The immune response to Herpes simplex virus 1 in patients with atopic dermatitis is hallmarked by Th2/Tc2 T cells

ABSTRACTWe previously reported that MORC3, a protein associated with promyelocytic leukemia nuclear bodies (PML NBs), is a target of herpes simplex virus 1 (HSV-1) ICP0-mediated degradation (E. Sloan, et al., PLoS Pathog11:e1005059, 2015,http://dx.doi.org/10.1371/journal.ppat.1005059). Since it is well known that certain other components of the PML NB complex play an important role during an intrinsic immune response to HSV-1 and are also degraded or inactivated by ICP0, here we further investigate the role of MORC3 during HSV-1 infection. We demonstrate that MORC3 has antiviral activity during HSV-1 infection and that this antiviral role is counteracted by ICP0. In addition, MORC3's antiviral role extends to wild-type (wt) human cytomegalovirus (HCMV) infection, as its plaque-forming efficiency increased in MORC3-depleted cells. We found that MORC3 is recruited to sites associated with HSV-1 genomes after their entry into the nucleus of an infected cell, and in wt infections this is followed by its association with ICP0 foci prior to its degradation. The RING finger domain of ICP0 was required for degradation of MORC3, and we confirmed that no other HSV-1 protein is required for the loss of MORC3. We also found that MORC3 is required for fully efficient recruitment of PML, Sp100, hDaxx, and γH2AX to sites associated with HSV-1 genomes entering the host cell nucleus. This study further unravels the intricate ways in which HSV-1 has evolved to counteract the host immune response and reveals a novel function for MORC3 during the host intrinsic immune response.IMPORTANCEHerpesviruses have devised ways to manipulate the host intrinsic immune response to promote their own survival and persistence within the human population. One way in which this is achieved is through degradation or functional inactivation of PML NB proteins, which are recruited to viral genomes in order to repress viral transcription. Because MORC3 associates with PML NBs in uninfected cells and is a target for HSV-1-mediated degradation, we investigated the role of MORC3 during HSV-1 infection. We found that MORC3 is also recruited to viral HSV-1 genomes, and importantly it contributes to the fully efficient recruitment of PML, hDaxx, Sp100, and γH2AX to these sites. Depletion of MORC3 resulted in an increase in ICP0-null HSV-1 and wt HCMV replication and plaque formation; therefore, this study reveals that MORC3 is an antiviral factor which plays an important role during HSV-1 and HCMV infection.

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Herpes simplex virus 1 evades cellular antiviral response by inducing microRNA-24, which attenuates STING synthesis

PLoS Pathogens ◽

10.1371/journal.ppat.1009950 ◽

2021 ◽

Vol 17 (9) ◽

pp. e1009950

Author(s):

Nikhil Sharma ◽

Chenyao Wang ◽

Patricia Kessler ◽

Ganes C. Sen

Keyword(s):

Immune Response ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

Virus Replication ◽

Map Kinases ◽

Nodal Point ◽

Type I ◽

Herpes Simplex Virus 1 ◽

Antiviral Immune Response ◽

Simplex Virus

STING is a nodal point for cellular innate immune response to microbial infections, autoimmunity and cancer; it triggers the synthesis of the antiviral proteins, type I interferons. Many DNA viruses, including Herpes Simplex Virus 1 (HSV1), trigger STING signaling causing inhibition of virus replication. Here, we report that HSV1 evades this antiviral immune response by inducing a cellular microRNA, miR-24, which binds to the 3’ untranslated region of STING mRNA and inhibits its translation. Expression of the gene encoding miR-24 is induced by the transcription factor AP1 and activated by MAP kinases in HSV1-infected cells. Introduction of exogenous miR-24 or prior activation of MAPKs, causes further enhancement of HSV1 replication in STING-expressing cells. Conversely, transfection of antimiR-24 inhibits virus replication in those cells. HSV1 infection of mice causes neuropathy and death; using two routes of infection, we demonstrated that intracranial injection of antimiR-24 alleviates both morbidity and mortality of the infected mice. Our studies reveal a new immune evasion strategy adopted by HSV1 through the regulation of STING and demonstrates that it can be exploited to enhance STING’s antiviral action.

