scholarly journals Evasion of the STING DNA-Sensing Pathway by VP11/12 of Herpes Simplex Virus 1

2017 ◽  
Vol 91 (16) ◽  
Author(s):  
Thibaut Deschamps ◽  
Maria Kalamvoki
Keyword(s):  
Innate Immunity ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Tegument Protein ◽  
Type I ◽  
Herpes Simplex Virus 1 ◽  
Growth Defects ◽  
Foreign Dna ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT The stimulator of interferon (IFN) genes (STING) is a broad antimicrobial factor that restricts herpes simplex virus (HSV) by activating type I interferon and proinflammatory responses upon sensing of foreign DNA. UL46 is one of the most abundant tegument proteins of HSV-1, but a well-established function has yet to be found. We found that the HSV-1 UL46 protein interacts with and colocalizes with STING. A ΔUL46 virus displayed growth defects and activated innate immunity, but both effects were alleviated in STING knockdown cells. UL46 was also required for the inhibition of the 2′,3′-cyclic GMP-AMP (cGAMP)-dependent immune responses during infection. In cells expressing UL46, out of the context of the infection, innate immunity to a ΔICP0 virus was largely compromised, and that permitted ICP0-deficient mutants to replicate. The UL46-expressing cell lines also rescued the defects of the ΔUL46 virus and enhanced wild-type virus infection. The UL46-expressing cell lines did not activate interferon-stimulated gene (ISG) transcription following treatment with the noncanonical cyclic dinucleotide 2′,3′-cGAMP, suggesting that the STING pathway may be compromised. Indeed, we found that both proteins STING and IFI16 were eliminated in cells constitutively expressing UL46 and that the accumulation of their transcripts was blocked. Finally, we demonstrated that UL46 via its N terminus binds to STING and, via its C terminus, to TBK1. These interactions appear to modulate the functions of STING during HSV-1 infection. Taken together, our studies describe a novel function for one of the least-studied proteins of HSV, the tegument protein UL46, and that function involves the evasion of foreign DNA-sensing pathways. IMPORTANCE Herpes simplex virus 1 (HSV-1) afflicts 80% of the population worldwide, causing various diseases. After initial infection, the virus establishes latent reservoirs in sensory neurons and persists for life. Here we describe novel interactions between HSV-1 and the DNA sensor STING. We found that (i) HSV-1 tegument protein UL46 interacts with and colocalizes with STING; (ii) UL46 expressed out of the context of the infection blocks type I interferon triggered by STING stimuli, through the elimination of STING and of interferon-inducible protein 16 (IFI16); (iii) a ΔUL46 virus displayed growth defects, which were rescued in STING knockdown cells; (iv) the ΔUL46 virus failed to block innate immunity triggered by ligands of STING such as 2′,3′-cGAMP and also activated IFN-β and ISG expression; and (v) UL46 binds to both STING and TBK1 through different domains. We conclude that UL46 counteracts the actions of STING during HSV-1 infection.

scholarly journals Herpes Simplex Virus 1 Tegument Protein UL46 Inhibits TANK-Binding Kinase 1-Mediated Signaling

mBio ◽  
2019 ◽  
Vol 10 (3) ◽  
Author(s):  
Hongjuan You ◽  
Sisilia Zheng ◽  
Zhiming Huang ◽  
Yingying Lin ◽  
Qingtang Shen ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Immune Evasion ◽  
Latent Infection ◽  
Tegument Protein ◽  
Type I ◽  
Simplex Virus ◽  
Antiviral Innate Immunity ◽  
Hsv 1

