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1.
Nat Commun ; 12(1): 6020, 2021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-34650053

RESUMO

Herpes simplex virus type-1 (HSV-1) causes ocular and orofacial infections. In rare cases, HSV-1 can cause encephalitis, which leads to permanent brain injuries, memory loss or even death. Host factors protect humans from viral infections by activating the immune response. However, factors that confer neuroprotection during viral encephalitis are poorly understood. Here we show that mammalian target of rapamycin complex 2 (mTORC2) is essential for the survival of experimental animals after ocular HSV-1 infection in vivo. We find the loss of mTORC2 causes systemic HSV-1 infection due to defective innate and adaptive immune responses, and increased ocular and neuronal cell death that turns lethal for the infected mice. Furthermore, we find that mTORC2 mediated cell survival channels through the inactivation of the proapoptotic factor FoxO3a. Our results demonstrate how mTORC2 potentiates host defenses against viral infections and implicate mTORC2 as a necessary factor for survival of the infected host.


Assuntos
Imunidade , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Neuroproteção , Viroses/imunologia , Animais , Apoptose , Citocinas , Modelos Animais de Doenças , Olho , Feminino , Herpes Simples/imunologia , Herpesvirus Humano 1/imunologia , Alvo Mecanístico do Complexo 2 de Rapamicina/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
2.
PLoS Pathog ; 17(9): e1009950, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34591940

RESUMO

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.


Assuntos
Herpes Simples/imunologia , Evasão da Resposta Imune/imunologia , Proteínas de Membrana/imunologia , MicroRNAs/imunologia , Animais , Regulação da Expressão Gênica/imunologia , Herpes Simples/metabolismo , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 1/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Celular/imunologia , Proteínas de Membrana/metabolismo , Camundongos
3.
J Gen Virol ; 102(8)2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34406117

RESUMO

Viperin is a gene with a broad spectrum of antiviral functions and various mechanisms of action. The role of viperin in herpes simplex virus type 1 (HSV-1) infection is unclear, with conflicting data in the literature that is derived from a single human cell type. We have addressed this gap by investigating viperin during HSV-1 infection in several cell types, spanning species and including immortalized, non-immortalized and primary cells. We demonstrate that viperin upregulation by HSV-1 infection is cell-type-specific, with mouse cells typically showing greater increases compared with those of human origin. Further, overexpression and knockout of mouse, but not human viperin significantly impedes and increases HSV-1 replication, respectively. In primary mouse fibroblasts, viperin upregulation by infection requires viral gene transcription and occurs in a predominantly IFN-independent manner. Further we identify the N-terminal domain of viperin as being required for the anti-HSV-1 activity. Interestingly, this is the region of viperin that differs most between mouse and human, which may explain the apparent species-specific activity against HSV-1. Finally, we show that HSV-1 virion host shutoff (vhs) protein is a key viral factor that antagonises viperin in mouse cells. We conclude that viperin can be upregulated by HSV-1 in mouse and human cells, and that mouse viperin has anti-HSV-1 activity.


Assuntos
Herpes Simples , Herpesvirus Humano 1/imunologia , Proteínas/fisiologia , Animais , Antivirais/imunologia , Linhagem Celular , Chlorocebus aethiops , Fibroblastos/citologia , Fibroblastos/imunologia , Herpes Simples/imunologia , Herpes Simples/virologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Ribonucleases/imunologia , Proteínas Virais/imunologia
4.
J Immunol ; 207(3): 888-901, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34290105