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Interleukin-12- and Gamma Interferon-Dependent Innate Immunity Are Essential and Sufficient for Long-Term Survival of Passively Immunized Mice Infected with Herpes Simplex Virus Type 1

Journal of Virology ◽

10.1128/jvi.75.20.9596-9600.2001 ◽

2001 ◽

Vol 75 (20) ◽

pp. 9596-9600 ◽

Cited By ~ 26

Author(s):

Sabine Vollstedt ◽

Marco Franchini ◽

Gottfried Alber ◽

Mathias Ackermann ◽

Mark Suter

Keyword(s):

Immune Response ◽

T Cells ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

Herpes Simplex Virus Type ◽

Interleukin 12 ◽

Type I ◽

Ifn Γ ◽

Simplex Virus ◽

Hsv 1

ABSTRACT Interferon (IFN) type I (alpha/beta IFN [IFN-α/β]) is very important in directly controlling herpes simplex virus type I (HSV-1) replication as well as in guiding and upregulating specific immunity against this virus. By contrast, the roles of IFN type II (IFN-γ) and antibodies in the defense against HSV-1 are not clear. Mice without a functional IFN system and no mature B and T cells (AGR mice) did not survive HSV-1 infection in the presence or absence of neutralizing antibodies to the virus. Mice without a functional IFN type I system and with no mature B and T cells (AR129 mice) were unable to control infection with as little as 10 PFU of HSV-1 strain F. By contrast, in the presence of passively administered neutralizing murine antibodies to HSV-1, some AR129 mice survived infection with up to104PFU of HSV-1. This acute immune response was dependent on the presence of interleukin-12 (IL-12) p75. Interestingly, some virus-infected mice stayed healthy for several months, at which time antibody to HSV-1 was no longer detectable. Treatment of these virus-exposed mice with dexamethasone led to death in approximately 40% of the mice. HSV-1 was found in brains of mice that did not survive dexamethasone treatment, whereas HSV-1 was absent in those that survived the treatment. We conclude that in the presence of passively administered HSV-1-specific antibodies, the IL-12-induced IFN-γ-dependent innate immune response is able to control low doses of virus infection. Surprisingly, in a significant proportion of these mice, HSV-1 appears to persist in the absence of antibodies and specific immunity.

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Latent Herpes Simplex Virus 1 Infection Does Not Induce Apoptosis in Human Trigeminal Ganglia

Journal of Virology ◽

10.1128/jvi.03481-14 ◽

2015 ◽

Vol 89 (10) ◽

pp. 5747-5750 ◽

Cited By ~ 2

Author(s):

Susanne Himmelein ◽

Anja Lindemann ◽

Inga Sinicina ◽

Michael Strupp ◽

Thomas Brandt ◽

...

Keyword(s):

T Cells ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

Caspase 3 ◽

Trigeminal Ganglia ◽

Herpes Simplex Virus 1 ◽

Reverse Transcription Quantitative Pcr ◽

Latently Infected ◽

Simplex Virus ◽

Hsv 1

Herpes simplex virus 1 (HSV-1) can establish lifelong latency in human trigeminal ganglia. Latently infected ganglia contain CD8+T cells, which secrete granzyme B and are thus capable of inducing neuronal apoptosis. Using immunohistochemistry and single-cell reverse transcription-quantitative PCR (RT-qPCR), higher frequency and transcript levels of caspase-3 were found in HSV-1-negative compared to HSV-1-positive ganglia and neurons, respectively. No terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) assay-positive neurons were detected. The infiltrating T cells do not induce apoptosis in latently infected neurons.