ABSTRACT TANK-binding kinase 1 (TBK1) is a key component of the antiviral immunity signaling pathway. It activates downstream interferon regulatory factor 3 (IRF3) and subsequent type I interferon (IFN-I) production. Herpes simplex virus type 1 (HSV-1) can antagonize host antiviral immune responses and lead to latent infection. Here, HSV-1 tegument protein UL46 was demonstrated to downregulate TBK1-dependent antiviral innate immunity. UL46 interacted with TBK1 and reduced TBK1 activation and its downstream signaling. Our results showed that UL46 impaired the interaction of TBK1 and IRF3 and downregulated the activation of IRF3 by inhibiting the dimerization of TBK1 to reduce the IFN-I production induced by TBK1 and immunostimulatory DNA. The IFN-I and its downstream antiviral genes induced by UL46-deficient HSV-1 (ΔUL46 HSV-1) were higher than those of wild-type HSV-1 (WT HSV-1). In addition, the stable knockdown of TBK1 facilitated the replication of ΔUL46 HSV-1, but not WT HSV-1. Together, these findings reveal a novel mechanism of immune evasion by HSV-1. IMPORTANCE HSV-1 has evolved multiple strategies to evade host antiviral responses and establish a lifelong latent infection, but the molecular mechanisms by which HSV-1 interrupts antiviral innate immunity are not completely understood. As TBK1 is very critical for antiviral innate immunity, it is of great interest to reveal the immune evasion mechanism of HSV-1 by targeting TBK1. In the present study, HSV-1 UL46 was found to inhibit the activation of IFN-I by targeting TBK1, suggesting that the evasion of TBK1 mediated antiviral innate immunity by HSV-1 UL46. Findings in this study will provide new insights into the host-virus interaction and help develop new approaches against HSV-1 infection.

scholarly journals Herpes Simplex Virus 1 Tegument Protein VP22 Abrogates cGAS/STING-Mediated Antiviral Innate Immunity

2018 ◽  
Vol 92 (15) ◽  
Author(s):  
Jian Huang ◽  
Hongjuan You ◽  
Chenhe Su ◽  
Yangxin Li ◽  
Shunhua Chen ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Signaling Pathway ◽  
Tegument Protein ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
Antiviral Innate Immunity ◽  
Protein Vp22 ◽  
Hsv 1

ABSTRACTCytosolic DNA arising from intracellular pathogens is sensed by cyclic GMP-AMP synthase (cGAS) and triggers a powerful innate immune response. However, herpes simplex virus 1 (HSV-1), a double-stranded DNA virus, has developed multiple mechanisms to attenuate host antiviral machinery and facilitate viral infection and replication. In the present study, we found that HSV-1 tegument protein VP22 acts as an inhibitor of cGAS/stimulator of interferon genes (cGAS/STING)-mediated production of interferon (IFN) and its downstream antiviral genes. Our results showed that ectopic expression of VP22 decreased cGAS/STING-mediated IFN-β promoter activation and IFN-β production. Infection with wild-type (WT) HSV-1, but not VP22-deficient virus (ΔVP22), inhibited immunostimulatory DNA (ISD)-induced activation of the IFN signaling pathway. Further study showed that VP22 interacted with cGAS and inhibited the enzymatic activity of cGAS. In addition, stable knockdown of cGAS facilitated the replication of ΔVP22 virus but not the WT. In summary, our findings indicate that HSV-1 VP22 acts as an antagonist of IFN signaling to persistently evade host innate antiviral responses.IMPORTANCEcGAS is very important for host defense against viral infection, and many viruses have evolved ways to target cGAS and successfully evade the attack by the immune system of their susceptible host. This study demonstrated that HSV-1 tegument protein VP22 counteracts the cGAS/STING-mediated DNA-sensing antiviral innate immunity signaling pathway by inhibiting the enzymatic activity of cGAS. The findings in this study will expand our understanding of the interaction between HSV-1 replication and the host DNA-sensing signaling pathway.

scholarly journals Herpes simplex virus 1 targets IRF7 via ICP0 to limit type I IFN induction

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
David Shahnazaryan ◽  
Rana Khalil ◽  
Claire Wynne ◽  
Caroline A. Jefferies ◽  
Joan Ní Gabhann-Dromgoole ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Immune Responses ◽  
Tear Film ◽  
Cell Protein ◽  
Type I ◽  
Type I Ifn ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
Hsv 1

