Epstein-Barr virus DNA modulates regulatory T-cell programming in addition to enhancing interleukin-17A production via Toll-like receptor 9

Salloum, Nelly; Hussein, Hadi; Jammaz, Rana; Jiche, Sara; Uthman, Imad; Abdelnoor, Alexander M.; Rahal, Elias A.

doi:10.1371/journal.pone.0200546

Cited by 28 publications

(31 citation statements)

References 47 publications

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“…EBV is thought to be involved in several autoimmune diseases since it appears to modulate human immune responses (33). We previously reported that EBV DNA was capable of enhancing the production of the proinflammatory cytokine IL-17A when injected into mice (25); moreover, we observed a linear correlation between EBV DNA and serum IL-17A levels in RA patients (6). Since IL-17A plays a critical role in the pathogenesis of a variety of inflammatory autoimmune diseases, EBV DNA may thus contribute to autoimmune disease development or exacerbation.…”

Section: Discussionmentioning

confidence: 59%

“…In another study, we found that the average serum IL-17A levels were higher in RA patients than in non-RA subjects. In addition, we detected a linear correlation between EBV DNA levels and serum IL-17A levels in RA patients but not in controls (6).…”

mentioning

confidence: 67%

“…Moreover, infection with EBV is associated with a higher risk of certain autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS) (4). RA patients have a considerable increase in the EBV DNA load in peripheral blood mononuclear cells (PBMCs) compared with that in controls (5,6). Moreover, RA patients have high numbers of circulating EBV-infected B cells (7) and EBV DNA loads in saliva (8).…”

mentioning

confidence: 99%

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Endosomal Toll-Like Receptors Mediate Enhancement of Interleukin-17A Production Triggered by Epstein-Barr Virus DNA in Mice

Shehab

Sherri

Hussein

et al. 2019

J Virol

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We previously demonstrated that Epstein-Barr virus (EBV) DNA increases the production of the proinflammatory cytokine interleukin-17A (IL-17A) in mice. This property may contribute to the established association between EBV and autoimmune diseases. The objective of the present study was to elucidate mechanisms through which EBV DNA modulates IL-17A levels in mice. To determine whether endosomal Toll-like receptors (TLRs) played a role in this pathway, the expression of TLR3, -7, or -9 was assessed by real-time reverse transcription-PCR in mouse spleens after injection of EBV DNA. Moreover, specific inhibitors were used for these TLRs in mouse peripheral blood mononuclear cells (PBMCs) cultured with EBV DNA and in mice injected with this viral DNA; IL-17A levels were then assessed using an enzyme-linked immunosorbent assay. The expression of the endosomal receptors TLR3, -7, and -9 was increased in mice injected with EBV DNA. When mouse immune cells were cultured with EBV DNA and a TLR3, -7, or -9 inhibitor or when mice were injected with the viral DNA along with either of these inhibitors, a significant decrease in IL-17A levels was detected. Therefore, endosomal TLRs are involved in the EBV DNA-mediated triggering of IL-17A production in mice. Targeting these receptors in EBV-positive subjects with autoimmunity may be useful pending investigations assessing whether they play a similar role in humans. IMPORTANCE Epstein-Barr virus is a pathogen that causes persistent infection with potential consistent viral DNA shedding. The enhancement of production of proinflammatory cytokines by viral DNA itself may contribute to autoimmune disease development or exacerbation. In this project, we identified that endosomal Toll-like receptors are involved in triggering proinflammatory mediators in response to viral DNA. Pathways and receptors involved may serve as future therapeutic targets for autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus.

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Section: Discussionmentioning

confidence: 59%

mentioning

confidence: 67%

mentioning

confidence: 99%

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Endosomal Toll-Like Receptors Mediate Enhancement of Interleukin-17A Production Triggered by Epstein-Barr Virus DNA in Mice

Shehab

Sherri

Hussein

et al. 2019

J Virol

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“…Similarly, increased levels of IL-17A and IL-8 were observed in the gastric mucosa of gastric ulcer and non-ulcer H. pylori-infected patients compared to uninfected non-ulcer patients, and both IL-17A and IL-8 are strongly correlated with an increase in neutrophil infiltration in infected patients. Interestingly, serum levels of IL-17 directly correlate with the EBV DNA load in individuals with rheumatoid arthritis, which was not observed in controls, and this IL-17 enhancement, in the course of EBV infection, is mediated by toll-like receptor 9 (TLR9) [34].…”

Section: Biology and Disease Associations Of H Pylori And Ebvmentioning

confidence: 99%

Epstein–Barr Virus and Helicobacter Pylori Co-Infection in Non-Malignant Gastroduodenal Disorders

