Innate Antiviral Immunity in the Skin

Handfield, Chelsea; Kwock, J.; MacLeod, Amanda S.

doi:10.1016/j.it.2018.02.003

Cited by 45 publications

(52 citation statements)

References 124 publications

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“…The ability of IL-27 to activate AVPs, including OAS family members known to play a role as antiviral effector proteins of RNA viruses (37) in keratinocytes, both independently and in conjunction with nucleic acid signaling, suggested to us that IL-27 may functionally mediate antiviral defenses against RNA viruses. Virus transmission and infection of the skin is frequently facilitated through microinjuries associated with skin barrier dysfunction, trauma, or mosquito bites (3). We found that human keratinocytes treated with IL-27 were less susceptible to infection by Sendai virus and ZIKV (Fig.…”

Section: Il-27 Induces the Expression Of Avps In Keratinocytes To Medmentioning

confidence: 85%

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IL-27 signaling activates skin cells to induce innate antiviral proteins and protects against Zika virus infection

et al. 2020

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In the skin, antiviral proteins and other immune molecules serve as the first line of innate antiviral defense. Here, we identify and characterize the induction of cutaneous innate antiviral proteins in response to IL-27 and its functional role during cutaneous defense against Zika virus infection. Transcriptional and phenotypic profiling of epidermal keratinocytes treated with IL-27 demonstrated activation of antiviral proteins OAS1, OAS2, OASL, and MX1 in the skin of both mice and humans. IL-27–mediated antiviral protein induction was found to occur in a STAT1- and IRF3-dependent but STAT2-independent manner. Moreover, using IL27ra mice, we demonstrate a significant role for IL-27 in inhibiting Zika virus morbidity and mortality following cutaneous, but not intravenous, inoculation. Together, our results demonstrate a critical and previously unrecognized role for IL-27 in cutaneous innate antiviral immunity against Zika virus.

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Section: Il-27 Induces the Expression Of Avps In Keratinocytes To Medmentioning

confidence: 85%

“…Given the critical role of keratinocytes in skin antimicrobial host defense (3,(10)(11)(12)(13)(14)(15)(16), we sought to investigate the expression, regulation, and function of keratinocyte innate AVPs by the IFN-independent cytokine, interleukin-27 (IL-27), and the impact this signaling pathway has on in vitro and in vivo ZIKV infection.…”

Section: Introductionmentioning

confidence: 99%

IL-27 signaling activates skin cells to induce innate antiviral proteins and protects against Zika virus infection

et al. 2020

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“…We next wanted to identify the cellular basis by which virus is detected and an anti-viral state induced and modulated by ALD at mosquito bites. Although a variety of cultured skin cells are known to express RNA-virus pattern recognition receptors, the cellular coordination of 265 innate immune responses to arbovirus at the mosquito bite are not described (10,33). We concentrated on studying cells of the dermis, as the majority of virus transmitted by mosquito is deposited here, and because epidermal cells do not express the IMQ receptor TLR7 in vivo (34).…”

Section: Skin Resident Cells Detect Topically-applied Imq and Are Sufmentioning

confidence: 99%

Pan-viral protection against arboviruses by targeting inoculation site-based skin macrophages

