Cellular Localization of the Herpes Simplex Virus ICP0 Protein Dictates Its Ability to Block IRF3-Mediated Innate Immune Responses

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.

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Impact of Increased Immunoglobulin E to Anti-herpes Simplex Virus -1 Innate Immune Responses in Atopic Dermatitis Patients With Eczema Herpeticum

Case Medical Research ◽

10.31525/ct1-nct04060550 ◽

2019 ◽

Author(s):

Keyword(s):

Atopic Dermatitis ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

Immune Responses ◽

Immunoglobulin E ◽

Innate Immune ◽

Innate Immune Responses ◽

Herpes Simplex Virus 1 ◽

Eczema Herpeticum ◽

Simplex Virus

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Role of Specific Innate Immune Responses in Herpes Simplex Virus Infection of the Central Nervous System

Journal of Virology ◽

10.1128/jvi.06010-11 ◽

2011 ◽

Vol 86 (4) ◽

pp. 2273-2281 ◽

Cited By ~ 68

Author(s):

J. P. Wang ◽

G. N. Bowen ◽

S. Zhou ◽

A. Cerny ◽

A. Zacharia ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Herpes Simplex ◽

Immune Responses ◽

Herpes Simplex Virus Infection ◽

Innate Immune ◽

Innate Immune Responses ◽

The Central Nervous System ◽

Simplex Virus

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Perillaldehyde Inhibition of cGAS Reduces dsDNA-Induced Interferon Response

Frontiers in Immunology ◽

10.3389/fimmu.2021.655637 ◽

2021 ◽

Vol 12 ◽

Author(s):

Lei Chu ◽

Chenhui Li ◽

Yongxing Li ◽

Qiuya Yu ◽

Huansha Yu ◽

...

Keyword(s):

Innate Immunity ◽

Herpes Simplex ◽

Immune Responses ◽

Therapeutic Benefit ◽

Perilla Frutescens ◽

Innate Immune ◽

Interferon Response ◽

Innate Immune Responses ◽

Simplex Virus

Cyclic GMP-AMP synthase (cGAS), serving as a primary sensor of intracellular DNA, is essential to initiate anti-microbial innate immunity. Inappropriate activation of cGAS by self-DNA promotes severe autoinflammatory diseases such as Aicardi–Goutières syndrome (AGS); thus, inhibition of cGAS may provide therapeutic benefit in anti-autoimmunity. Here we report that perillaldehyde (PAH), a natural monoterpenoid compound derived from Perilla frutescens, suppresses cytosolic-DNA-induced innate immune responses by inhibiting cGAS activity. Mice treated with PAH are more susceptible to herpes simplex virus type 1 (HSV-1) infection. Moreover, administration with PAH markedly ameliorates self-DNA-induced autoinflammatory responses in a mouse model of AGS. Collectively, our study reveals that PAH can effectively inhibit cGAS-STING signaling and could be developed toward the treatment of cGAS-mediated autoimmune diseases.

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Ankyrin repeat domain 1 regulates innate immune responses against herpes simplex virus 1: A potential role in eczema herpeticum

Journal of Allergy and Clinical Immunology ◽

10.1016/j.jaci.2018.01.001 ◽

2018 ◽

Vol 141 (6) ◽

pp. 2085-2093.e1 ◽

Cited By ~ 7

Author(s):

Lianghua Bin ◽

Xiaozhao Li ◽

Brittany Richers ◽

Joanne E. Streib ◽

Jack W. Hu ◽

...

Keyword(s):

Herpes Simplex ◽

Immune Responses ◽

Potential Role ◽

Innate Immune ◽

Innate Immune Responses ◽

Herpes Simplex Virus 1 ◽

Eczema Herpeticum ◽

Repeat Domain ◽

Ankyrin Repeat Domain ◽

Simplex Virus

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Increased Cell-Mediated Immune Responses in Patients with Recurrent Herpes Simplex Virus Type 2 Meningitis

Clinical and Vaccine Immunology ◽

10.1128/cvi.00333-10 ◽

2011 ◽

Vol 18 (4) ◽

pp. 655-660 ◽

Cited By ~ 9

Author(s):

Elisabeth Franzen-Röhl ◽

Danika Schepis ◽

Maria Lagrelius ◽

Kristina Franck ◽

Petra Jones ◽

...