RESUMO

Because most of animal viruses are enveloped, cytoplasmic entry of these viruses via fusion with cellular membrane initiates their invasion. However, the strategies in which host cells counteract cytoplasmic entry of such viruses are incompletely understood. Pore-forming toxin aerolysin-like proteins (ALPs) exist throughout the animal kingdom, but their functions are mostly unknown. In this study, we report that ßγ-crystallin fused aerolysin-like protein and trefoil factor complex (ßγ-CAT), an ALP and trefoil factor complex from the frog Bombina maxima, directly blocks enveloped virus invasion by interfering with cytoplasmic entry. ßγ-CAT targeted acidic glycosphingolipids on the HSV type 1 (HSV-1) envelope to induce pore formation, as indicated by the oligomer formation of protein and potassium and calcium ion efflux. Meanwhile, ßγ-CAT formed ring-like oligomers of ∼10 nm in diameter on the liposomes and induced dye release from liposomes that mimic viral envelope. Unexpectedly, transmission electron microscopy analysis showed that the ßγ-CAT-treated HSV-1 was visibly as intact as the vehicle-treated HSV-1, indicating that ßγ-CAT did not lyse the viral envelope. However, the cytoplasmic entry of the ßγ-CAT-treated HSV-1 into HeLa cells was totally hindered. In vivo, topical application of ßγ-CAT attenuated the HSV-1 corneal infection in mice. Collectively, these results uncovered that ßγ-CAT possesses the capacity to counteract enveloped virus invasion with its featured antiviral-acting manner. Our findings will also largely help to illustrate the putative antiviral activity of animal ALPs.


Assuntos
Proteínas de Anfíbios/metabolismo , Antivirais/metabolismo , Córnea/patologia , Herpes Simples/imunologia , Herpesvirus Humano 1/fisiologia , Complexos Multiproteicos/metabolismo , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Fatores Trefoil/metabolismo , Proteínas de Anfíbios/genética , Animais , Anuros , Toxinas Bacterianas/genética , Córnea/virologia , Feminino , Células HeLa , Interações Hospedeiro-Patógeno , Humanos , Camundongos , Microscopia Eletrônica de Transmissão , Proteínas Citotóxicas Formadoras de Poros/química , Proteínas Citotóxicas Formadoras de Poros/genética , Envelope Viral/metabolismo , Envelope Viral/ultraestrutura , Internalização do Vírus , gama-Cristalinas/química
5.
PLoS One ; 16(7): e0254129, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34197543

RESUMO

SARS-CoV-2 infection can lead to severe acute respiratory distress syndrome with the need of invasive ventilation. Pulmonary herpes simplex-1 (HSV-1) reactivation in invasively ventilated patients is a known phenomenon. To date very little is known about the frequency and the predisposing factors of HSV-1 reactivation in COVID-19. Therefore, we evaluated our cohort of invasively ventilated COVID-19 patients with severe pneumonia for HSV-1 in respiratory specimens and combined these results with functional immunomonitoring of the peripheral blood. Tracheal secretions and bronchial lavages were screened by PCR for HSV-1 positivity. Comprehensive immunophenotyping and quantitative gene expression analysis of Interferon-stimulated genes (IFI44L, MX1, RSAD2, ISIG15 and IFIT1) and IL-1 beta were performed in whole blood. Time course of infection beginning at symptom onset was grouped into three phases ("early" phase 1: day 1-10, "middle" phase 2: day 11-30 and "late" phase 3: day 31-40). Pulmonary HSV-1 reactivation was exclusively observed in the later phases 2 and 3 in 15 of 18 analyzed patients. By FACS analysis a significant increase in activated CD8 T cells (CD38+HLADR+) in phase 2 was found when compared with phase 1 (p<0.05). Expression of Interferon-stimulated genes (IFI44L, RSAD2 ISIG15, MX1, IFIT1) was significantly lower after HSV-1 detection than before. Taken together, reactivation of HSV-1 in the later phase of SARS-CoV-2- infection occurs in parallel with a drop of antiviral innate responsiveness as shown by decreased expression of Interferon-stimulated genes and a concurrent increase of highly activated CD38+HLADR+ CD8 T cells.


