TLR9 Contributes to Antiviral Immunity during Gammaherpesvirus Infection

Guggemoos, Simone; Hangel, Doris; Hamm, Svetlana; Heit, Antje; Bauer, Stefan; Adler, Heiko

doi:10.4049/jimmunol.180.1.438

Cited by 78 publications

(99 citation statements)

References 53 publications

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“…The virus may otherwise alter the development of autoimmunity by modulating DCs, which are known to contribute to the development of lupus in B6.Sle123 mice by producing large amounts of proinflammatory cytokines and driving high levels of B-cell and T-cell proliferation (68)(69)(70). Acute infection of DCs with γHV68 decreases their ability to present antigen and to express proinflammatory cytokines (20,21,29,61,71). Reduced endocytic function of DCs during γHV68 acute infection was also observed in the context of the autoimmune NOD genetic background (29).…”

Section: Discussionmentioning

confidence: 99%

“…The significant decrease of anti-Smith autoantibodies and of ABC numbers in aged B6.Sle123 females with γHV68 infection is compatible with a general inhibition of TLR7 signaling. Although speculative, γHV68 might impinge on TLR7 signaling and, consequently, on ABC accumulation and function and autoimmune development, either by reducing receptor expression as shown for EBV in human B-cell lines (58-60) or by opposing its function via the activation of TLR9 signaling (54,57,61,62). In preliminary studies, we did not find a difference in the response (CD69 up-regulation) of total B cells to a TLR7 agonist in noninfected and γHV68-infected B6.Sle123 mice, suggesting that a general alteration of this pathway in B cells is not likely the cause of the reduced autoimmune phenotype.…”

Section: Discussionmentioning

confidence: 99%

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Murine gammaherpesvirus 68 infection protects lupus-prone mice from the development of autoimmunity

Larson

Thurman

Rubtsov

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Gammaherpesvirus infections, such as those caused by EBV, have been suggested to promote the development of autoimmunity. To test this idea, we infected healthy WT and lupus-prone B6.Sle123 mice with an EBV-related and rodent-specific gammaherpesvirus, γHV68. Although acute γHV68 infection increased autoantibody levels for 4 to 6 wk, latent infection inhibited these responses for 1 y. The inhibition of autoantibody expression was only observed in B6.Sle123 females and not in males, which already displayed lower autoantibody titers. Contrary to the initial hypothesis, infection of young B6.Sle123 mice, both male and female, resulted in suppression of lymphoid activation and expansion and of glomerular inflammation and sclerosis, preserving kidney function. Moreover, γHV68 infection led to reduced autoantibody titers, lymphoid activation, and glomerular inflammation whether lupus-prone females were infected before or during disease manifestation. Finally, γHV68 infection also inhibited autoantibody production in the genetically distinct MRL/ lpr lupus-prone mice. Our findings indicate that γHV68 infection strongly inhibits the development and progression of lupus-like disease in mice that spontaneously develop this condition mediating its beneficial effects at the humoral, cellular, and organ levels. The mechanisms by which the virus exerts this down-modulatory action are not yet clear, but appear to operate via reduced activation of dendritic cells, T cells, and B cells. Gammaherpesviruses coevolved with the vertebrate immune systems, establishing lifelong infections in humans and other mammals. Our findings that γHV68 infection prevents rather than exacerbates autoimmunity in mice suggest that infection with gammaherpesviruses may be protective rather than pathological in most individuals.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Murine gammaherpesvirus 68 infection protects lupus-prone mice from the development of autoimmunity

Larson

Thurman

Rubtsov

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…54 EBV, perhaps the most common infectious trigger of secondary HLH, is a DNA virus that triggers TLR9. 55 Furthermore, as opposed to patients with EBV-mononucleosis, patients with EBV-HLH have very high titers of viral particles in the blood, 56 meaning that there is an excess of TLR9 ligand present in these patients. As described above, polymorphisms of the TLR9 signaling molecule IRF5 that result in the hyperactivation have been strongly associated with sJIA-related MAS.…”