AbstractHerpes simplex keratitis (HSK), caused by herpes simplex virus type 1 (HSV-1) infection, is the commonest cause of infectious blindness in the developed world. Following infection the virus is initially suspended in the tear film, where it encounters a multi-pronged immune response comprising enzymes, complement, immunoglobulins and crucially, a range of anti-viral and pro-inflammatory cytokines. However, given that HSV-1 can overcome innate immune responses to establish lifelong latency throughout a susceptible individual’s lifetime, there is significant interest in understanding the mechanisms employed by HSV-1 to downregulate the anti-viral type I interferon (IFN) mediated immune responses. This study aimed to investigate the interactions between infected cell protein (ICP)0 and key elements of the IFN pathway to identify possible novel targets that contribute to viral immune evasion. Reporter gene assays demonstrated the ability of ICP0 to inhibit type I IFN activity downstream of pathogen recognition receptors (PRRs) which are known to be involved in host antiviral defences. Further experiments identified interferon regulatory factor (IRF)7, a driver of type I IFN, as a potential target for ICP0. These findings increase our understanding of the pathogenesis of HSK and suggest IRF7 as a potential therapeutic target.

scholarly journals The Solute Carrier Transporter SLC15A3 Participates in Antiviral Innate Immune Responses against Herpes Simplex Virus-1

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Longzhen He ◽  
Baocheng Wang ◽  
Yuanyuan Li ◽  
Leqing Zhu ◽  
Peiling Li ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Immune Responses ◽  
Innate Immune ◽  
Host Cells ◽  
Type I ◽  
Innate Immune Responses ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
Hsv 1

The innate immune response is the first line defense against viral infections. Novel genes involved in this system are continuing to emerge. SLC15A3, a proton-coupled histidine and di-tripeptide transporter that was previously found in lysosomes, has been reported to inhibit chikungunya viral replication in host cells. In this study, we found that SLC15A3 was significantly induced by DNA virus herpes simplex virus-1(HSV-1) in monocytes from human peripheral blood mononuclear cells. Aside from monocytes, it can also be induced by HSV-1 in 293T, HeLa cells, and HaCaT cells. Overexpression of SLC15A3 in 293T cells inhibits HSV-1 replication and enhances type I and type III interferon (IFN) responses, while silencing SLC15A3 leads to enhanced HSV-1 replication with reduced IFN production. Moreover, we found that SLC15A3 interacted with MAVS and STING and potentiated MAVS- and STING-mediated IFN production. These results demonstrate that SLC15A3 participates in anti-HSV-1 innate immune responses by regulating MAVS- and STING-mediated signaling pathways.

scholarly journals Herpes Simplex Virus 1 Interaction with Myeloid CellsIn Vivo

2016 ◽  
Vol 90 (19) ◽  
pp. 8661-8672 ◽  
Author(s):  
Maitreyi Shivkumar ◽  
Clara Lawler ◽  
Ricardo Milho ◽  
Philip G. Stevenson
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Myeloid Cells ◽  
Nerve Cells ◽  
Type I ◽  
Herpes Simplex Virus 1 ◽  
Viral Spread ◽  
Systemic Spread ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACTHerpes simplex virus 1 (HSV-1) enters mice via olfactory epithelial cells and then colonizes the trigeminal ganglia (TG). Most TG nerve endings are subepithelial, so this colonization implies subepithelial viral spread, where myeloid cells provide an important line of defense. The outcome of infection of myeloid cells by HSV-1in vitrodepends on their differentiation state; the outcomein vivois unknown. Epithelial HSV-1 commonly infected myeloid cells, and Cre-Lox virus marking showed nose and lung infections passing through LysM-positive (LysM+) and CD11c+cells. In contrast, subcapsular sinus macrophages (SSMs) exposed to lymph-borne HSV-1 were permissive only when type I interferon (IFN-I) signaling was blocked; normally, their infection was suppressed. Thus, the outcome of myeloid cell infection helped to determine the HSV-1 distribution: subepithelial myeloid cells provided a route of spread from the olfactory epithelium to TG neurons, while SSMs blocked systemic spread.IMPORTANCEHerpes simplex virus 1 (HSV-1) infects most people and can cause severe disease. This reflects its persistence in nerve cells that connect to the mouth, nose, eye, and face. Established infection seems impossible to clear. Therefore, we must understand how it starts. This is difficult in humans, but mice show HSV-1 entry via the nose and then spread to its preferred nerve cells. We show that this spread proceeds in part via myeloid cells, which normally function in host defense. Myeloid infection was productive in some settings but was efficiently suppressed by interferon in others. Therefore, interferon acting on myeloid cells can stop HSV-1 spread, and enhancing this defense offers a way to improve infection control.

