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Epstein-Barr virus (EBV) DNA is known to be shed upon reactivation of latent EBV. Based on our previous findings linking Toll-like receptor-9 (TLR9) to an EBV DNA-driven surge in IL-17A production, we aimed to examine the therapeutic potential of TLR9 inhibition in EBV DNA-exacerbated arthritis in a collagen-induced arthritis (CIA) mouse model. C57BL/6J mice were administered either collagen, EBV DNA + collagen, EBV DNA + collagen + TLR9 inhibitor, or only the TLR9 inhibitor. After 70 days, paw thicknesses, clinical scores, and gripping strength were recorded. Moreover, affected joints, footpads, and colons were histologically scored. Furthermore, the number of cells co-expressing IL-17A, IFN-γ, and FOXP3 in joint sections was determined by immunofluorescence assays. Significantly decreased paw thicknesses, clinical scores, and histological scores with a significantly increased gripping strength were observed in the group receiving EBV DNA + collagen + TLR9 inhibitor, compared to those receiving EBV DNA + collagen. Similarly, this group showed decreased IL-17A+ IFN-γ+, IL-17A+ FOXP3+, and IL-17A+ IFN-γ+ FOXP3+ foci counts in joints. We show that inhibiting TLR9 limits the exacerbation of arthritis induced by EBV DNA in a CIA mouse model, suggesting that TLR9 could be a potential therapeutic target for rheumatoid arthritis management in EBV-infected individuals.
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Artrite Experimental , DNA Viral , Modelos Animais de Doenças , Herpesvirus Humano 4 , Receptor Toll-Like 9 , Animais , Camundongos , Artrite Experimental/virologia , Artrite Experimental/patologia , Artrite Experimental/metabolismo , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Artrite Reumatoide/virologia , DNA Viral/genética , Infecções por Vírus Epstein-Barr/virologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/patologia , Herpesvirus Humano 4/fisiologia , Interleucina-17/metabolismo , Camundongos Endogâmicos C57BL , Receptor Toll-Like 9/metabolismoRESUMO
Introduction: The Epstein-Barr virus has been associated with a considerable number of autoimmune diseases. We have previously demonstrated that EBV DNA enhances the production of IL-17A, a pro-inflammatory cytokine, via endosomal Toll-like receptor signalling. Methods: We used RNA-seq to analyze the transcriptional profile of mouse immune cells treated with EBV DNA. Results: We observed that EBV DNA upregulates an IL-17A-centric network of mediators. Ensemble Gene Set Enrichment Analysis (EGSEA) showed enriched expression of sets involved in inflammatory responses including IFNγ and TNF-α-associated pathways as well as proinflammatory diseases. On the other hand, while macrophages and B cells were somewhat able to induce an IL-17A response from T cells to EBV DNA, they were less potent than dendritic cells. EBV virions were also capable of eliciting the production of inflammatory mediators from dendritic cell-T cell cultures largely mirroring responses to the viral DNA. Conclusions: Given the wide prevalence of EBV in the population, our analyses reveal a network of mediators and cell types that may serve as therapeutic targets in a large proportion of people affected by autoimmune diseases.
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Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder resulting from a balanced translocation leading to BCR::ABL1 oncogene with increased tyrosine kinase activity. Despite the advancements in the development of tyrosine kinase inhibitors (TKIs), the T315I gatekeeper point mutation in the BCR::ABL1 gene remains a challenge. We have previously reported in a Drosophila CML model an increased hemocyte count and disruption in sessile hemocyte patterns upon expression of BCR::ABL1p210 and BCR::ABL1T315I in the hemolymph. In this study, we performed RNA sequencing to determine if there is a distinct gene expression that distinguishes BCR::ABL1p210 and BCR::ABL1T315I. We identified six genes that were consistently upregulated in the fly CML model and validated in adult and pediatric CML patients and in a mouse cell line expressing BCR::ABL1T315I. This study provides a comprehensive analysis of gene signatures in BCR::ABL1p210 and BCR::ABL1T315I, laying the groundwork for targeted investigations into the role of these genes in CML pathogenesis.
