Effect of Epstein-Barr Virus DNA on the Incidence and Severity of Arthritis in a Rheumatoid Arthritis Mouse Model

Fadlallah, Sukayna; Hussein, Hadi; Jallad, Mary-Ann; Shehab, Marwa; Matar, Ghassan M.; Rahal, Elias A.

doi:10.3389/fimmu.2021.672752

Cited by 9 publications

(10 citation statements)

References 61 publications

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“…They were co-housed in nonindividually ventilated cages (non-IVC) in the same room and had access to unlimited water and food. Induction of arthritis was carried out as previously described in a recent study ( 15 ). The study included an arthritis control group that received the inducing agent and the booster.…”

Section: Methodsmentioning

confidence: 99%

“…Previous research by our group showed that EBV DNA induces proinflammatory responses in mice and that the EBV DNA load in patients with RA corresponds to a higher serum level of IL-17A, a proinflammatory cytokine ( 13 , 14 ). In addition, a recent study by our group showed that EBV DNA enhances the incidence and severity of RA in a collagen-induced arthritis (CIA) mouse model ( 15 ). Hence, in this study, we intended to determine the effect of EBV DNA on the composition and diversity of intestinal microbiota and identify whether this plays a role in arthritis development in this mouse model.…”

Section: Introductionmentioning

confidence: 99%

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The interplay between Epstein-Barr virus DNA and gut microbiota in the development of arthritis in a mouse model

Fadlallah,

Bitar,

Hussein

et al. 2023

Microbiol Spectr

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Epstein-Barr virus (EBV) DNA may influence the development of autoimmune diseases by increasing the production of proinflammatory cytokines. Such cytokines have been associated with inducing the dysbiosis of colonic microbiota, which, in turn, is a risk factor for autoimmune diseases such as rheumatoid arthritis (RA). Therefore, we investigated the role that EBV DNA may play in modulating the intestinal microbiota and consequent exacerbation of arthritis in a mouse model. Mice were treated with collagen (arthritis-inducing agent), EBV DNA and collagen, EBV DNA, or water. Fecal samples were collected from arthritic and control mice, and 16S rRNA sequencing was performed to determine the effect of EBV DNA on the composition of colonic microbiota. EBV DNA causes a change in the alpha diversity of the microbiota resulting in an increased Chao1 microbial richness and decreased Shannon diversity index in the RA mouse model. In addition, the abundance of particular genera/genus clusters was significantly altered among the various groups, with the EBV DNA-exacerbated arthritic group having the highest number of altered genera/genus cluster abundances. This group also had the highest number of cells co-expressing IL-17A, FOXP3, and IFNγ in the colons. Antimicrobial-cleared mice transplanted with fecal samples from EBV DNA-exacerbated arthritic mice showed a higher incidence and enhanced severity of RA compared to those transplanted with fecal samples from water or collagen-treated mice. IMPORTANCE Epstein-Barr virus (EBV) DNA alters the composition and diversity of the gut microbiota in a rheumatoid arthritis (RA) mouse model. These induced changes are associated with enhanced severity of symptoms. This better understanding of the various factors involved in the development of RA will possibly help in creating individualized treatments for RA patients including target mediators triggered by viral DNA. Given that a large swathe of the population harbors EBV, a significant proportion of subjects with arthritis may benefit from possible approaches that target EBV or mediators triggered by this virus.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The interplay between Epstein-Barr virus DNA and gut microbiota in the development of arthritis in a mouse model

Fadlallah,

Bitar,

Hussein

et al. 2023

Microbiol Spectr

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“…Using endosomal Toll-like receptor inhibitors, we reported that this immune signaling pathway was involved in the increase in IL-17A levels [ 5 ]. Therefore, EBV induces a pro-autoimmune response causing an elevation in systemic and tissue IL-17A levels, thus acting as a risk factor for the development of autoimmune diseases [ 6 ]. Recent studies have suggested that EBV may contribute to the pathophysiology of inflammatory bowel disease (IBD), a chronic inflammatory condition with a rising incidence worldwide [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