Assuntos
COVID-19/terapia , Herpes Simples/etiologia , Herpesvirus Humano 1/fisiologia , Respiração Artificial , Ativação Viral , Idoso , Idoso de 80 Anos ou mais , COVID-19/complicações , COVID-19/imunologia , Feminino , Herpes Simples/imunologia , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 1/isolamento & purificação , Humanos , Imunidade Inata , Masculino , Pessoa de Meia-Idade , Respiração Artificial/efeitos adversos , SARS-CoV-2/imunologia , SARS-CoV-2/isolamento & purificação
6.
Mol Cell ; 81(15): 3171-3186.e8, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34171297

RESUMO

Accurate control of innate immune responses is required to eliminate invading pathogens and simultaneously avoid autoinflammation and autoimmune diseases. Here, we demonstrate that arginine monomethylation precisely regulates the mitochondrial antiviral-signaling protein (MAVS)-mediated antiviral response. Protein arginine methyltransferase 7 (PRMT7) forms aggregates to catalyze MAVS monomethylation at arginine residue 52 (R52), attenuating its binding to TRIM31 and RIG-I, which leads to the suppression of MAVS aggregation and subsequent activation. Upon virus infection, aggregated PRMT7 is disabled in a timely manner due to automethylation at arginine residue 32 (R32), and SMURF1 is recruited to PRMT7 by MAVS to induce proteasomal degradation of PRMT7, resulting in the relief of PRMT7 suppression of MAVS activation. Therefore, we not only reveal that arginine monomethylation by PRMT7 negatively regulates MAVS-mediated antiviral signaling in vitro and in vivo but also uncover a mechanism by which PRMT7 is tightly controlled to ensure the timely activation of antiviral defense.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Arginina/metabolismo , Interações Hospedeiro-Patógeno/fisiologia , Imunidade Inata/fisiologia , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Animais , Proteína DEAD-box 58/metabolismo , Fibroblastos/virologia , Células HEK293 , Herpes Simples/imunologia , Herpes Simples/metabolismo , Herpes Simples/virologia , Humanos , Metilação , Camundongos , Camundongos Knockout , Alcamidas Poli-Insaturadas , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/imunologia , Receptores Imunológicos/metabolismo , Infecções por Respirovirus/imunologia , Infecções por Respirovirus/metabolismo , Infecções por Respirovirus/virologia , Proteínas com Motivo Tripartido/genética , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
7.
Front Immunol ; 12: 644664, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34135889

RESUMO

Alphaherpesviruses (α-HV) are a large family of double-stranded DNA viruses which cause many human and animal diseases. There are three human α-HVs: Herpes Simplex Viruses (HSV-1 and HSV-2) and Varicella Zoster Virus (VZV). All α-HV have evolved multiple strategies to suppress or exploit host cell innate immune signaling pathways to aid in their infections. All α-HVs initially infect epithelial cells (primary site of infection), and later spread to infect innervating sensory neurons. As with all herpesviruses, α-HVs have both a lytic (productive) and latent (dormant) stage of infection. During the lytic stage, the virus rapidly replicates in epithelial cells before it is cleared by the immune system. In contrast, latent infection in host neurons is a life-long infection. Upon infection of mucosal epithelial cells, herpesviruses immediately employ a variety of cellular mechanisms to evade host detection during active replication. Next, infectious viral progeny bud from infected cells and fuse to neuronal axonal terminals. Here, the nucleocapsid is transported via sensory neuron axons to the ganglion cell body, where latency is established until viral reactivation. This review will primarily focus on how HSV-1 induces various innate immune responses, including host cell recognition of viral constituents by pattern-recognition receptors (PRRs), induction of IFN-mediated immune responses involving toll-like receptor (TLR) signaling pathways, and cyclic GMP-AMP synthase stimulator of interferon genes (cGAS-STING). This review focuses on these pathways along with other mechanisms including autophagy and the complement system. We will summarize and discuss recent evidence which has revealed how HSV-1 is able to manipulate and evade host antiviral innate immune responses both in neuronal (sensory neurons of the trigeminal ganglia) and non-neuronal (epithelial) cells. Understanding the innate immune response mechanisms triggered by HSV-1 infection, and the mechanisms of innate immune evasion, will impact the development of future therapeutic treatments.


