour in children aged 5-9 years livings in sub-Saharan Africa and Papua New Guinea [12-14]. Previous studies have demonstrated that acute Epstein-Barr virus infection can suppress the development of humoral and adaptive immunity against malaria, becoming a risk factor for severe malaria [11, 15]. In a well-defined mouse model, Matar et al have shown that acute infection with murine gammaherpesvirus 68 (MHV68) suppresses humoral antimalarial responses by disrupting B-cell formation and differentiation into antibody-producing plasma cells at the germinal centre in the spleen [16]. However, the reactivation of EBV infection has been involved in the pathogenesis of numerous diseases in general [17]. Recently, it has been revealed that reactivated EBV can infect human brain microvascular endothelial cells (HBECs), increase RBC adhesion on ECs, and thus aid in exacerbation of cerebral malaria pathology [18]. Nevertheless, little is known about the association of EBV reactivation and the severity of malaria. Furthermore, the mechanisms by which reactivated EBV infection leads to severe malaria are not clear. The aim of this article is to review the most recent document on the association of EBV reactivation and the severity of malaria. We will also examine and discuss the possible mechanisms via which EBV may alter the development of an effective immune response and control against malaria.

2. Biology and Epidemiology of Epstein-Barr virus

Epstein-Barr Virus (EBV) was discovered in 1964 by Epstein et al. in a culture of Burkitt lymphoma cells. Its genome has a double-stranded DNA genome of about 170 kbp that is maintained in the nucleus of a host cell as an episome [19]. In sub-Saharan Africa, children get infected early in life (from 6 months of age) while in developed countries infections occur in adolescence and adulthood [20, 21]. Once the virus penetrates in the host, it interacts with the CDß1 molecule present on the cell plasma membrane and persists preferentially in B-lymphocytes and oropharyngeal epithelial cells for life [22]. However, the virus is also capable of infecting Dendritic Cells (DC), T-lymphocytes, neutrophils (N), macrophages (MA), and monocytes (MO) [23-26]. The main route of transmission is oral via direct contact with saliva. Nevertheless, infections through blood transfusion, sexual contact, organ transplantation, breast milk, and during childbirth have been reported [27-30].

Generally, the primary EBV infection is asymptomatic but in immunocompromised conditions, EBV DNA loads increase may cause various complications progressing to lymphoid or epithelial malignancies [31, 32]. EBV can undergo two life cycles, namely latent (non-productive) or lytic replication (reproductive) (Figure 1) [1]. The virus spreads from cell to cell and from host to host thanks to the lytic replication whereas latency facilitates the episomal persistence of the viral genome [3, 4]. However, under certain physiological conditions, the virus may undergo lytic reactivation leading to the expression of lytic proteins, followed by the assembly and exit of virions capable of infecting other cells and infecting other hosts [33].

Figure 1: Schematic representation of the EBV life cycle. EBV is transmitted mainly by the oral route. Once in the oral cavity, the virus spreads through saliva and infects epithelial cells and naive B cells (CD21 and CD35). The naive B cells that have been in contact with the antigen transform into active lymphoblast cells capable of presenting the antigen to the CD4+ T cells of the germinal center. In the germinal center, the infected B cells will undergo a latent phase through the expression of latency genes. This phase favors the persistence of the virus in the host. Under certain conditions, EBV present in reactive memory B cells induces a lytic phase of replication characterized by release of numerous virions and expression of immediate, early and late lytic genes. Subsequently, memory B cells may migrate to the oral compartment and excrete the virus. This phase allows the transmission of the virus. Source: Own elaboration (Created with BioRender.com).

3. Stimulators factors of EBV reactivation

The reactivation of the lytic infection from latently infected cells in an infected host is most often due to an alteration of the cellular immune response. During the reactivation, early viral genes are expressed mainly, BamHI Z fragment leftward open reading frame 1 (BZLF1) (also known as Zta, Z, ZEBRA, EB1) and BRLF1 (also known as Rta, R, EB2) two transactivators [33]. Many factors are involved in the reactivation process.

