Exposure to Holoendemic Malaria Results in Suppression of Epstein‐Barr Virus–Specific T Cell Immunosurveillance in Kenyan Children

Moormann, Ann M.; Chelimo, Kiprotich; Sumba, Peter Odada; Tisch, Daniel J.; Rochford, Rosemary; Kazura, James W.

doi:10.1086/511984

Cited by 85 publications

(86 citation statements)

References 43 publications

(52 reference statements)

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“…A distinct possibility exists for genetic variation that alters the balance between antiinflammatory and proinflammatory cytokines to contribute to the immunologic dysregulation over EBV observed in eBL. [32][33][34] IL-6 and IL-10 are two cytokines that have been implicated in the pathogenesis and progression of other lymphoproliferative disorders. 14,35,36 We hypothesized that these cytokines could potentially provide a permissive milieu for eBL oncogenesis, and therefore, patients with eBL might be more likely to possess genotypes that predispose them to higher levels of inducible IL-6 and IL-10.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-6 and Interleukin-10 Gene Promoter Polymorphisms and Risk of Endemic Burkitt Lymphoma

Oduor¹,

Chelimo²,

Ouma³

et al. 2014

The American Society of Tropical Medicine and Hygiene

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Abstract. Overexpression of interleukin-6 (IL-6) and IL-10 in endemic Burkitt lymphoma (eBL) may facilitate tumorigenesis by providing a permissive cytokine milieu. Promoter polymorphisms influence interindividual differences in cytokine production. We hypothesized that children genetically predisposed for elevated cytokine levels may be more susceptible to eBL. Using case-control samples from western Kenya consisting of 117 eBL cases and 88 ethnically matched healthy controls, we tested for the association between eBL risk and IL-10 (rs1800896, rs1800871, and rs1800872) and IL-6 (rs1800795) promoter single nucleotide polymorphisms (SNPs) as well as IL-10 promoter haplotypes. In addition, the association between these variants and Epstein Barr Virus (EBV) load was examined. Results showed that selected IL-10 and IL-6 promoter SNPs and IL-10 promoter haplotypes were not associated with risk eBL or EBV levels in EBV-seropositive children. Findings from this study reveal that common variants within the IL-10 and IL-6 promoters do not independently increase eBL risk in this vulnerable population.

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Section: Discussionmentioning

confidence: 99%

Interleukin-6 and Interleukin-10 Gene Promoter Polymorphisms and Risk of Endemic Burkitt Lymphoma

Oduor¹,

Chelimo²,

Ouma³

et al. 2014

The American Society of Tropical Medicine and Hygiene

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“…Our previous study revealed a deficiency in IFN-␥ production by EBV-specific CD8 ϩ T cells in children residing in a region with holoendemic malaria (23). However, the events that precede this immune deficiency are unclear.…”

Section: Interestingly Cd8mentioning

confidence: 97%

“…Although these observations suggest that P. falciparum malaria infection disrupts EBV-specific immunity, the effector cells or mediators responsible for controlling EBV-infected B-cell growth were not identified, and overall immune competence was not assessed in the small number of individuals studied. More recently, an age-related deficiency in IFN-␥ recall responses to EBV lytic and latent antigens was demonstrated in children (i.e., 5 to 9 years of age) with ho-loendemic malaria exposure compared to those from an area of malaria hypoendemicity (23). In addition, EBV load in African children correlates with malaria exposure (24,25), further implicating coinfection as a risk factor for eBL tumorigenesis.…”

mentioning

confidence: 99%

Holoendemic Malaria Exposure Is Associated with Altered Epstein-Barr Virus-Specific CD8 ⁺ T-Cell Differentiation

Chattopadhyay

Chelimo

Embury

et al. 2013

J Virol

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e Coinfection with Plasmodium falciparum malaria and Epstein-Barr virus (EBV) is a major risk factor for endemic Burkitt lymphoma (eBL), still one of the most prevalent pediatric cancers in equatorial Africa. Although malaria infection has been associated with immunosuppression, the precise mechanisms that contribute to EBV-associated lymphomagenesis remain unclear. In this study, we used polychromatic flow cytometry to characterize CD8 ؉ T-cell subsets specific for EBV-derived lytic (BMFL1 and BRLF1) and latent (LMP1, LMP2, and EBNA3C) antigens in individuals with divergent malaria exposure. No malaria-associated differences in EBV-specific CD8 ؉ T-cell frequencies were observed. However, based on a multidimensional analysis of CD45RO, CD27, CCR7, CD127, CD57, and PD-1 expression, we found that individuals living in regions with intense and perennial (holoendemic) malaria transmission harbored more differentiated EBV-specific CD8 ؉ T-cell populations that contained fewer central memory cells than individuals living in regions with little or no (hypoendemic) malaria. This profile shift was most marked for EBV-specific CD8؉ T-cell populations that targeted latent antigens. Importantly, malaria exposure did not skew the phenotypic properties of either cytomegalovirus (CMV)-specific CD8 ؉ T cells or the global CD8 ؉ memory T-cell pool. These observations define a malaria-associated aberration localized to the EBV-specific CD8 ؉ T-cell compartment that illuminates the etiology of eBL.