Dávila-Collado¹,

Jarquín-Durán²,

Dong

et al. 2020

Pathogens

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Epstein–Barr virus (EBV) and Helicobacter pylori (H. pylori) are two pathogens associated with the development of various human cancers. The coexistence of both microorganisms in gastric cancer specimens has been increasingly reported, suggesting that crosstalk of both pathogens may be implicated in the carcinogenesis process. Considering that chronic inflammation is an initial step in the development of several cancers, including gastric cancer, we conducted a systematic review to comprehensively evaluate publications in which EBV and H. pylori co-infection has been documented in patients with non-malignant gastroduodenal disorders (NMGDs), including gastritis, peptic ulcer disease (PUD), and dyspepsia. We searched the PubMed database up to August 2019, as well as publication references and, among the nine studies that met the inclusion criteria, we identified six studies assessing EBV infection directly in gastric tissues (total 949 patients) and three studies in which EBV infection status was determined by serological methods (total 662 patients). Due to the substantial methodological and clinical heterogeneity among studies identified, we could not conduct a meta-analysis. The overall prevalence of EBV + H. pylori co-infection in NMGDs was 34% (range 1.8% to 60%). A higher co-infection rate (EBV + H. pylori) was reported in studies in which EBV was documented by serological methods in comparison with studies in which EBV infection was directly assessed in gastric specimens. The majority of these studies were conducted in Latin-America and India, with most of them comparing NMGDs with gastric cancer, but there were no studies comparing the co-infection rate in NMGDs with that in asymptomatic individuals. In comparison with gastritis caused by only one of these pathogens, EBV + H. pylori co-infection was associated with increased severity of gastric inflammation. In conclusion, only relatively small studies testing EBV and H. pylori co-infection in NMGDs have been published to date and the variable report results are likely influenced by geographic factors and detection methods.

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“…The reduction in plasma IL-17A and CCL28 levels after INMEST and the restored MAIT/Regulatory T-cell relationship indicate a modulation of this axis by INMEST treatment and mitigation of an inflammatory state originating at the immune microbe interface in the intestine. Also, the common Epstein-Barr virus, EBV, often associated with ME have been reported to induce IL-17 and reactivation of this virus is another possible chronic immune stimulation in ME-patients (36).…”

Section: Cell-cell Relationships Are Perturbed In Mementioning

confidence: 99%

Achieving symptom relief in patients with Myalgic encephalomyelitis by targeting the neuro-immune interface and inducing disease tolerance

Lakshmikanth

et al. 2020

Preprint

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Myalgic encephalomyelitis, ME, previously also known as chronic fatigue syndrome (CFS) is a heterogeneous, debilitating syndrome of unknown etiology responsible for long-lasting disability in millions of patients worldwide. The most well-known symptom of ME is post-exertional malaise, but many patients also experience autonomic dysregulation, cranial nerve dysfunction and signs of immune system activation. Many patients also report a sudden onset of disease following an infection. The brainstem is a suspected focal point in ME pathogenesis and patients with structural impairment to the brainstem often show ME-like symptoms. The brainstem is also where the vagus nerve originates, a critical neuro-immune interface and mediator of the inflammatory reflex which regulate systemic inflammation. Here we report the results of a randomized, placebo-controlled trial using intranasal mechanical stimulation (INMEST) targeting the vagus nuclei, and higher centers in the brain of ME-patients and induce a sustainable, ~30% reduction in overall symptom scores after eight weeks of treatment. By performing longitudinal, systemslevel monitoring of the blood immune system in these patients, we uncover chronic immune activation in ME, as well as immunological correlates of improvement that center around the IL-17 axis, gut-homing immune cells and reduced inflammation. The mechanisms of symptom relief remains to be determined, but transcriptional analyses suggest an upregulation of disease tolerance mechanisms. We wish for these results to bring some hope to patients suffering from ME and inspire researchers to help test our new hypothesis that ME is a condition caused by a failure of inducing disease tolerance upon infection and persistent immune activation.

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Epstein-Barr virus DNA modulates regulatory T-cell programming in addition to enhancing interleukin-17A production via Toll-like receptor 9

Cited by 28 publications

References 47 publications

Endosomal Toll-Like Receptors Mediate Enhancement of Interleukin-17A Production Triggered by Epstein-Barr Virus DNA in Mice

Endosomal Toll-Like Receptors Mediate Enhancement of Interleukin-17A Production Triggered by Epstein-Barr Virus DNA in Mice

Epstein–Barr Virus and Helicobacter Pylori Co-Infection in Non-Malignant Gastroduodenal Disorders

Achieving symptom relief in patients with Myalgic encephalomyelitis by targeting the neuro-immune interface and inducing disease tolerance

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