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

T Cell ◽

Dendritic Cell ◽

Immune Responses ◽

Herpes Simplex Virus Type ◽

Nk Cell ◽

Innate Immune ◽

Simplex Virus

ABSTRACTThe clinical picture of herpes simplex virus type 2 (HSV-2) infection includes genital blisters and less frequently meningitis, and some individuals suffer from recurrent episodes of these manifestations. We hypothesized that adaptive and/or innate immune functional deficiencies may be a major contributing factor in susceptibility to recurrent HSV-2 meningitis. Ten patients with recurrent HSV-2 meningitis were studied during clinical remission. For comparison, 10 patients with recurrent genital HSV infections as well as 21 HSV-seropositive and 19 HSV-seronegative healthy blood donors were included. HSV-specific T cell blasting and cytokine secretion were evaluated in whole blood cultures. HSV-2-induced NK cell gamma interferon production, dendritic cell Toll-like receptor (TLR) expression, and TLR agonist-induced alpha interferon secretion were analyzed. Patients with recurrent HSV-2 meningitis had elevated T cell blasting and Th1 and Th2 cytokine production in response to HSV antigens compared to those of patients with recurrent genital infections. A somewhat increased NK cell response, increased dendritic cell expression of TLR3 and -9, and increased TLR-induced alpha interferon responses were also noted. Contrary to our expectation, recurrent HSV-2 meningitis patients have increased HSV-specific adaptive and innate immune responses, raising the possibility of immune-mediated pathology in the development of recurrent HSV2 meningitis.

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Faculty Opinions recommendation of Reduced immune responses after vaccination with a recombinant herpes simplex virus type 1 vector in the presence of antiviral immunity.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.724408935.793546289 ◽

2018 ◽

Author(s):

Moriya Tsuji ◽

Jordana Reis

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Immune Responses ◽

Virus Type ◽

Herpes Simplex Virus Type ◽

Antiviral Immunity ◽

Simplex Virus

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

Scientific Reports ◽

10.1038/s41598-020-77725-4 ◽

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.

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The Effect of Herpes Simplex Virus-Type-1 (HSV-1) Oncolytic Immunotherapy on the Tumor Microenvironment

Viruses ◽

10.3390/v13071200 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1200

Author(s):

Ifeanyi Kingsley Uche ◽

Konstantin G. Kousoulas ◽

Paul J. F. Rider

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Tumor Microenvironment ◽

Immune Responses ◽

Virus Type ◽

Herpes Simplex Virus Type ◽

Checkpoint Inhibitors ◽

Significant Proportion ◽

Simplex Virus

The development of cancer causes disruption of anti-tumor immunity required for surveillance and elimination of tumor cells. Immunotherapeutic strategies aim for the restoration or establishment of these anti-tumor immune responses. Cancer immunotherapies include immune checkpoint inhibitors (ICIs), adoptive cellular therapy (ACT), cancer vaccines, and oncolytic virotherapy (OVT). The clinical success of some of these immunotherapeutic modalities, including herpes simplex virus type-1 derived OVT, resulted in Food and Drug Administration (FDA) approval for use in treatment of human cancers. However, a significant proportion of patients do not respond or benefit equally from these immunotherapies. The creation of an immunosuppressive tumor microenvironment (TME) represents an important barrier preventing success of many immunotherapeutic approaches. Mechanisms of immunosuppression in the TME are a major area of current research. In this review, we discuss how oncolytic HSV affects the tumor microenvironment to promote anti-tumor immune responses. Where possible we focus on oncolytic HSV strains for which clinical data is available, and discuss how these viruses alter the vasculature, extracellular matrix and immune responses in the tumor microenvironment.

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