scholarly journals Comprehensive Mutagenesis of Herpes Simplex Virus 1 Genome Identifies UL42 as an Inhibitor of Type I Interferon Induction

2019 ◽  
Vol 93 (23) ◽  
Author(s):  
Maxime Chapon ◽  
Kislay Parvatiyar ◽  
Saba Roghiyh Aliyari ◽  
Jeffrey S. Zhao ◽  
Genhong Cheng
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
High Throughput ◽  
Type I Interferon ◽  
Viral Proteins ◽  
Interferon Response ◽  
Type I ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT In spite of several decades of research focused on understanding the biology of human herpes simplex virus 1 (HSV-1), no tool has been developed to study its genome in a high-throughput fashion. Here, we describe the creation of a transposon insertion mutant library of the HSV-1 genome. Using this tool, we aimed to identify novel viral regulators of type I interferon (IFN-I). HSV-1 evades the host immune system by encoding viral proteins that inhibit the type I interferon response. Applying differential selective pressure, we identified the three strongest viral IFN-I regulators in HSV-1. We report that the viral polymerase processivity factor UL42 interacts with the host transcription factor IFN regulatory factor 3 (IRF-3), inhibiting its phosphorylation and downstream beta interferon (IFN-β) gene transcription. This study represents a proof of concept for the use of high-throughput screening of the HSV-1 genome in investigating viral biology and offers new targets both for antiviral therapy and for oncolytic vector design. IMPORTANCE This work is the first to report the use of a high-throughput mutagenesis method to study the genome of HSV-1. We report three novel viral proteins potentially involved in regulating the host type I interferon response. We describe a novel mechanism by which the viral protein UL42 is able to suppress the production of beta interferon. The tool we introduce in this study can be used to study the HSV-1 genome in great detail to better understand viral gene functions.

The US3 kinase of Herpes Simplex virus phosphorylates the RNA sensor RIG-I to suppress innate immunity

2021 ◽  
Author(s):  
Michiel van Gent ◽  
Jessica J. Chiang ◽  
Santoshi Muppala ◽  
Cindy Chiang ◽  
Walid Azab ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Immune Escape ◽  
Type I ◽  
Dependent Manner ◽  
Herpes Simplex Virus 1 ◽  
E3 Ligases ◽  
Immune Evasion Mechanism ◽  
Simplex Virus ◽  
Hsv 1

Recent studies demonstrated that the signaling activity of the cytosolic pathogen sensor retinoic acid-inducible gene-I (RIG-I) is modulated by a variety of post-translational modifications (PTMs) to fine-tune the antiviral type I interferon (IFN) response. Whereas K63-linked ubiquitination of the RIG-I caspase activation and recruitment domains (CARDs) catalyzed by TRIM25 or other E3 ligases activates RIG-I, phosphorylation of RIG-I at S8 and T170 represses RIG-I signal transduction by preventing the TRIM25-RIG-I interaction and subsequent RIG-I ubiquitination. While strategies to suppress RIG-I signaling by interfering with its K63-polyubiquitin-dependent activation have been identified for several viruses, evasion mechanisms that directly promote RIG-I phosphorylation to escape antiviral immunity are unknown. Here, we show that the serine/threonine (Ser/Thr) kinase US3 of herpes simplex virus 1 (HSV-1) binds to RIG-I and phosphorylates RIG-I specifically at S8. US3-mediated phosphorylation suppressed TRIM25-mediated RIG-I ubiquitination, RIG-I-MAVS binding, and type I IFN induction. We constructed a mutant HSV-1 encoding a catalytically-inactive US3 protein (K220A) and found that, in contrast to the parental virus, the US3 mutant HSV-1 is unable to phosphorylate RIG-I at S8 and elicited higher levels of type I IFNs, IFN-stimulated genes (ISGs), and proinflammatory cytokines in a RIG-I-dependent manner. Finally, we show that this RIG-I evasion mechanism is conserved among the alphaherpesvirus US3 kinase family. Collectively, our study reveals a novel immune evasion mechanism of herpesviruses in which their US3 kinases phosphorylate the sensor RIG-I to keep it in the signaling-repressed state. IMPORTANCE Herpes simplex virus 1 (HSV-1) establishes life-long latency in the majority of the human population worldwide. HSV-1 occasionally reactivates to produce infectious virus and to facilitate dissemination. While often remaining subclinical, both primary infection and reactivation occasionally cause debilitating eye diseases, which can lead to blindness, as well as life-threatening encephalitis and newborn infections. To identify new therapeutic targets for HSV-1-induced diseases, it is important to understand the HSV-1-host interactions that may influence infection outcome and disease. Our work uncovered direct phosphorylation of the pathogen sensor RIG-I by alphaherpesvirus-encoded kinases as a novel viral immune escape strategy and also underscores the importance of RNA sensors in surveilling DNA virus infection.