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Epstein-Barr Virus (EBV), a dsDNA herpesvirus, is believed to play a significant role in exacerbating and potentially triggering autoimmune and autoinflammatory maladies. Around 90% of the world is infected with the virus, which establishes latency within lymphocytes. EBV is also known to cause infectious mononucleosis, a self-limited flu-like illness, in adolescents. EBV is often reactivated and it employs several mechanisms of evading the host immune system. It has also been implicated in inducing host immune dysfunction potentially resulting in exacerbation or triggering of inflammatory processes. EBV has therefore been linked to a number of autoimmune diseases, including systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, and Sjögren's syndrome. The review examines the molecular mechanisms through which the virus alters host immune system components thus possibly resulting in autoimmune processes. Understanding the mechanisms underpinning EBV-associated autoimmunity is pivotal; however, the precise causal pathways remain elusive. Research on therapeutic agents and vaccines for EBV has been stagnant for a long number of years until recent advances shed light on potential therapeutic targets. The implications of EBV in autoimmunity underscore the importance of developing targeted therapeutic strategies and, potentially, vaccines to mitigate the autoimmune burden associated with this ubiquitous virus.
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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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DNA Viral , Herpesvirus Humano 4 , Doenças Inflamatórias Intestinais , Receptores Toll-Like , Animais , Feminino , Camundongos , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/virologia , Sulfato de Dextrana , Modelos Animais de Doenças , DNA Viral/efeitos adversos , DNA Viral/farmacologia , Endossomos/efeitos dos fármacos , Endossomos/metabolismo , Infecções por Vírus Epstein-Barr/virologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Doenças Inflamatórias Intestinais/induzido quimicamente , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/virologia , Interleucina-17/metabolismo , Camundongos Endogâmicos C57BL , Receptor 3 Toll-Like/antagonistas & inibidores , Receptor 3 Toll-Like/metabolismo , Receptor 7 Toll-Like/antagonistas & inibidores , Receptor 7 Toll-Like/metabolismo , Receptor Toll-Like 9/antagonistas & inibidores , Receptor Toll-Like 9/metabolismo , Receptores Toll-Like/antagonistas & inibidores , Receptores Toll-Like/metabolismoRESUMO
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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BACKGROUND: Dental infections, which are the main cause of tooth loss, are known to be caused by bacteria. However, recent research suggests that other organisms, such as viruses, may also play a role. In this study, we aim to detect the presence of human papillomavirus (HPV)-16 and assess its prevalence in tissues infected with various dental infections, including aggressive and chronic periodontitis, pericoronitis, and periapical infection, as well as healthy gingival tissues, saliva, and gingival crevicular fluid, for comparison. METHODS: A cross-sectional study including 124 adult healthy patients presenting with dental infections requiring dental extractions were conducted to assess the prevalence of HPV-16 in saliva, infected, and healthy tissues using quantitative polymerase chain reaction (PCR) tests. Samples were collected and a categorical scale was used for the prevalence. Statistical analyses were performed using Chi-square for the prevalence of HPV-16. RESULTS: Among the HPV-16-positive PCR cases, the prevalence of HPV-16 was highest in periapical infection tissues as compared to chronic periodontitis, aggressive periodontitis, pericoronitis, and control tissues. CONCLUSION: The prevalence of HPV-16 in periapical infection samples was the highest among the studied dental infection samples. Thus, a primary conclusion can be drawn about the presence of an association between HPV-16 and the occurrence of periapical infection.
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The Epstein-Barr virus (EBV), formally designated as Human herpesvirus 4 (HHV-4), is the first isolated human tumor virus. Nearly 90-95% of the world's adult population is infected by EBV. With the recent advancements in molecular biology and immunology, the application of both in vitro and in vivo experimental models has provided deep and meaningful insight into the pathogenesis of EBV in many diseases as well as into EBV-associated tumorigenesis. The aim of this visualized experiment paper is to provide an overview of the isolation of EBV viral particles from cells of the P3HR1 cell line, followed by quantification of the viral preparation. P3HR1 cells, originally isolated from a human Burkitt lymphoma, can produce a P3HR1 virus, which is a type 2 EBV strain. The EBV lytic cycle can be induced in these P3HR1 cells by treatment with phorbol 12-myristate 13-acetate (PMA), yielding EBV viral particles. Using this protocol for the isolation of EBV particles, P3HR1 cells are cultured for 5 days at 37 °C and 5% CO2 in complete RPMI-1640 medium containing 35 ng/mL PMA. Subsequently, the culture medium is centrifuged at a speed of 120 x g for 8 min to pellet the cells. The virus-containing supernatant is then collected and spun down at a speed of 16,000 x g for 90 min to pellet the EBV particles. The viral pellet is then resuspended in a complete RPMI-1640 medium. This is followed by DNA extraction and quantitative real-time PCR to assess the concentration of EBV particles in the preparation.