3.1 Physiological and Environmental Inductors

Studies have shown that chemical and biological agents like 12-O-tetradecanoylphorbol-13-acetate (TPA), sodium butyrate, anti-Ig M, transforming growth factor-beta (TGF-β), calcium ionophores, histone deacetylase inhibitors (HDAC) and Inhibitors of DNA methyltransferase can trigger EBV reactivation by the two immediate-early transactivators (EI) induced, Zt and Rta [34-36]. It has been revealed that E. tirucalli can reactivate EBV thanks to the 4-deoxyphorbol ester, the latter is related to the TPA which is present in the milky, rubbery sap of this plant [37]. B-cell receptor (BCR) stimulation and epithelial cell differentiation are also known to activate the lytic replication form of EBV infection from latency in the host [4, 38]. Signaling pathways mediated by cellular stress such as DNA damage, PKC, MAPK (ERKs, JNKs, and p38), and PI3K pathways appear to be involved in the reactivation of lytic infection [39]. Previous research has shown that EBV uses the autophagy mechanism to promote viral replication, yet in the host, this mechanism serves as a defence against viral infection [40,41]. Other studies reveal that activation of autophagic mechanisms through Rta-mediated ERK and PKCθ-p38 signaling promotes the reactivation of EBV [40, 42]. According to Pei Tung Yiu and colleagues in 2019, an iron chelator, C7, activates the lytic cycle of Epstein-Barr virus by activating the ERK1/2 autophagy pathway in epithelial cancers [43].

3.2 Psychological Stress

Previous evidence suggested a link between the reactivation of Epstein-Barr virus and chronic stress due to a decrease in cellular immune responses [44]. Among the various types of stress, psychological stress like pregnancy-related stress, student exam stress, marital stress, attachment anxiety or fear of abandonment can reduce immune responses [45-50]. People with more attachment anxiety have been shown to have higher VCA EBV IgG antibody titers than those with less attachment anxiety [48]. In recent years, the association between EBV reactivation and depression during pregnancy has been the subject of some studies and it has been found that women with depression are more likely to have EBV reactivation [51]. In addition, Purtilo and Sakamoto, 1982 reported an increase in several serological markers of reactivation during pregnancy and suggested that pregnant women have a higher incidence of EBV reactivation because cellular immune responses to EBV appear to be suppressed during pregnancy [52]. In 2010, Haeri et al showed that among 98% of women with EBV, 35% showed EBV reactivation during pregnancy in the second trimester [5]. With regard to physical stress, it has not been implicated in the reactivation of EBV or altered response to the disease [53].

3.3 Immunosuppression and tobacco consumption

EBV-positive individuals treated with immunosuppressive drugs, individuals with congenital or acquired immune deficiencies, or individuals who have undergone organ or stem cell transplants, are more susceptible to viral reactivation of EBV [54, 55]. The association between tobacco consumption and the reactivation of EBV has been much studied. It is known that smoking decreases oxygen and increases hypoxia. Previous studies have suggested that smoking may significantly increase the long-term risk of Nasopharyngeal Carcinoma (NPC) by reactivating EBV infection [56]. Eleanor V. et al also suggest that there is a relationship between Hodgkin's lymphoma and smoking and the reactivation of Epstein-Barr virus [57]. In vitro experiments conducted by Feng-Hua Xu, et al 2012 demonstrate that cigarette smoke promotes the expression of the immediate and early transcriptional activators Zta and Rta. Indeed, these transactivators promote the lytic replication of EBV [58].