scholarly journals GADD45γ Activated Early in the Course of Herpes Simplex Virus 1 Infection Suppresses the Activation of a Network of Innate Immunity Genes

2019 ◽  
Vol 93 (7) ◽  
Author(s):  
Mingmin She ◽  
Haifang Jiang ◽  
Xiaoxiang Chen ◽  
Xiaoqing Chen ◽  
Xianjie Liu ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Significant Loss ◽  
Gene Encoding ◽  
Herpes Simplex Virus 1 ◽  
Immunity Genes ◽  
Simplex Virus ◽  
Preceding Study ◽  
Hsv 1

ABSTRACTThe stress response genes encoding GADD45γ, and to a lesser extent GADD45β, are activated early in infection with herpes simplex virus 1 (HSV-1). Cells that had been depleted of GADD45γ by transfection of short hairpin RNA (shRNA) or in which the gene had been knocked out (ΔGADD45γ) yielded significantly less virus than untreated infected cells. Consistent with lower virus yields, the ΔGADD45γ cells (either uninfected or infected with HSV-1) exhibited significantly higher levels of transcripts of a cluster of innate immunity genes, including those encoding IFI16, IFIT1, MDA5, and RIG-I. Members of this cluster of genes were reported by this laboratory to be activated concurrently with significantly reduced virus yields in cells depleted of LGP2 or HDAC4. We conclude that innate immunity to HSV-1 is normally repressed in unstressed cells and repression appears to be determined by two mechanisms. The first, illustrated here, is through activation by HSV-1 infection of the gene encoding GADD45γ. The second mechanism requires constitutively active expression of LGP2 and HDAC4.IMPORTANCEPrevious studies from our laboratory reported that knockout of some innate immunity genes was associated with increases in the expression of overlapping networks of genes and significant loss of the ability to support the replication of HSV-1; knockout of other genes was associated with decreases in the expression of overlapping networks of genes and had no effect on virus replication. In this report, we document that depletion of GADD45γ reduced virus yields concurrently with significant upregulation of the expression of a cluster of innate immunity genes comprising IFI16, IFIT1, MDA5, and RIG-I. This report differs from the preceding study in an important respect; i.e., the preceding study found no evidence to support the hypothesis that HSV-1 maintained adequate levels of LGP2 or HDAC4 to block upregulation of the cluster of innate immunity genes. We show that HSV-1 causes upregulation of the GADD45γ gene to prevent the upregulation of innate immunity genes.

scholarly journals Role of Herpes Simplex Virus 1 γ34.5 in the Regulation of IRF3 Signaling