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Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Humanos , Herpesvirus Humano 4/genética , Dióxido de Carbono , Miristatos , Linhagem Celular , Acetato de Tetradecanoilforbol , Acetatos , DNARESUMO
INTRODUCTION: The role of bacteria in the pathogenesis of periodontitis, pericoronitis, and periapical infections has been well-established. However, the variation in the severity and prognosis of these lesions could suggest a potential role of other microorganisms, such as viruses and fungi. This study aims to evaluate the presence of adenovirus, human papillomavirus-16, Epstein-Barr virus, Candida, and non-Candida fungi in these infections. METHODOLOGY: A cross-sectional study including 120 healthy adult patients presenting with dental infections requiring dental extractions were conducted to assess the prevalence and the relative quantity of viruses and fungi in saliva, infected, and healthy tissues using quantitative polymerase chain reaction tests. Samples were collected, and a categorical scale was used for the prevalence and a continuous scale for the relative quantification. Statistical analyses were performed using Chi-square for the prevalence and Wilcoxon rank test for the relative quantification. RESULTS: Except for the Epstein-Barr virus and Candida, the presence of viruses and fungi was significantly associated with dental infections. Adenovirus showed an association with pericoronitis, while human papilloma virus-16 exhibited an association with periapical infections. Non-Candida fungi, on the other hand, showed a positive association with all infected tissues and saliva as compared to healthy control lesions except for periapical infections. CONCLUSIONS: According to this study, viruses and fungi were found to be prevalent in dental infections. However, their associations with those infections vary depending on the types of viruses or fungi involved and the category of dental infections.
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Infecções por Vírus Epstein-Barr , Periodontite Periapical , Pericoronite , Humanos , Adulto , Herpesvirus Humano 4 , Infecções por Vírus Epstein-Barr/epidemiologia , Estudos Transversais , Citomegalovirus , Periodontite Periapical/patologia , Fungos , Candida/genética , AdenoviridaeRESUMO
INTRODUCTION: Numerous reviews, commentaries and opinion pieces have suggested targeting IL-17A as part of managing Coronavirus disease 2019 (COVID-19), the notorious pandemic caused by the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). IL-17A is a proinflammatory cytokine attributed with homeostatic roles but that is also involved in autoimmune disease pathogenesis. While some studies have reported an increase in IL-17A in COVID-19 cases, no significant associations were found by others. Hence, we undertook this meta-analysis to study serum IL-17A levels in COVID-19 patients in relation to disease severity. METHODOLOGY: Multiple databases were systematically reviewed for literature published on the topic from January 1, 2019 to April 30, 2021. A random effects model was used to calculate weighted mean differences (WMDs) and 95% confidence interval (CIs) as well as the t2 and I2 statistics for heterogeneity analysis. RESULTS: We report that IL-17A increases in COVID-19 subjects irrespective of disease severity compared to controls [WMD = 2.51 pg/ml (95% CI 1.73-3.28), p < 0.00001]. It is also higher in patients with moderate disease compared to controls [WMD = 2.41 pg/ml (95% CI:1.40-3.43), p < 0.00001] as well as higher in patients with severe COVID-19 [WMD = 4.13 pg/ml (95% CI:1.65-6.60), p = 0.001]. While the increase in serum levels in subjects with severe disease over those with moderate disease was statistically significant, the association was not as robust as the other comparisons [WMD = 2.07 pg/ml (95% CI:0.20-3.95), p = 0.03]. Variable heterogeneity was observed in the various analyses with no significant publication bias detected. CONCLUSIONS: Hence, IL-17A may be of relevance when considering management approaches to COVID-19.
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COVID-19/sangue , Interleucina-17/sangue , SARS-CoV-2 , Saúde Global , Humanos , PandemiasRESUMO
Infection with EBV has been associated with various inflammatory disorders including inflammatory bowel diseases (IBD). Contribution of this virus to intestinal disease processes has not been assessed. We previously detected that EBV DNA triggers proinflammatory responses via the activation of endosomal Toll-like receptor (TLR) signaling. Hence, to examine the colitogenic potential of EBV DNA, we used the dextran sodium sulfate (DSS) mouse colitis model. C57BL/6J mice received either DSS-containing or regular drinking water. Mice were then administered EBV DNA by rectal gavage. Administration of EBV DNA to the DSS-fed mice aggravated colonic disease activity as well as increased the damage to the colon histologic architecture. Moreover, we observed enhanced expression of IL-17A, IFNγ and TNFα in colon tissues from the colitis mice (DSS-treated) given the EBV DNA compared to the other groups. This group also had a marked decrease in expression of the CTLA4 immunoregulatory marker. On the other hand, we observed enhanced expression of endosomal TLRs in colon tissues from the EBV DNA-treated colitis mice. These findings indicate that EBV DNA exacerbates proinflammatory responses in colitis. The ubiquity of EBV in the population indicates that possible similar responses may be of pertinence in a relevant proportion of IBD patients.