4. EBV reactivation and malaria outcomes

4.1 The link between EBV reactivation and malaria

Coinfection between EBV and Plasmodium is common in Africa because of their high geographical distribution [8-10]. In equatorial Africa, these two pathogens have long been associated with the genesis of endemic Burkitt lymphoma (eBL), the most prevalent paediatric cancer in children aged 5-9 years [12, 13]. In this region, the age of EBV seropositivity in children (early at 6 months) coincides with the decline in protective maternal antibodies and increased susceptibility to primary Plasmodium infection [20]. The association of P. falciparum malaria infection and EBV reactivation has been the subject of many studies. It was reported that acute Plasmodium falciparum infection affects the persistence of EBV by increasing the levels of circulating EBV and antibody titers to viral capsid antigen (VCA) and the Z Epstein-Barr replication activator (ZEBRA) protein in peripherical blood [59-62]. Donati et al showed that EBV loads can drop to undetectable levels after antimalaria treatment in children living in malaria-endemic areas (85% of the cases [60]. The mechanisms by which acute malaria reactivate EBV lytic infection is not fully understood, but prolonged and intense exposure to P. falciparum malaria leads to a loss of viral control by compromising T-cell immunity (CD8⁺ T cells) to EBV [13, 63, 64]. Other studies suggest that apart from the inhibitory effect of Plasmodium on EBV-specific T cell responses, P. falciparum affects the B cell compartment by the expansion of EBV-carrying B cells; induction of apoptosis in the infected B cell pool, with consequent release of virus/viral DNA; or increase of viral replication [60, 65-68]. Additionally, Cysteine-rich inter-domain region 1α (CIDR1α) of the Plasmodium falciparum membrane protein 1 a polyclonal B cell activator has been showed to directly induce EBV reactivation during malaria infection increases the risk of BL development for children living in malaria-endemic areas [59].

Cases of co-infection with EBV and other Plasmodium species have been observed in recent years. The first case of P. vivax malaria and EBV coinfection was reported in 2013 in a 5-year old Turkish boy from the Southeast Anatolia and Cukurova regions of Turkey where P. vivax is the most common cause of malaria [69]. Recently in the United States, an 11-year-old boy was diagnosed with malaria and EBV coinfection. The patient had traveled for a 1-month visit to Sierra Leone (his native country and an endemic area for chloroquine-resistant malaria). The current symptoms were pancytopenia with neutropenia. In this country, co-infection with malaria and EBV is extremely rare [70].

4.2 EBV reactivation as a predisposing factor to severe malaria

To date, a handful of studies have already been carried out on the influence of EBV infection on the innate or adaptative immune response against malaria (Table 1). However, these have focused only on acute infection. This is the case of the work carried out by Wedderburn et al. in 1988 on the impact of Epstein-Barr virus and P. brasilianum coinfection on the development of glomerulonephritis in infected marmoset mice. In a well-developed model, the latter observed an increase in the severity and mortality of the disease in animals infected simultaneously with both agents. It is also noted that animals co-infected with P. brasilianum and EBV had a more prolonged parasitaemia compared to those mono-infected with P. brasilianum, suggesting that co-infection could lead to the etiology of quarantine malarial nephropathy [71]. A few years ago, Caline M. et al, 2015 demonstrated the immunosuppressive effect of acute EBV infection on the development of humoral antimalarial immunity [16]. In 2018, a study conducted in Brazil on two distinct malaria area, one from the Amazon region (sporadically exposed to malaria transmission) and the other from the agricultural area of Rio Pardo (long term exposure to malaria) suggested that EBV infection influence the morbidity to P. vivax malaria with altered haematological parameters, including low haemoglobin, haematocrit, and platelet levels; and impaired the long-term acquired antibody responses to P. vivax proteins (PvDBPII and PvAMA1) [72]. These results demonstrate that acute EBV infection disrupts the malaria immune response. Given that under the influence of some risk factors mentioned above, EBV can undergo a reactivation of its lytic infection inside latent cells leading to the expression of many lytic genes, it is plausible that reactivated EBV similarly to acute infection alters malaria immunity leading to the exacerbation of malaria.