Assuntos
Axônios/imunologia , Herpes Simples/imunologia , Herpesvirus Humano 1/imunologia , Evasão da Resposta Imune , Imunidade Inata , Células Receptoras Sensoriais/imunologia , Animais , Herpes Simples/terapia , Humanos , Transdução de Sinais/imunologia
8.
Rheumatology (Oxford) ; 60(Suppl 2): ii24-ii30, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33950230

RESUMO

As efficacy and safety data emerge, differences between JAK inhibitor subclasses are appearing. JAK1 selective drugs, upadacitinib and filgotinib, have broadly come with the same overarching safety recommendations as other immunosuppressive drugs for RA: caution is needed regarding infection risk; monitoring for laboratory abnormalities, including lipids and muscle enzymes, is indicated. A distinguishing feature of JAK inhibitors is a risk for zoster reactivation. Numerically, overall rates of serious infection are similar among JAK inhibitor classes. There are currently no signals for diverticular perforation. VTE incidence rates were similar across comparator groups for the JAK1 selective agents. These observations are not yet conclusive evidence for different safety profiles between JAK1 selective agents and other JAK inhibitors. Differences in study population, design, and concomitant steroid use are examples of potential confounders. It is too early to draw conclusions on long-term outcomes such as malignancy and cardiovascular risk. Post-marketing pharmacovigilance studies will be essential.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Janus Quinase 1/antagonistas & inibidores , Inibidores de Janus Quinases/uso terapêutico , Piridinas/uso terapêutico , Triazóis/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Doenças Diverticulares/epidemiologia , Herpes Simples/epidemiologia , Herpes Simples/imunologia , Herpes Zoster/epidemiologia , Herpes Zoster/imunologia , Humanos , Hospedeiro Imunocomprometido , Infecções/epidemiologia , Infecções/imunologia , Perfuração Intestinal/epidemiologia , Infecção Latente/epidemiologia , Infecção Latente/imunologia , Infecções Oportunistas/epidemiologia , Infecções Oportunistas/imunologia
9.
Front Immunol ; 12: 655637, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33968056

RESUMO

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.


Assuntos
DNA/metabolismo , Interferons/metabolismo , Monoterpenos/farmacologia , Nucleotidiltransferases/metabolismo , Animais , Autoanticorpos/imunologia , Doenças Autoimunes/etiologia , Doenças Autoimunes/metabolismo , Autoimunidade/efeitos dos fármacos , Biomarcadores , DNA/imunologia , Modelos Animais de Doenças , Ativação Enzimática , Herpes Simples/imunologia , Herpes Simples/virologia , Herpesvirus Humano 1/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Camundongos
10.
Nat Commun ; 12(1): 2936, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34006861

RESUMO

Host protection against cutaneous herpes simplex virus 1 (HSV-1) infection relies on the induction of a robust adaptive immune response. Here, we show that Nav1.8+ sensory neurons, which are involved in pain perception, control the magnitude of CD8 T cell priming and expansion in HSV-1-infected mice. The ablation of Nav1.8-expressing sensory neurons is associated with extensive skin lesions characterized by enhanced inflammatory cytokine and chemokine production. Mechanistically, Nav1.8+ sensory neurons are required for the downregulation of neutrophil infiltration in the skin after viral clearance to limit the severity of tissue damage and restore skin homeostasis, as well as for eliciting robust CD8 T cell priming in skin-draining lymph nodes by controlling dendritic cell responses. Collectively, our data reveal an important role for the sensory nervous system in regulating both innate and adaptive immune responses to viral infection, thereby opening up possibilities for new therapeutic strategies.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Herpes Simples/imunologia , Herpesvirus Humano 1/imunologia , Dor Nociceptiva/imunologia , Células Receptoras Sensoriais/imunologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/virologia , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Herpes Simples/genética , Herpes Simples/virologia , Herpesvirus Humano 1/fisiologia , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Canal de Sódio Disparado por Voltagem NAV1.8/genética , Canal de Sódio Disparado por Voltagem NAV1.8/imunologia , Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo , Infiltração de Neutrófilos/imunologia , Dor Nociceptiva/genética , Dor Nociceptiva/metabolismo , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/virologia , Pele/imunologia , Pele/metabolismo , Pele/virologia
11.
Front Immunol ; 12: 662234, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34012447