Bryden

Pingen

Lefteri

et al. 2019

Preprint

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One-sentence summaryWe demonstrate that activation of innate immune responses to arbovirus at the mosquito bite is a limiting factor for preventing efficient systemic dissemination of virus and that therapeutic targeting of skin-resident macrophages can have defining inhibitory effects on the later systemic course. 25Abstract Arthropod-borne viruses (arboviruses) are important human pathogens for which there are no specific antiviral medicines. The large number of genetically-distinct arbovirus species, coupled with the unpredictable nature of their outbreaks, has made developing virus-specific 30 anti-viral medicines challenging. Instead, we have defined and targeted a key aspect of the host innate immune response to virus at the arthropod bite that is common to all arbovirus infections, potentially circumventing the need for virus-specific therapies at this site. Using mouse models and human skin explants, we identify innate immune responses by dermal macrophages in the skin as a key determinant of disease severity. Post-exposure treatment of 35 the inoculation site by a topical innate immune agonist significantly suppressed both the local and subsequent systemic course of infection and improved clinical outcome in mice to infection with a variety of arboviruses from the Alphavirus, Flavivirus and Orthobunyavirus genuses. In the absence of treatment, anti-viral interferon expression to virus in the skin was restricted to dermal dendritic cells. In contrast, targeting the more populous skin-resident 40 macrophages with an immune agonist elicited protective responses in key cellular targets of virus that otherwise replicated virus to high levels. By defining and targeting a key aspect of the innate immune response to virus at the mosquito bite site, we have shown that it is possible to improve outcome to infection by targeting pathways activated at the site of inoculation, and thereby identified a putative new strategy for limiting disease following 45 infection with a variety of genetically-distinct arboviruses. IntroductionEmerging and re-emerging arboviruses pose an increasing threat to human health. There has been a substantial increase in both the incidence and geographical range of medicallyimportant arboviruses spread by mosquitoes, which infect hundreds of millions of people each 50 year and include the Zika (ZIKV), dengue (DENV) and chikungunya (CHIKV) viruses.Arboviruses are a large, genetically-diverse group of viruses that cause a wide spectrum of diseases in humans (1-5). Despite their genetic diversity, it is nonetheless difficult to clinically differentiate between these infections in the early stages of disease, as they are either asymptomatic or present as a non-specific febrile viral illness. In many geographic areas this 55 is compounded by the widespread co-circulation of distinct species of arboviruses in the same geographic area (6). Together, these factors complicate the use of putative virus-specific antivirals, which for acute infections are most often only efficacious when given during e...

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“…We next wanted to identify the cellular basis by which virus is detected and an anti-viral state induced and modulated by topical IMQ at mosquito bites. Although a variety of cultured skin cells are known to express RNA-virus pattern recognition receptors (34), the cellular coordination of innate immune responses to arbovirus at the mosquito bite are not described.…”

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confidence: 99%

Pan-viral protection against arboviruses by activating skin macrophages at the inoculation site

et al. 2020

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Arthropod-borne viruses (arboviruses) are important human pathogens for which there are no specific antiviral medicines. The abundance of genetically distinct arbovirus species, coupled with the unpredictable nature of their outbreaks, has made the development of virus-specific treatments challenging. Instead, we have defined and targeted a key aspect of the host innate immune response to virus at the arthropod bite that is common to all arbovirus infections, potentially circumventing the need for virus-specific therapies. Using mouse models and human skin explants, we identify innate immune responses by dermal macrophages in the skin as a key determinant of disease severity. Post-exposure treatment of the inoculation site by a topical TLR7 agonist suppressed both the local and subsequent systemic course of infection with a variety of arboviruses from the Alphavirus, Flavivirus, and Orthobunyavirus genera. Clinical outcome was improved in mice after infection with a model alphavirus. In the absence of treatment, antiviral interferon expression to virus in the skin was restricted to dermal dendritic cells. In contrast, stimulating the more populous skin-resident macrophages with a TLR7 agonist elicited protective responses in key cellular targets of virus that otherwise proficiently replicated virus. By defining and targeting a key aspect of the innate immune response to virus at the mosquito bite site, we have identified a putative new strategy for limiting disease after infection with a variety of genetically distinct arboviruses.

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Innate Antiviral Immunity in the Skin

Cited by 45 publications

References 124 publications

IL-27 signaling activates skin cells to induce innate antiviral proteins and protects against Zika virus infection

IL-27 signaling activates skin cells to induce innate antiviral proteins and protects against Zika virus infection

Pan-viral protection against arboviruses by targeting inoculation site-based skin macrophages

Pan-viral protection against arboviruses by activating skin macrophages at the inoculation site

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