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DNA Viral/genética , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/patogenicidade , Doenças Inflamatórias Intestinais/virologia , Animais , Colo/imunologia , Colo/patologia , Colo/virologia , Modelos Animais de Doenças , Progressão da Doença , Feminino , Herpesvirus Humano 4/imunologia , Doenças Inflamatórias Intestinais/imunologia , Mucosa Intestinal/patologia , Mucosa Intestinal/virologia , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Receptores Toll-Like/genética , Receptores Toll-Like/imunologia , Receptores Toll-Like/metabolismoRESUMO
Objective: We recently demonstrated that EBV DNA is correlated with proinflammatory responses in mice and in rheumatoid arthritis (RA) patients; hence, we utilized an RA mouse model to examine whether EBV DNA enhances the risk and severity of arthritis and to assess its immunomodulatory effects. Methods: C57BL/6J mice 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 clinical signs and affected joints/footpads were histologically analysed. The relative concentration of IgG anti- chicken collagen antibodies and serum cytokine levels of IL-17A and IFNÏ were determined by ELISA. The number of cells co-expressing IL-17A and IFNÏ in joint histological sections was determined by immunofluorescence. Results: The incidence of arthritis was significantly higher in mice that received EBV DNA prior to collagen compared to mice that only received collagen. Similarly, increased clinical scores, histological scores and paw thicknesses with a decreased gripping strength were observed in groups treated with EBV DNA and collagen. The relative concentration of IgG anti-chicken collagen antibodies was significantly increased in the group that received EBV DNA 6 days prior to collagen in comparison to the collagen receiving group. On the other hand, the highest number of cells co-expressing IFNÏ and IL-17A was observed in joints from mice that received both collagen and EBV DNA. Conclusion: EBV DNA increases the incidence and severity of arthritis in a RA mouse model. Targeting mediators triggered by viral DNA may hence be a potential therapeutic avenue.
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Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , DNA Viral/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Animais , Artrite Experimental/patologia , Artrite Experimental/virologia , Artrite Reumatoide/patologia , Artrite Reumatoide/virologia , Infecções por Vírus Epstein-Barr/complicações , Feminino , Herpesvirus Humano 4 , Incidência , Camundongos , Camundongos Endogâmicos C57BLRESUMO
The Epstein-Barr virus (EBV) commonly infects humans and is highly associated with different types of cancers and autoimmune diseases. EBV has also been detected in inflamed gastrointestinal mucosa of patients suffering from prolonged inflammation of the digestive tract such as inflammatory bowel disease (IBD) with no clear role identified yet for EBV in the pathology of such diseases. Since we have previously reported immune-stimulating capabilities of EBV DNA in various models, in this study we investigated whether EBV DNA may play a role in exacerbating intestinal inflammation through innate immune and regeneration responses using the Drosophila melanogaster model. We have generated inflamed gastrointestinal tracts in adult fruit flies through the administration of dextran sodium sulfate (DSS), a sulfated polysaccharide that causes human ulcerative colitis- like pathologies due to its toxicity to intestinal cells. Intestinal damage induced by inflammation recruited plasmatocytes to the ileum in fly hindguts. EBV DNA aggravated inflammation by enhancing the immune deficiency (IMD) pathway as well as further increasing the cellular inflammatory responses manifested upon the administration of DSS. The study at hand proposes a possible immunostimulatory role of the viral DNA exerted specifically in the fly hindgut hence further developing our understanding of immune responses mounted against EBV DNA in the latter intestinal segment of the D. melanogaster gut. These findings suggest that EBV DNA may perpetuate proinflammatory processes initiated in an inflamed digestive system. Our findings indicate that D. melanogaster can serve as a model to further understand EBV-associated gastroinflammatory pathologies. Further studies employing mammalian models may validate the immunogenicity of EBV DNA in an IBD context and its role in exacerbating the disease through inflammatory mediators.