The impact of EBV reactivation on others diseases has long been studied. Indeed, it has already been shown that chronic and uncontrolled EBV reactivation may exacerbate certain diseases and be a risk factor in the etiology of many cancers and tumours such as nasopharyngeal carcinoma, and post-transplant lymphoproliferative diseases [73, 74]. According to Ramroodi N. et al., the reactivation of EBV also aggravates the pathogenesis of multiple sclerosis. People with multiple sclerosis subtypes and patients with relapses of the disease (exacerbations) had strong reactivation of Epstein-Barr virus with high viral DNA loads. This suggests that EBV reactivation exacerbates multiple sclerosis and promotes relapses [75]. Similarly, in the article written by Larry Beresford in (2020) in the journal the Rheumatologist, Dr. James, co-author of the study, published in Annals of the Rheumatic Diseases, reveals that reactivation of lytic EBV infection is a risk factor for the development of Systemic Lupus Erythematosus (SLE). This is thought to be due to increased EBV reactivation (increase in EBV viral capsid antigen (VCA) and IgG against early antigens). Previous research work conducted by Keiko Nagata et al in 2011 suggests that reactivation of EBV is associated with the etiology of Graves' disease, through stimulation of antibody-producing B cells predisposed to make TRAb (Thyroid Autoantibody), which could contribute to or exacerbate the disease [76].

A first study on the impact of EBV reactivated on malaria severity, has recently been studied by Indari et al., the results revealed that during malaria, the reactivated EBV can infect human brain microvascular endothelial cells (HBECs) and modify the blood-brain barriers microenvironment (BBB). Addionally EBV infection of HBECs significantly elevated inflammatory cytokines (TNFα, CCL2) and endothelial markers (integrin β3, PECAM, VEGFA, VWF, claudin-5, cx37). EBV and P. falciparum co-infection significantly (P < 0.05) enhanced RBC adhesion to HBECs compared to mono-infection, this could facilitate iRBCs sequestration at the BBB and exacerbation of CM pathology [18]. Based on the results of these studies, malaria immune response may be impaired during the reactivation of lytic EBV infection, which could worsen the clinical condition of co-infected individuals.

Table 1: Reported experimental and epidemiological studies on the impact of acute and reactivated EBV infection on malaria

Source: Own elaboration

4.3 Impairment of antimalaria humoral response during reactivated EBV infection

The reactivation of EBV during acute malaria has been reported in several studies [59, 60]. Humoral response plays an important role in the mechanisms to control peripheral parasitaemia in human malaria infection and is essential in the natural acquisition of partial immunity to malaria [77-79]. It consists of blocking parasite invasion of red blood cells (RBCs) by blocking ligand-receptor interactions on the surface of RBCs, promoting the formation of antibody- dependent cytotoxicity on Plasmodium infected RBCs (iRBC), blocking the activity of parasite toxins, and inhibiting the development of intraerythrocytic parasites [80]. Thus, a disruption of this immune response would aggravate the malaria infection. It has been observed that during acute gammaherpesvirus infection in animals co-infected with P. yoelii XNL, these animals developed severe malarial anaemia due to a reduction in the antibody response (IgM and total IgG levels) compared to those infected individually with P. yoelii XNL [16]. In addition, the authors showed that increased replication of MHV68 contributes to the lethality of P. yoelii in co-infected mice [16].

The reactivation of EBV infection has been associated with increased susceptibility and frequency of malaria episodes in children in Gabon, due to altered cytokine activity [81]. Cytokines are important modulators of lymphocytes. There are essential for generating many of the known subsets of CD4 T cells (Th1, Th2, Th17, and iTreg). Studies have shown that the combined absence of IL-6 and IL-21 leads to a reduction in the differentiation of Tfh cells and a reduction in the expression of the Bcl6 protein [82]. Direct induction of Bcl6, a critical regulator of germinal centres (GCs) by cytokines is sufficient to generate the Tfh subset [83,84]. It is clear that cytokines contribute to Tfh differentiation at the germinal centre and ensure that the humoral immune response is effective [85]. Furthermore, alteration of cytokine (IL-10, IL-12p70, IL-12p40, TNF-α, and IFN-γ) activity during persistent EBV has been suggested to be one of the immunomodulatory mechanisms influencing pathogen interactions [81].