RESUMO

Herpes simplex virus type 1 (HSV-1) infection is highly prevalent in humans, with approximately two-thirds of the world population living with this virus. However, only a fraction of those carrying HSV-1, which elicits lifelong infections, are symptomatic. HSV-1 mainly causes lesions in the skin and mucosae but reaches the termini of sensory neurons innervating these tissues and travels in a retrograde manner to the neuron cell body where it establishes persistent infection and remains in a latent state until reactivated by different stimuli. When productive reactivations occur, the virus travels back along axons to the primary infection site, where new rounds of replication are initiated in the skin, in recurrent or secondary infections. During this process, new neuron infections occur. Noteworthy, the mechanisms underlying viral reactivations and the exit of latency are somewhat poorly understood and may be regulated by a crosstalk between the infected neurons and components of the immune system. Here, we review and discuss the immune responses that occur at the skin during primary and recurrent infections by HSV-1, as well as at the interphase of latently-infected neurons. Moreover, we discuss the implications of neuronal signals over the priming and migration of immune cells in the context of HSV-1 infection.


Assuntos
Células Epiteliais/metabolismo , Herpes Simples/imunologia , Herpesvirus Humano 1/imunologia , Células Receptoras Sensoriais/metabolismo , Dermatopatias Virais/imunologia , Animais , Técnicas de Cultura de Células , Células Epiteliais/imunologia , Regulação Viral da Expressão Gênica , Herpesvirus Humano 1/genética , Humanos , Camundongos , Células Receptoras Sensoriais/imunologia , Ativação Viral , Latência Viral , Replicação Viral
12.
Nat Commun ; 12(1): 2992, 2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-34016976

RESUMO

Rapid death of infected cells is an important antiviral strategy. However, fast decisions that are based on limited evidence can be erroneous and cause unnecessary cell death and subsequent tissue damage. How cells optimize their death decision making strategy to maximize both speed and accuracy is unclear. Here, we show that exposure to TNF, which is secreted by macrophages during viral infection, causes cells to change their decision strategy from "slow and accurate" to "fast and error-prone". Mathematical modeling combined with experiments in cell culture and whole organ culture show that the regulation of the cell death decision strategy is critical to prevent HSV-1 spread. These findings demonstrate that immune regulation of cellular cognitive processes dynamically changes a tissues' tolerance for self-damage, which is required to protect against viral spread.


Assuntos
Apoptose/imunologia , Herpes Simples/imunologia , Herpesvirus Humano 1/imunologia , Macrófagos/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Córnea/imunologia , Córnea/virologia , Modelos Animais de Doenças , Feminino , Herpes Simples/virologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Microscopia Intravital , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Modelos Imunológicos , Células NIH 3T3 , Técnicas de Cultura de Órgãos , Cultura Primária de Células , Imagem com Lapso de Tempo , Fator de Necrose Tumoral alfa/genética
13.
Sci Rep ; 11(1): 10247, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33986436

RESUMO

Corneal transparency is an essential characteristic necessary for normal vision. In response to microbial infection, the integrity of the cornea can become compromised as a result of the inflammatory response and the ensuing tissue pathology including neovascularization (NV) and collagen lamellae destruction. We have previously found complement activation contributes to cornea pathology-specifically, denervation in response to HSV-1 infection. Therefore, we investigated whether the complement system also played a role in HSV-1-mediated neovascularization. Using wild type (WT) and complement component 3 deficient (C3 KO) mice infected with HSV-1, we found corneal NV was accelerated associated with an increase in inflammatory monocytes (CD11b+CCR2+CD115+/-Ly6G-Ly6Chigh), macrophages (CD11b+CCR2+CD115+Ly6G-Ly6Chigh) and a subpopulation of granulocytes/neutrophils (CD11b+CCR2-CD115+Ly6G+Ly6Clow). There were also increases in select pro-inflammatory and pro-angiogenic factors including IL-1α, matrix metalloproteinases (MMP)-2, MMP-3, MMP-8, CXCL1, CCL2, and VEGF-A that coincided with increased inflammation, neovascularization, and corneal opacity in the C3 KO mice. The difference in inflammation between WT and C3 KO mice was not driven by changes in virus titer. However, viral antigen clearance was hindered in C3 KO mouse corneas suggesting the complement system has a dynamic regulatory role within the cornea once an inflammatory cascade is initiated by HSV-1.