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Natural Killer Cells as Novel Helpers in Anti-Herpes Simplex Virus Immune Response

Journal of Virology ◽

10.1128/jvi.00365-08 ◽

2008 ◽

Vol 82 (21) ◽

pp. 10820-10831 ◽

Cited By ~ 34

Author(s):

Subhadra Nandakumar ◽

Stacie N. Woolard ◽

Dorothy Yuan ◽

Barry T. Rouse ◽

Uday Kumaraguru

Keyword(s):

Immune Response ◽

T Cells ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

Nk Cells ◽

Nk Cell ◽

Adaptive Immune Response ◽

T Cell Response ◽

Simplex Virus

ABSTRACT Innate defenses help to eliminate infection, but some of them also play a major role in shaping the magnitude and efficacy of the adaptive immune response. With regard to influencing subsequent adaptive immunity, NK cells aided by dendritic cells may be the most relevant components of the innate reaction to herpes simplex virus (HSV) infection. We confirm that mice lacking or depleted of NK cells are susceptible to HSV-induced lesions. The quantity and quality of CD8+ cytotoxic T lymphocytes generated in the absence of NK cells were diminished, thereby contributing to susceptibility to HSV-induced encephalitis. We demonstrate a novel helper role for NK cells, in that NK cells compensate for the loss of CD4 helper T cells and NK cell supplementation enhances the function of wild type anti-HSV CD8 T cells. In addition, NK cells were able to partially rescue the dysfunctional CD8+ T cells generated in the absence of CD4 T helper cells, thereby performing a novel rescue function. Hence, NK cells may well be exploited for enhancing and rescuing the T-cell response in situations where the CD4 helper response is affected.

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122 Ex vivo infection of skin from atopic dermatitis patients reveals facilitated invasion of herpes simplex virus 1

Journal of Investigative Dermatology ◽

10.1016/j.jid.2021.08.125 ◽

2021 ◽

Vol 141 (10) ◽

pp. S169

Author(s):

M. Möckel ◽

D. Knebel-Mörsdorf

Keyword(s):

Atopic Dermatitis ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

Ex Vivo ◽

Herpes Simplex Virus 1 ◽

Simplex Virus

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Species-Specific Deamidation of RIG-I Reveals Collaborative Action between Viral and Cellular Deamidases in HSV-1 Lytic Replication

mBio ◽

10.1128/mbio.00115-21 ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Huichao Huang ◽

Jun Zhao ◽

Ting-Yu Wang ◽

Shu Zhang ◽

Yuzheng Zhou ◽

...

Keyword(s):

Immune Response ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

Host Defense ◽

Immune Evasion ◽

Herpes Simplex Virus 1 ◽

Species Specific ◽

Simplex Virus ◽

Phosphoribosylpyrophosphate Amidotransferase ◽

Hsv 1

ABSTRACT Retinoic acid-inducible gene I (RIG-I) is a sensor that recognizes cytosolic double-stranded RNA derived from microbes to induce host immune response. Viruses, such as herpesviruses, deploy diverse mechanisms to derail RIG-I-dependent innate immune defense. In this study, we discovered that mouse RIG-I is intrinsically resistant to deamidation and evasion by herpes simplex virus 1 (HSV-1). Comparative studies involving human and mouse RIG-I indicate that N495 of human RIG-I dictates species-specific deamidation by HSV-1 UL37. Remarkably, deamidation of the other site, N549, hinges on that of N495, and it is catalyzed by cellular phosphoribosylpyrophosphate amidotransferase (PPAT). Specifically, deamidation of N495 enables RIG-I to interact with PPAT, leading to subsequent deamidation of N549. Collaboration between UL37 and PPAT is required for HSV-1 to evade RIG-I-mediated antiviral immune response. This work identifies an immune regulatory role of PPAT in innate host defense and establishes a sequential deamidation event catalyzed by distinct deamidases in immune evasion. IMPORTANCE Herpesviruses are ubiquitous pathogens in human and establish lifelong persistence despite host immunity. The ability to evade host immune response is pivotal for viral persistence and pathogenesis. In this study, we investigated the evasion, mediated by deamidation, of species-specific RIG-I by herpes simplex virus 1 (HSV-1). Our findings uncovered a collaborative and sequential action between viral deamidase UL37 and a cellular glutamine amidotransferase, phosphoribosylpyrophosphate amidotransferase (PPAT), to inactivate RIG-I and mute antiviral gene expression. PPAT catalyzes the rate-limiting step of the de novo purine synthesis pathway. This work describes a new function of cellular metabolic enzymes in host defense and viral immune evasion.

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