UNC93B1 Mediates Innate Inflammation and Antiviral Defense in the Liver during Acute Murine Cytomegalovirus Infection

Crane, Meredith J.; Gaddi, Pamela J.; Salazar-Mather, Thais P.

doi:10.1371/journal.pone.0039161

Cited by 19 publications

(18 citation statements)

References 62 publications

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“…For the dsDNA herpesviruses HSV-1, MCMV, and murid herpesvirus 68 (MHV-68), more than one TLR contributes to control of the infection (10,50,71). For example, during i.p.…”

Section: Discussionmentioning

confidence: 99%

“…If redundancy in the innate immune system means that TLR2 alone is not required, there may still be a requirement for TLR2 in combination with other MyD88-dependent pathways. Synergy between two or more TLRs has been found to be important in other viral infections (10,50). Therefore, we looked for evidence that other MyD88-dependent receptors are involved in controlling VACV replication and pathogenesis in this natural route of infection.…”

Section: Fig 5 Tlr2 Contributes To Defense Against Disseminated Vaccimentioning

confidence: 99%

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MyD88-Dependent Immunity to a Natural Model of Vaccinia Virus Infection Does Not Involve Toll-Like Receptor 2

Davies

Sei

Siciliano

et al. 2014

J Virol

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Although the pattern recognition receptor Toll-like receptor 2 (TLR2) is typically thought to recognize bacterial components, it has been described to alter the induction of both innate and adaptive immunity to a number of viruses, including vaccinia virus (VACV). However, many pathogens that reportedly encode TLR2 agonists may actually be artifactually contaminated during preparation, possibly with cellular debris or merely with molecules that sensitize cells to be activated by authentic TLR2 agonists. In both humans and mice, the most relevant natural route of infection with VACV is through intradermal infection of the skin. Therefore, we examined the requirement for TLR2 and its signaling adaptor MyD88 in protective immunity to VACV after intradermal infection. We find that although TLR2 may recognize virus preparations in vitro and have a minor role in preventing dissemination of VACV following systemic infection with large doses of virus, it is wholly disposable in both control of virus replication and induction of adaptive immunity following intradermal infection. In contrast, MyD88 is required for efficient induction of CD4 T cell and B cell responses and for local control of virus replication following intradermal infection. However, even MyD88 is not required to induce local inflammation, inflammatory cytokine production, or recruitment of cells that restrict virus from spreading systemically after peripheral infection. Thus, an effective antiviral response does require MyD88, but TLR2 is not required for control of a peripheral VACV infection. These findings emphasize the importance of studying relevant routes of infection when examining innate sensing mechanisms. IMPORTANCEVaccinia virus (VACV) provides the backbone for some of the most widely used and successful viral vaccine vectors and is also related to the human pathogens Cantagalo virus and molluscum contagiosum virus that infect the skin of patients. Therefore, it is vital to understand the mechanisms that induce a strong innate immune response to the virus following dermal infection. Here, we compare the ability of the innate sensing molecule Toll-like receptor 2 (TLR2) and the signaling molecule MyD88 to influence the innate and adaptive immune response to VACV following systemic or dermal infection.

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“…For the dsDNA herpesviruses HSV-1, MCMV, and murid herpesvirus 68 (MHV-68), more than one TLR contributes to control of the infection (10,50,71). For example, during i.p.…”

Section: Discussionmentioning

confidence: 99%

Section: Fig 5 Tlr2 Contributes To Defense Against Disseminated Vaccimentioning

confidence: 99%

MyD88-Dependent Immunity to a Natural Model of Vaccinia Virus Infection Does Not Involve Toll-Like Receptor 2

Davies

Sei

Siciliano

et al. 2014

J Virol

View full text Add to dashboard Cite

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“…However, we previously found that 3d did not reduce T-dependent humoral immune responses in mice immunized with NA-free adjuvant (8). Moreover, UNC93B1-deficient cell lines showed no defects in MHC class I or MHC II molecules (29) or class II Ag presentation (55), there was no defect in CD8 T cell responses in UNC93B1-deficient mice infected with murine CMV (56), and in vitro activation of CD8 T cells by WT and 3d APCs was reportedly equivalent (57). Thus, it seems unlikely that the partial reduction in Ag presentation in 3d mice is responsible for our findings.…”

Section: Discussionmentioning

confidence: 99%

Role of Nucleic Acid–Sensing TLRs in Diverse Autoantibody Specificities and Anti-Nuclear Antibody–Producing B Cells