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“…DNA was extracted from the cells using a Qiagen DNeasy kit (Qiagen) according to the manufacturer's protocol. EBV DNA levels were determined as previously described using primers and probes designed to detect a 70-bp region of the EBV BALF5 gene and the ␤-actin gene as a control for DNA input (25,26).…”

Section: Production Of Ebvmentioning

confidence: 99%

Epstein-Barr Virus Type 2 Latently Infects T Cells, Inducing an Atypical Activation Characterized by Expression of Lymphotactic Cytokines

Coleman

Wohlford

Smith

et al. 2015

J Virol

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Epstein-Barr virus (EBV) is a well-established B-cell-tropic virus associated with various lymphoproliferative diseases of both B-cell and non-B-cell origin.EBV is associated with a number of T-cell lymphomas; however, in vitro studies utilizing prototypical EBV type 1 (EBV-1) laboratory strains have generally failed to readily infect mature T cells in culture. The difficulties in performing in vitro T-cell experiments have left questions regarding the role of EBV in the pathogenesis of EBV-positive T-cell lymphoproliferative diseases largely unresolved. We report here that the EBV type 2 (EBV-2) strain displays a unique cell tropism for T cells. In remarkable contrast to EBV-1, EBV-2 readily infects primary T cells in vitro, demonstrating a propensity for CD8 ؉ T cells. EBV-2 infection of purified T cells results in expression of latency genes and ultimately leads to T-cell activation, substantial proliferation, and profound alteration of cytokine expression. The pattern of cytokine production is strikingly skewed toward chemokines with roles in lymphocyte migration, demonstrating that EBV-2 has the ability to modulate normal T-cell processes. Collectively, these novel findings identify a previously unknown cell population potentially utilized by EBV-2 to establish latency and lay the foundation for further studies to elucidate the role of EBV in the pathogenesis of T-cell lymphoproliferative diseases. IMPORTANCE The ability of EBV to infect T cells is made apparent by its association with a variety of T-cell lymphoproliferative disorders.However, studies to elucidate the pathogenic role of EBV in these diseases have been limited by the inability to conduct in vitro T-cell infection experiments. Here, we report that EBV-2 isolates, compromised in the capacity to immortalize B cells, infect CD3 ؉ T cells ex vivo and propose a working model of EBV-2 persistence where alteration of T-cell functions resulting from EBV-2 infection enhances the establishment of latency in B cells. If indeed EBV-2 utilizes T cells to establish a persistent infection, this could provide one mechanism for the association of EBV with T-cell lymphomas. The novel finding that EBV-2 infects T cells in culture will provide a model to understand the role EBV plays in the development of T-cell lymphomas. While Epstein-Barr virus (EBV) establishes lifelong latency in B cells and is associated with B-cell malignancies, it is also associated with malignancies and diseases that originate from T cells, including NK/T-cell lymphomas (1), hemophagocytic lymphohistiocytosis (2), hydroa vacciniforme (HV) (3), and chronic active EBV (CAEBV) (4, 5). In these diseases, EBV can be detected in CD4 ϩ T cells, CD8 ϩ T cells, or ␥␦ T cells (6, 7), with the virus predominantly existing as a latent infection (8, 9). The etiology of these T-cell diseases, and in particular whether EBV infection of T cells is an aberrancy in a virus known for its B-cell tropism in vitro and in vivo, remains unknown.Based on genetic differences in the Epstein-Barr nuclear ...

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Exposure to Holoendemic Malaria Results in Suppression of Epstein‐Barr Virus–Specific T Cell Immunosurveillance in Kenyan Children

Abstract: Children living in malaria-holoendemic areas have diminished EBV-specific T cell immunosurveillance between the ages of 5 and 9 years, which coincides with the peak age incidence of eBL.

Cited by 85 publications

References 43 publications

Interleukin-6 and Interleukin-10 Gene Promoter Polymorphisms and Risk of Endemic Burkitt Lymphoma

Interleukin-6 and Interleukin-10 Gene Promoter Polymorphisms and Risk of Endemic Burkitt Lymphoma

Holoendemic Malaria Exposure Is Associated with Altered Epstein-Barr Virus-Specific CD8 ⁺ T-Cell Differentiation

Epstein-Barr Virus Type 2 Latently Infects T Cells, Inducing an Atypical Activation Characterized by Expression of Lymphotactic Cytokines

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Exposure to Holoendemic Malaria Results in Suppression of Epstein‐Barr Virus–Specific T Cell Immunosurveillance in Kenyan Children

Abstract: Children living in malaria-holoendemic areas have diminished EBV-specific T cell immunosurveillance between the ages of 5 and 9 years, which coincides with the peak age incidence of eBL.

Cited by 85 publications

References 43 publications

Interleukin-6 and Interleukin-10 Gene Promoter Polymorphisms and Risk of Endemic Burkitt Lymphoma

Interleukin-6 and Interleukin-10 Gene Promoter Polymorphisms and Risk of Endemic Burkitt Lymphoma

Holoendemic Malaria Exposure Is Associated with Altered Epstein-Barr Virus-Specific CD8 + T-Cell Differentiation

Epstein-Barr Virus Type 2 Latently Infects T Cells, Inducing an Atypical Activation Characterized by Expression of Lymphotactic Cytokines

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Holoendemic Malaria Exposure Is Associated with Altered Epstein-Barr Virus-Specific CD8 ⁺ T-Cell Differentiation