Section: Proposed Pathophysiology Of Mas In Children With Sjiamentioning

confidence: 99%

Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment

et al. 2012

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Macrophage activation syndrome (MAS) is a severe, frequently fatal complication of systemic juvenile idiopathic arthritis (sJIA) with features of hemophagocytosis leading to coagulopathy, pancytopenia, and liver and central nervous system dysfunction. MAS is overt in 10% of children with sJIA but occurs subclinically in another 30 --40%. It is difficult to distinguish sJIA disease flare from MAS. Development of criteria for establishing MAS as part of sJIA are under way and will hopefully prove sensitive and specific. Mutations in cytolytic pathway genes are increasingly being recognized in children who develop MAS as part of sJIA. Identification of these mutations may someday assist in MAS diagnosis. Defects in cytolytic genes have provided murine models of MAS to study pathophysiology and treatment. Recently, the first mouse model of MAS not requiring infection but rather dependent on repeated stimulation through Toll-like receptors was reported. This provides a model of MAS that may more accurately reflect MAS pathology in the setting of autoinflammation or autoimmunity. This model confirms the importance of a balance between pro-and anti-inflammatory cytokines. There has been remarkable progress in the use of anti-pro-inflammatory cytokine therapy, particularly against interleukin-1, in the treatment of secondary forms of MAS, such as in sJIA.

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“…Viruses, as well as other pathogens, encode for various proteins containing pathogenassociated molecular patterns (PAMP), 3 which are recognized by immune sensor molecules that are referred to as pattern recognition receptors (PRR). TLRs, which are PRRs, are responsible for the primary recognition of a broad range of pathogens (1), leading to the initiation of the innate and adaptive immune responses (2)(3)(4).…”

mentioning

confidence: 99%

The EBV-Encoded dUTPase Activates NF-κB through the TLR2 and MyD88-Dependent Signaling Pathway

Ariza

Glaser

Kaumaya

et al. 2009

The Journal of Immunology

138

161

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The innate immune response plays a key role as the primary host defense against invading pathogens including viruses. We have previously shown that treatment of human monocyte-derived macrophages with EBV-encoded dUTPase induces the expression of proinflammatory cytokines through the activation of NF-κB. However, the receptor responsible for EBV-encoded dUTPase-mediated biological effects is not known. In this study, we demonstrate that the purified EBV-encoded dUTPase activates NF-κB in a dose-dependent manner through TLR2 and requires the recruitment of the adaptor molecule MyD88 but not CD14. Furthermore, activation of NF-κB was abrogated by anti-TLR2, anti-EBV-encoded dUTPase blocking Abs and the overexpression of a dominant negative construct of MyD88 in human embryonic kidney 293 cells expressing TLR2. In addition, treatment of human monocyte-derived macrophages with the anti-EBV-encoded dUTPase Ab 7D6 or the anti-TLR2 Ab blocked the production of IL-6 by the EBV-encoded dUTPase. To our knowledge, this is the first report demonstrating that a nonstructural protein encoded by EBV is a pathogen-associated molecular pattern and that it has immunomodulatory functions. Although additional studies are necessary to define the signaling pathways activated by the EBV-encoded dUTPase and to determine its role in modulating immune responses to EBV infection, our results suggest that the dUTPase could be a potential target for the development of novel therapeutic agents against infections caused by EBV.

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TLR9 Contributes to Antiviral Immunity during Gammaherpesvirus Infection

Cited by 78 publications

References 53 publications

Murine gammaherpesvirus 68 infection protects lupus-prone mice from the development of autoimmunity

Murine gammaherpesvirus 68 infection protects lupus-prone mice from the development of autoimmunity

Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment

The EBV-Encoded dUTPase Activates NF-κB through the TLR2 and MyD88-Dependent Signaling Pathway

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