Koh

Scatizzi

Gahan

et al. 2013

The Journal of Immunology

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Nucleic acid (NA)–sensing TLRs (NA-TLRs) promote the induction of anti-nuclear Abs in systemic lupus erythematosus. However, the extent to which other nonnuclear pathogenic autoantibody specificities that occur in lupus and independently in other autoimmune diseases depend on NA-TLRs, and which immune cells require NA-TLRs in systemic autoimmunity, remains to be determined. Using Unc93b13d lupus-prone mice that lack NA-TLR signaling, we found that all pathogenic nonnuclear auto-antibody specificities examined, even anti-RBC, required NA-TLRs. Furthermore, we document that NA-TLRs in B cells were required for the development of antichromatin and rheumatoid factor. These findings support a unifying NA-TLR–mediated mechanism of autoantibody production that has both pathophysiological and therapeutic implications for systemic lupus erythematosus and several other humoral-mediated autoimmune diseases. In particular, our findings suggest that targeting of NA-TLR signaling in B cells alone would be sufficient to specifically block production of a broad diversity of autoantibodies.

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“…Moreover, Epstein-Barr virus interacts with the TLR7 pathway and enhances B cell proliferation [56]. Although TLR7 alone does not appear to have a strong role in cytomegalovirus recognition, TLR7/TLR9 and TLR3/TLR7/TLR9 combined deficiencies were shown to impair responses to MCMV [57, 58]. …”

Section: Discussionmentioning

confidence: 99%

Association of TLR3 L412F Polymorphism with Cytomegalovirus Infection in Children

et al. 2017

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Intracellular Toll-like receptor 3 (TLR3) recognizes viral double-stranded RNA (dsRNA) and activates antiviral immune responses through the production of type I interferons (IFNs) and inflammatory cytokines. This receptor binds to dsRNA molecules produced during human cytomegalovirus (HCMV) replication. TLR7 senses viral single-stranded RNA (ssRNA) in endosomes, and it can interact with endogenous RNAs. We determined the genotype distribution of single-nucleotide polymorphisms (SNPs) within the TLR3 and TLR7 genes in children with HCMV infection and the relationship between TLR polymorphisms and viral infection. We genotyped 59 children with symptomatic HCMV infection and 78 healthy individuals for SNPs in the TLR3 (rs3775290, c.1377C>T, F459F; rs3775291, c.1234C>T, L412F; rs3775296, c.-7C>A) and TLR7 (rs179008, c.32A>T, Q11L; rs5741880, c.3+1716G>T) genes. SNP genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and capillary electrophoresis. The HCMV DNA load was quantified by real-time PCR. We found an increased frequency of the heterozygous genotype TLR3 L412F in children with HCMV infection compared with uninfected cases. In individuals with a mutation present in at least one allele of the L412F SNP, an increased risk of HCMV disease was found, and this result remained highly significant after Bonferroni’s correction for multiple testing (Pc < 0.001). The heterozygous genotype of this SNP was associated with the increased risk of HCMV disease in an adjusted model that included the HCMV DNA copy number in whole blood and urine (P < 0.001 and P = 0.008, respectively). Moreover, those with a heterozygous genotype of rs3775296 showed an increased relative risk of HCMV infection (P = 0.042), but this association did not reach statistical significance after correction for multiple testing. In contrast, the rs3775290 SNP of TLR3 and TLR7 SNPs were not related to viral infection. A moderate linkage disequilibrium (LD) was observed between the SNPs rs3775291 and rs3775296 (r2 = 0.514). We suggest that the L412F polymorphism in the TLR3 gene could be a genetic risk factor for the development of HCMV disease.

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UNC93B1 Mediates Innate Inflammation and Antiviral Defense in the Liver during Acute Murine Cytomegalovirus Infection

Cited by 19 publications

References 62 publications

MyD88-Dependent Immunity to a Natural Model of Vaccinia Virus Infection Does Not Involve Toll-Like Receptor 2

MyD88-Dependent Immunity to a Natural Model of Vaccinia Virus Infection Does Not Involve Toll-Like Receptor 2

Role of Nucleic Acid–Sensing TLRs in Diverse Autoantibody Specificities and Anti-Nuclear Antibody–Producing B Cells

Association of TLR3 L412F Polymorphism with Cytomegalovirus Infection in Children

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