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The Interplay Between Epstein-Barr Virus DNA and the Gut Microbiota in the Pathogenesis of Rheumatoid Arthritis in a Mouse Model

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dc.contributor.advisor Elias, Rahal
dc.contributor.advisor Matar, Ghassan Fadlallah, Sukayna 2022-01-20T11:18:40Z 2022-01-20T11:18:40Z 1/20/2022 11/12/2021
dc.description.abstract Background: The pathogenesis of rheumatoid arthritis (RA) is not fully understood; however, risk factors including genetic predisposition and environmental challenges such as infectious agents and alterations in the gut microbiota can act as a trigger. One such infectious agent is the Epstein - Barr virus (EBV), which establishes latency but then can reactivate, produce viral DNA and result in immunomodulation. We recently demonstrated that EBV DNA is correlated with proinflammatory responses in mice and in rheumatoid arthritis (RA) patients. Hence, we aimed at utilizing an RA mouse model to examine the interplay between the proinflammatory effects of EBV DNA and gut microbiota changes in the development of RA. Methods: Female C57BL/6J mice, 12 weeks of age, were treated with collagen (arthritis-inducing agent), EBV DNA 6 days before collagen, EBV DNA 15 days after collagen, Staphylococcus epidermidis DNA 6 days before collagen, EBV DNA alone, or water. Mice were then monitored for 70 days for clinical signs after which the paw thickness was measured, gripping strength was determined, and affected joints/footpads were histologically analyzed. Serum cytokine levels of interleukin 17A (IL-17A) and interferon gamma (IFNγ) were determined by enzyme-linked immunosorbent assay (ELISA). The number of cells either co-expressing IL-17A and IFNγ in joint and colon histological sections or IL-17A, FOXP3 and IFNγ in colon histological sections were determined by immunofluorescence (IF) and confocal microscopy. To determine the effect of EBV DNA on the composition of colonic microbiota, fecal samples were collected and 16S rRNA sequencing was carried out. To determine if intestinal microbiota contribute to arthritis progression directly, antimicrobial-cleared C57BL/6J mice were conventionalized with microbiota from arthritis-affected mice by fecal transplantation followed by arthritis induction with collagen and assessing the incidence and severity of RA. Results: The incidence of arthritis was significantly higher in mice that received EBV DNA prior to collagen compared to mice that only received collagen or mice that received S. epidermidis DNA. Similarly, significantly increased clinical scores, histological scores and paw thicknesses with a significantly decreased gripping strength were observed in groups treated with EBV DNA and collagen when compared to mice treated only with collagen. The highest increase in IFNγ serum levels was in the group that received collagen alone. Mice that received EBV DNA in addition to collagen showed the highest elevation in IL-17A serum levels. Additionally, the lattergroup showed the highest number of cells co-expressing IFNγ and IL-17A in joints and colons as well as the highest number of cells co-expressing IL-17A, FOXP3, and IFNγ in colons. Analysis of 16S rRNA sequencing of microbiota from feces showed that EBV DNA resulted in a change in alpha diversity of the microbiota resulting in an increased Chao1 microbial richness and decreased Shannon diversity index in the RA mouse model. The beta diversity in terms of Principal Coordinate Analysis (PCOA) was not dissimilar among the various groups. Additionally, the abundance of 33 different genera/genus clusters was significantly altered among the various groups, with the the group that received EBV DNA 6 days prior to collagen having the most number of genera/genus clusters altered. On the other hand, antimicrobial-cleared mice conventionalized with microbiota from mice treated with EBV DNA in addition to collagen showed a higher incidence and enhanced severity of RA compared to those conventionalized with microbiota from water or collagen treated mice. Conclusions: EBV DNA enhances proinflammatory cytokines, increases the incidence and severity of arthritis, and alters the gut microbiota in an RA mouse model. This better understanding of the various factors involved in the development of RA will possibly help in creating individualized treatments for RA patients. Such treatments may target mediators triggered by viral DNA.
dc.language.iso en_US
dc.subject Rheumatoid arthritis
dc.subject Epstein-Barr virus
dc.subject microbiota
dc.subject IL-17A
dc.subject C57bl/6 mice
dc.subject collagen induced arthritis
dc.title The Interplay Between Epstein-Barr Virus DNA and the Gut Microbiota in the Pathogenesis of Rheumatoid Arthritis in a Mouse Model
dc.type Dissertation
dc.contributor.department Department of Experimental Pathology, Immunology, and Microbiology
dc.contributor.faculty Faculty of Medicine
dc.contributor.institution American University of Beirut
dc.contributor.commembers Jurjus, Abdo
dc.contributor.commembers Abou Fayad, Antoine
dc.contributor.commembers Daoud, Ziad
dc.contributor.commembers Mira, El-Chaar PhD
dc.contributor.AUBidnumber 201211139

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