2017 ◽  
Vol 91 (23) ◽  
Author(s):  
Richard Manivanh ◽  
Jesse Mehrbach ◽  
David M. Knipe ◽  
David A. Leib
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Binding Domain ◽  
Type I Interferons ◽  
Type I ◽  
Herpes Simplex Virus 1 ◽  
Infection Pattern ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT During viral infection, pattern recognition receptors (PRRs) and their associated adaptors recruit TANK-binding kinase 1 (TBK1) to activate interferon regulatory factor 3 (IRF3), resulting in production of type I interferons (IFNs). ICP0 and ICP34.5 are among the proteins encoded by herpes simplex virus 1 (HSV-1) that modulate type I IFN signaling. We constructed a recombinant virus (ΔXX) that lacks amino acids 87 to 106, a portion of the previously described TBK1-binding domain of the γ34.5 gene (D. Verpooten, Y. Ma, S. Hou, Z. Yan, and B. He, J Biol Chem 284:1097–1105, 2009, https://doi.org/10.1074/JBC.M805905200 ). These 20 residues are outside the γ34.5 beclin1-binding domain (BBD) that interacts with beclin1 and regulates autophagy. Unexpectedly, ΔXX showed no deficit in replication in vivo in a variety of tissues and showed virulence comparable to that of wild-type and marker-rescued viruses following intracerebral infection. ΔXX was fully capable of mediating the dephosphorylation of eIF2α, and the virus was capable of controlling the phosphorylation of IRF3. In contrast, a null mutant in γ34.5 failed to control IRF3 phosphorylation due to an inability of the mutant to sustain expression of ICP0. Our data show that while γ34.5 regulates IRF3 phosphorylation, the TBK1-binding domain itself has no impact on IRF3 phosphorylation or on replication and pathogenesis in mice. IMPORTANCE Interferons (IFNs) are potent activators of a variety of host responses that serve to control virus infections. The Herpesviridae have evolved countermeasures to IFN responses. Herpes simplex virus 1 (HSV-1) encodes the multifunctional neurovirulence protein ICP34.5. In this study, we investigated the biological relevance of the interaction between ICP34.5 and TANK-binding kinase 1 (TBK1), an activator of IFN responses. Here, we establish that although ICP34.5 binds TBK1 under certain conditions through a TBK1-binding domain (TBD), there was no direct impact of the TBD on viral replication or virulence in mice. Furthermore, we showed that activation of IRF3, a substrate of TBK1, was independent of the TBD. Instead, we provided evidence that the ability of ICP34.5 to control IRF3 activation is through its ability to reverse translational shutoff and sustain the expression of other IFN inhibitors encoded by the virus. This work provides new insights into the immunomodulatory functions of ICP34.5.

scholarly journals Interferon Kappa Is Important for Keratinocyte Host Defense against Herpes Simplex Virus-1

2020 ◽  
Vol 2020 ◽  
pp. 1-8 ◽  
Author(s):  
Yuanyuan Li ◽  
Yueqi Song ◽  
Leqing Zhu ◽  
Xiao Wang ◽  
Brittany Richers ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Host Defense ◽  
Expression Level ◽  
Poly I:C ◽  
Epidermal Keratinocytes ◽  
Type I ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
Hsv 1

Type I interferon kappa (IFNκ) is selectively expressed in human keratinocytes. Herpes simplex virus-1 (HSV-1) is a human pathogen that infects keratinocytes and causes lytic skin lesions. Whether IFNκ plays a role in keratinocyte host defense against HSV-1 has not been investigated. In this study, we found that IFNκ mRNA expression was induced by addition of recombinant IFNκ and poly (I:C); and its expression level was significantly greater than IFNa2, IFNb1, and IFNL1 in both undifferentiated and differentiated normal human epidermal keratinocytes (NHEKs) under resting and stimulation conditions. Although IFNe was expressed at a relatively higher level than other IFNs in resting undifferentiated NHEK, its expression level did not change after stimulation with recombinant IFNκ and poly (I:C). HSV-1 infection inhibited gene expression of IFNκ and IFNe in NHEK. Silencing IFNκ in NHEK led to significantly enhanced HSV-1 replication in both undifferentiated and differentiated NHEK compared to scrambled siRNA-transfected cells, while the addition of recombinant IFNκ significantly reduced HSV-1 replication in NHEK. In addition, we found that IFNκ did not regulate protein expression of NHEK differentiation markers. Our results demonstrate that IFNκ is the dominant type of IFNs in keratinocytes and it has an important function for keratinocytes to combat HSV-1 infection.

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