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DNA Viral , Suscetibilidade a Doenças , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4 , Doenças Inflamatórias Intestinais/etiologia , Animais , Biomarcadores , Contagem de Células , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Proteínas de Drosophila/genética , Drosophila melanogaster , Hemócitos , Herpesvirus Humano 4/genética , Humanos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Regeneração , Células-Tronco/imunologia , Células-Tronco/metabolismoRESUMO
Background: Melanoma is a malignancy with increasing incidence that underlies most skin cancer-related deaths. Advanced melanoma patients still have poor prognosis despite recently developed immunotherapies. This study devises a triple immunotherapy to treat melanoma in a mouse model. The combination includes anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) antibodies, Monophosphoryl-lipid-A (MPLA), and an Indolamine-Dioxygenase-1 (IDO1) inhibitor. The aim of the study is, first, to rule out any major toxic effects related to this therapy and, second, to assess its antitumor effects. Methods: Cancer-free C57BL/6 mice were randomized into control groups and groups receiving single, dual, or triple therapies of the defined treatments. Clinical signs, weight gain, and histological sections from their main organs were assessed. Then, melanoma-bearing mice were segregated into similar groups, monitored for survival, and their tumor size was measured repeatedly. Finally, flow cytometry was used to analyze immune cell populations in the tumor masses including CD4+, CD8+, and regulatory T cells in addition to natural killer cells. Results: No adverse effects were detected in any of the treated groups. Survival analysis indicated that the groups receiving dual or triple therapies had prolonged survival compared to the controls. However, the group receiving triple therapy was the only group to show statistically significant increase in survival compared to the controls. Tumor size progression paralleled the survival outcome. The group receiving the triple therapy showed statistically significant smaller tumor sizes compared to all the other groups throughout the whole monitoring period. Flow cytometry used to analyze immune cell populations in the tumor mass indicated that the triple immune therapy was capable of significantly enhancing the natural killer cell counts as well as the CD3+CD4+/Treg and CD3+CD8+/Treg ratios possibly enhancing the anti-tumorigenic environment. Conclusions: Generated data rule out any major adverse events pertaining to the triple immunotherapy and reveal its enhanced effectiveness in thwarting melanoma progression over all other tested treatments.
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To assess whether the immunosuppressive effects of atorvastatin outweigh its antibacterial ones in an infection, mice were infected with Escherichia coli and administered atorvastatin; survival rates were then monitored. Mice treated with atorvastatin post-infection showed a remarkable decrease in their survival rate. On the other hand, the higher the level of serum IFN-γ in the infected mice treated with atorvastatin, the lower was the survival rate. Levels of IL-4 were markedly depressed in all groups infected with E. coli and treated with atorvastatin. Since atorvastatin inhibits IFN-γ expression in the absence of bacterial infection, we examined whether bacterial lipopolysaccharide (LPS) was the element capable of overriding this inhibition. Mouse peripheral blood mononuclear cells were treated with atorvastatin and lipopolysaccharide ex vivo then proinflammatory (IFN-γ, TNFα, IL-6) and prohumoral/regulatory (IL-4, IL-13, IL-10) cytokine levels were analyzed in culture supernatants. While proinflammatory cytokine levels were decreased upon treatment with atorvastatin alone, their levels were markedly elevated by treatment with LPS, bacterial lysate or bacterial culture supernatant. On the other hand, atorvastatin exerted an inhibitory effect on production of the prohumoral/regulatory cytokines. Our data indicates that any consideration for statins as antimicrobial treatment should assess the possible adverse outcomes.
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Atorvastatina/efeitos adversos , Infecções por Escherichia coli/mortalidade , Escherichia coli/patogenicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Imunossupressores/efeitos adversos , Interferon gama/imunologia , Animais , Atorvastatina/administração & dosagem , Escherichia coli/imunologia , Infecções por Escherichia coli/imunologia , Infecções por Escherichia coli/microbiologia , Infecções por Escherichia coli/patologia , Feminino , Imunossupressores/administração & dosagem , Inflamação , Interferon gama/genética , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-13/genética , Interleucina-13/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/microbiologia , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Cultura Primária de Células , Análise de Sobrevida , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologiaRESUMO
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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Endossomos/metabolismo , Infecções por Vírus Epstein-Barr/metabolismo , Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4/fisiologia , Interleucina-17/biossíntese , Receptores Toll-Like/metabolismo , Animais , DNA Viral/imunologia , Humanos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Camundongos , Baço/imunologia , Baço/metabolismoRESUMO
The exact aetiology of most autoimmune diseases remains unknown, nonetheless, several factors contributing to the induction or exacerbation of autoimmune reactions have been suggested. These include the genetic profile and lifestyle of the affected individual in addition to environmental triggers such as bacterial, parasitic, fungal and viral infections. Infections caused by viruses usually trigger a potent immune response that is necessary for the containment of the infection; however, in some cases, a failure in the regulation of this immune response may lead to harmful immune reactions directed against the host's antigens. The autoimmune attack can be carried out by different arms and components of the immune system and through different possible mechanisms including molecular mimicry, bystander activation, and epitope spreading among others. In this review, we examine the data available for the involvement of viral infections in triggering or exacerbating autoimmune diseases in addition to discussing the mechanisms by which these viral infections and the immune pathways they trigger possibly contribute to the development of autoimmunity.