Toll‐Like Receptor (TLR)–3, but Not TLR4, Agonist Protects against Genital Herpes Infection in the Absence of Inflammation Seen with CpG DNA

Ashkar, Ali A.; Yao, Xiao‐Dan; Gill, Navkiran; Sajic, Dusan; Patrick, Amy; Rosenthal, Kenneth L.

doi:10.1086/425079

Cited by 132 publications

(130 citation statements)

References 35 publications

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“…In the nonhemopoietic compartment, we found that keratinocytes and vaginal epithelial cells were responsive to IFN-, whereas fibroblasts did not induce expression of ISGs in response to IFN-treatment (Fig. 3B) Thus, type III IFN is able to stimulate both tissue cells at important portals of entry, and also pDCs, which are specialized IFN-producing cells thought to play important roles in antiviral defense (37,38).…”

Section: Type III Ifn Targets Only a Subset Of Cell Typesmentioning

confidence: 86%

An Important Role for Type III Interferon (IFN-λ/IL-28) in TLR-Induced Antiviral Activity

Ank

Iversen

Bartholdy

et al. 2008

The Journal of Immunology

385

410

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Type III IFNs (IFN-λ/IL-28/29) are cytokines with type I IFN-like antiviral activities, which remain poorly characterized. We herein show that most cell types expressed both types I and III IFNs after TLR stimulation or virus infection, whereas the ability of cells to respond to IFN-λ was restricted to a narrow subset of cells, including plasmacytoid dendritic cells and epithelial cells. To examine the role of type III IFN in antiviral defense, we generated IL-28Rα-deficient mice. These mice were indistinguishable from wild-type mice with respect to clearance of a panel of different viruses, whereas mice lacking the type I IFN receptor (IFNAR−/−) were significantly impaired. However, the strong antiviral activity evoked by treatment of mice with TLR3 or TLR9 agonists was significantly reduced in both IL-28RA−/− and IFNAR−/− mice. The type I IFN receptor system has been shown to mediate positive feedback on IFN-αβ expression, and we found that the type I IFN receptor system also mediates positive feedback on IFN-λ expression, whereas IL-28Rα signaling does not provide feedback on either type I or type III IFN expression in vivo. Finally, using bone-marrow chimeric mice we showed that TLR-activated antiviral defense requires expression of IL-28Rα only on nonhemopoietic cells. In this compartment, epithelial cells responded to IFN-λ and directly restricted virus replication. Our data suggest type III IFN to target a specific subset of cells and to contribute to the antiviral response evoked by TLRs.

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Section: Type III Ifn Targets Only a Subset Of Cell Typesmentioning

confidence: 86%

An Important Role for Type III Interferon (IFN-λ/IL-28) in TLR-Induced Antiviral Activity

Ank

Iversen

Bartholdy

et al. 2008

The Journal of Immunology

385

410

View full text Add to dashboard Cite

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“…TLR agonists act as immunomodulators and have been studied as potential adjuvant agents for a variety of vaccines: influenza virus (21), HSV (22), hepatitis B virus (23), and different types of cancer (24,25). After an initial screen of different TLR agonists, based on strongest immunomodulation, we selected PIC, a TLR3 agonist, and CL097, a TLR7/8 agonist, to test in combination with an EIC vaccine.…”

Section: Discussionmentioning

confidence: 99%

A nonreplicating subunit vaccine protects mice against lethal Ebola virus challenge

Phoolcharoen

Dye

Kilbourne

et al. 2011

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

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Ebola hemorrhagic fever is an acute and often deadly disease caused by Ebola virus (EBOV). The possible intentional use of this virus against human populations has led to design of vaccines that could be incorporated into a national stockpile for biological threat reduction. We have evaluated the immunogenicity and efficacy of an EBOV vaccine candidate in which the viral surface glycoprotein is biomanufactured as a fusion to a monoclonal antibody that recognizes an epitope in glycoprotein, resulting in the production of Ebola immune complexes (EICs). Although antigen–antibody immune complexes are known to be efficiently processed and presented to immune effector cells, we found that codelivery of the EIC with Toll-like receptor agonists elicited a more robust antibody response in mice than did EIC alone. Among the compounds tested, polyinosinic:polycytidylic acid (PIC, a Toll-like receptor 3 agonist) was highly effective as an adjuvant agent. After vaccinating mice with EIC plus PIC, 80% of the animals were protected against a lethal challenge with live EBOV (30,000 LD 50 of mouse adapted virus). Surviving animals showed a mixed Th1/Th2 response to the antigen, suggesting this may be important for protection. Survival after vaccination with EIC plus PIC was statistically equivalent to that achieved with an alternative viral vector vaccine candidate reported in the literature. Because nonreplicating subunit vaccines offer the possibility of formulation for cost-effective, long-term storage in biothreat reduction repositories, EIC is an attractive option for public health defense measures.

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“…Thus, poly(I:C) might have most potential as a topical strategy that could be applied immediately within 24 h after exposure to curb local spread. In addition, the ability of TLR3 ligation to limit herpes simplex virus infection (4,28,33,63,76) would also help to control the spread of HIV (11).…”

Section: Discussionmentioning

confidence: 99%

Double-Stranded RNA Analog Poly(I:C) Inhibits Human Immunodeficiency Virus Amplification in Dendritic Cells via Type I Interferon-Mediated Activation of APOBEC3G

Trapp

Derby

Singer

et al. 2009

J Virol

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Toll‐Like Receptor (TLR)–3, but Not TLR4, Agonist Protects against Genital Herpes Infection in the Absence of Inflammation Seen with CpG DNA

Cited by 132 publications

References 35 publications

An Important Role for Type III Interferon (IFN-λ/IL-28) in TLR-Induced Antiviral Activity

An Important Role for Type III Interferon (IFN-λ/IL-28) in TLR-Induced Antiviral Activity

A nonreplicating subunit vaccine protects mice against lethal Ebola virus challenge

Double-Stranded RNA Analog Poly(I:C) Inhibits Human Immunodeficiency Virus Amplification in Dendritic Cells via Type I Interferon-Mediated Activation of APOBEC3G

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