A change in the activity of these cytokines could lead not only to a decrease in the differentiation of Tfh cells from the germinal centre to the spleen but also to a reduction in GC B cells, which would disrupt the humoral response against secondary infections by the mechanisms induced [86]. It has been shown that a defect in the formation and maintenance of total Tfh cells (CD4+ CXCR5+ PD-1+), activated/antigen-specific Tfh cells (CD4+ PD-1+ CD44hi CXCR5+) and germinal centre Tfh cells (GL7+ CXCR5+) suppress the humoral immune response against malaria in animals infected with MHV68 [16,87]. Kaneko et al. has showed abnormally high concentrations of the cytokine TNF- α could block the differentiation of T cells into Bcl-6 helper follicular T cells [88]. We hypothesize that during EBV reactivation, the alteration of cytokine activity may disrupt the production of anti-malarial antibodies through a defect in the maintenance of Tfh cells in patients with malaria (figure 2). Nevertheless, further studies need to be carried out to elucidate these mechanisms during EBV reactivation and malaria coinfection.

Figure 2: Illustrative schema of the interference model of EBV reactivation during the antimalarial immune response. During EBV reactivation, infected B cells and other EBV-infected immune cells secrete large amounts of inflammatory and immunosuppressive cytokines. To regulate, the immunosuppressive cytokines will inhibit the production of IFN-alpha, IL-6 and TNF-beta cytokines by helper T cells (CD4+) and cytotoxic T cells (CD8+). Overall, the reduction of these cytokines will negatively affect the clearance of Plasmodium-infected red blood cells and the production of T cell-dependent cytotoxic antibodies. The reduction of Il-6 reduces the expression of the transcription factor BCl-6 important in the regulation of T-helper cell proliferation. On the other hand, Il-10 hypersecretion also affects the formation and differentiation of Tfh, important in the production of antibodies against malaria. Source: Own elaboration (Created with BioRender.com).

EBV reactivation has been correlated with the expression of PD-1/PD-L1 antigens in patients with proliferative glomerulonephritis [89]. PD-1, also known as CD279, is a cell surface receptor that, in humans, is expressed on T cells, B cells, monocytes/macrophages, and certain cancer cells [90,91]. PD-L1/L2-PD-1 signaling has been shown to influence germinal centre responses, thus an increased expression of PD-L1 negatively regulates the expansion of Tfh [92]. According to Matar et al, this is one of the mechanisms necessary to hinder humoral immunity to malaria during acute gammaherpesvirus infection [16]. We think that the expression of PD-L1 on the cell surface of T cells, B cells, and monocytes/macrophages infected with the virus may contribute to the disruption of humoral antimalarial immunity.

4.4 Disruption of innate immune cells infected by EBV during malaria

Innate immunity plays a key role in parasitaemia control thanks to the phagocytic activity of monocytes and macrophages. Many studies have described the essential role of activated monocytes/macrophages and Dendritic Cells (CDs) function in the reduction of parasite burden through plasmodium-infected red blood cells (iRBCs) and free merozoites, cytokine production, and antigen presentation [93]. Previous studies have shown that Epstein-Barr virus is capable of affecting the functional capacities of the cells it infects, thus reducing their phagocytic potential to respond to the challenges of other pathogens such as bacteria and inhibiting the secretion of key cytokines (TNF-α) [94, 95]. EBV can also inhibit the development of dendritic cells by promoting the apoptosis of their monocytic precursors in the presence of granulocyte macrophage-colony-stimulating factor and interleukin-4 [96].

Early production of pro-inflammatory cytokines such as tumour necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-6, and other inflammatory cytokines by innate immune cells allows faster inhibition and elimination of the parasite and stimulation of the phagocytosis [97, 98]. Smith CM et al (2007) demonstrated that Dendritic Cells (DCs) infected with the gammaherpesvirus MHV68 are unable to present the antigen as effectively as those not infected with MHV68 [99]. Reactivated EBV infection has been shown to alter the activity of cells present in the brain-blood barriers microenvironment (BBB) and increase RBC adhesion on ECs (Endothelial Cells). These change lead to an overexpression of endothelial and surface markers, and an elevation of several inflammatory cytokines (TNFα, CCL2), exacerbating cerebral malaria pathology [18].