The Effects of Endosomal Toll-like Receptor Inhibitors in an EBV DNA-Exacerbated Inflammatory Bowel Disease Mouse Model

Karout,

Salhab,

Sherri

et al. 2024

Viruses

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Epstein–Barr virus (EBV), a Herpesviridae family member, is associated with an increased risk of autoimmune disease development in the host. We previously demonstrated that EBV DNA elevates levels of the pro-inflammatory cytokine IL-17A and that inhibiting Toll-like receptor (TLR) 3, 7, or 9 reduces its levels. Moreover, this DNA exacerbated colitis in a mouse model of inflammatory bowel disease (IBD). In the study at hand, we examined whether inhibition of TLR3, 7, or 9 alleviates this exacerbation. Mice were fed 1.5% dextran sulfate sodium (DSS) water and administered EBV DNA. Then, they were treated with a TLR3, 7, or 9 inhibitor or left untreated. We also assessed the additive impact of combined inhibition of all three receptors. Mice that received DSS, EBV DNA, and each inhibitor alone, or a combination of inhibitors, showed significant improvement. They also had a decrease in the numbers of the pathogenic colonic IL-17A+IFN-γ+ foci. Inhibition of all three endosomal TLR receptors offered no additive benefit over administering a single inhibitor. Therefore, inhibition of endosomal TLRs reduces EBV DNA exacerbation of mouse colitis, offering a potential approach for managing IBD patients infected with EBV.

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“…The etiology of RA has not yet been fully elucidated and may be related to a variety of genetic and environmental factors, of which the strongest risk factors include female gender, family history of RA, genetic factors, and exposure to tobacco smoke (3). In addition, infections are also considered to be an important cause of RA, and some bacterial and viral infections including periodontal bacteria, Epstein-Barr virus, parvovirus B19 and Chikungunya virus are considered to be associated with RA (4)(5)(6)(7). The mechanism of how infection affects RA remains undetermined, and it is commonly believed that the antigen of the pathogen may trigger cross-reactivity between autoantigen and viral proteins through a molecular mimicry mechanism (7).…”

Section: Introductionmentioning

confidence: 99%

Association between human papillomavirus infection or immunization and risk for rheumatoid arthritis

2023

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BackgroundHuman papillomavirus (HPV) is a virus primarily transmitted through sexual contact. Little is known about the association between HPV infection or immunization and the risk for rheumatoid arthritis (RA). The purpose of this study was to evaluate whether HPV infection or immunization is related to the risk for RA in adults.MethodsData were obtained from the 2007-2016 National Health and Nutrition Examination Survey (NHANES). We developed three independent multivariate logistic regression models to evaluate the association between HPV infection or immunization and the risk for RA in adults.ResultsFinally, we analyzed 15,677 and 8,944 subjects, respectively. In all models, HPV infection was positively associated with an increased prevalence of RA in adults aged 18-59 years, with the highest value of the odds ratio (OR) in model 2 (after weighting: OR 1.095, 95% CI 1.092, 1.097), whereas HPV immunization significantly reduced the prevalence of RA in adults aged 18-59 years, with the lowest OR in model C (after weighting: OR 0.477, 95% CI 0.472, 0.481). These associations persisted after correction for confounders such as age, sex, race, education level, marital status, smoking, diabetes, hypertension, hyperlipidemia, and BMI.ConclusionIn summary, our study suggests that HPV infection is positively associated with the prevalence of RA in adults, and HPV immunization can reduce the prevalence of RA in adults. However, our findings need more powerful to prove these associations through rigorously designed prospective studies.

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Effect of Epstein-Barr Virus DNA on the Incidence and Severity of Arthritis in a Rheumatoid Arthritis Mouse Model

Cited by 9 publications

References 61 publications

The interplay between Epstein-Barr virus DNA and gut microbiota in the development of arthritis in a mouse model

The interplay between Epstein-Barr virus DNA and gut microbiota in the development of arthritis in a mouse model

The Effects of Endosomal Toll-like Receptor Inhibitors in an EBV DNA-Exacerbated Inflammatory Bowel Disease Mouse Model

Association between human papillomavirus infection or immunization and risk for rheumatoid arthritis

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