The Fc-gamma receptors antibodies to P. falciparum merozoites are important for the opsonic phagocytosis of merozoites [100]. It will be interesting to study the cellular characteristic and membrane receptor markers for phagocytosis (CD16, CD32, CD64) of monocyte/macrophage with EBV. Since pregnancy, immunosuppression, and tobacco consumption are risk factors for reactivation of EBV, it will be also interesting to study in vivo the activity of macrophages against iRBCs during the co-infection in these patient groups. Complementary studies are required.

4.5 Modulation of INF-type I and IL-10 during the EBV/Plasmodium coinfection

Adaptive immunity during malaria infection involve Interferon-γ (IFN-γ) the production and antibodies under the coordination of CD4 cells [101]. It is well known that IFN-α and IFN-β can inhibit the development of P. falciparum in the liver and blood stages. The regulation of the interferons activities is an important aspect of establishing an effective and controlled adaptive immune response. This mechanism includes interferon regulatory factors (IRFs). It has been suggested that inhibition of IRF prevents the production of key inflammatory cytokines such as IFN type I (IFN-α and IFN-β) [102]. Hwang S et al, 2009, have reported that ORF36, a kinase of murine gammaherpesvirus 68 (MHV-68) is capable of inhibiting IFN by binding to interferon regulatory factor 3 (IRF-3) [103, 104]. Furthermore, chronic IFN type I signaling has an important role in the severity of malaria anaemia (SMA) due to the ability to reduce the production of haematopoietic stem cells [105].

Given that EBV inhibits IRF and TLR signaling pathways in infected B lymphocytes, this may influence humoral responses during subsequent infection with an infectious agent like malaria.  Rangaswamy et al, revealed that viral protein M2 is capable of promoting BCR signals and inducing IL-10 secretion from EBV- infected B cells [106, 107]. IL-10 produced is capable of negatively regulating the survival of T follicular helper cells (Tfh) and consequently affecting the maintenance and development of the germinal centre. Concerning IL-10 producing T cells, these cells have been found to exacerbate P. yoelii parasitaemia in mice in mouse models [108, 109].  It is thought that stimulation of BCR signaling pathways by the EBV viral protein M2 may reactivate EBV infection and contribute to increased production of IL-10 which will aggravate malaria. The same observation was made by Saraiva M & O'Garra A. 2010, who found in rodent malaria models that homologous EBV-encoded viral IL-10 can impair control of Plasmodium parasitaemia in the peripheral circulation [110, 111].

5. Conclusion

In this review, the association between EBV reactivation and malaria severity was demonstrated. Studies showed that lytic EBV infection can be reactivated during malaria coinfection, pregnancy, physiological and environmental factors, stress, and immunosuppression. Reactivated EBV infection can negatively impact the pathogenesis of malarial infection and thus can be considered as a risk factor for severe malaria.

Different immunological mechanisms have been incriminated in this process namely: (1) the reduction of the production of antibodies against Plasmodium via the alteration of inflammatory cytokines (2) impairment of the function of innate immune cells (monocyte, macrophage, dendritic cells, B cells, and T cells) latently infected by the virus, and (3) inhibition of germinal centre (GC) regulators (Bcl6). The limit of these studies is that most are in vitro and there is very little human evidence. More immunological and epidemiological studies addressing the influence of reactivated EBV infection on the development of innate and adaptative immune response to Plasmodium in patients should be carried and further studies on the secretome of EBV-infected monocyte and macrophage cells should be also investigated.

Contributions of the authors

All the authors cited have made a substantial, direct, and intellectual contribution to the work and have approved its publication.

Declaration of conflict of interest

The authors state that the research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest.

Acknowledgements

This work is supported by the University of Yaounde I, Cameroon.

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