Assuntos
Complemento C3/imunologia , Herpes Simples/imunologia , Herpesvirus Humano 1/fisiologia , Animais , Complemento C3/genética , Complemento C3/metabolismo , Córnea/patologia , Neovascularização da Córnea/patologia , Opacidade da Córnea/patologia , Feminino , Granulócitos/patologia , Herpes Simples/metabolismo , Herpes Simples/veterinária , Herpesvirus Humano 1/metabolismo , Herpesvirus Humano 1/patogenicidade , Infecções/patologia , Inflamação/patologia , Ceratite Herpética/patologia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/imunologia
14.
Mol Immunol ; 135: 28-35, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33857816

RESUMO

Type I interferon (IFN-I) plays pivotal roles in defense against viral infection. HSV-1 has evolved multiple strategies to evade IFN-I antiviral response. In this study, we revealed a new mechanism that HSV-1-encoded ICP0 regulates the host deubiquitinase BRCC36 to inhibit IFN-I antiviral response. We found that HSV-1 infection rapidly downregulates BRCC36 proteins at the early stage of infection. Further studies demonstrated that HSV-1-encoded ICP0 induces K48-linked polyubiquitination and degradation of BRCC36. Importantly, HSV-1-induced BRCC36 degradation promotes downmodulation of IFN-I receptor IFNAR1, thus restricting host IFN-I antiviral response to facilitate HSV-1 early infection. These findings uncover a novel immune evasion mechanism exploited by HSV-1 and could provide potential strategies for anti-HSV-1 therapy.


Assuntos
Enzimas Desubiquitinantes/metabolismo , Herpesvirus Humano 1/imunologia , Proteínas Imediatamente Precoces/metabolismo , Evasão da Resposta Imune/imunologia , Interferon Tipo I/antagonistas & inibidores , Ubiquitina-Proteína Ligases/metabolismo , Animais , Linhagem Celular Tumoral , Chlorocebus aethiops , Regulação para Baixo , Células HEK293 , Células HeLa , Células Hep G2 , Herpes Simples/imunologia , Herpes Simples/terapia , Humanos , Interferon Tipo I/imunologia , Camundongos , Células RAW 264.7 , Receptor de Interferon alfa e beta/metabolismo , Ubiquitinação/fisiologia , Células Vero
15.
J Exp Med ; 218(6)2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-33914023

RESUMO

Tissue-resident memory T cells (TRM cells) are key elements of tissue immunity. Here, we investigated the role of the regulator of T cell receptor and cytokine signaling, Ptpn2, in the formation and function of TRM cells in skin. Ptpn2-deficient CD8+ T cells displayed a marked defect in generating CD69+ CD103+ TRM cells in response to herpes simplex virus type 1 (HSV-1) skin infection. This was accompanied by a reduction in the proportion of KLRG1- memory precursor cells and a transcriptional bias toward terminal differentiation. Of note, forced expression of KLRG1 was sufficient to impede TRM cell formation. Normalizing memory precursor frequencies by transferring equal numbers of KLRG1- cells restored TRM generation, demonstrating that Ptpn2 impacted skin seeding with precursors rather than downstream TRM cell differentiation. Importantly, Ptpn2-deficient TRM cells augmented skin autoimmunity but also afforded superior protection from HSV-1 infection. Our results emphasize that KLRG1 repression is required for optimal TRM cell formation in skin and reveal an important role of Ptpn2 in regulating TRM cell functionality.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/imunologia , Lectinas Tipo C/imunologia , Proteína Tirosina Fosfatase não Receptora Tipo 2/imunologia , Receptores Imunológicos/imunologia , Animais , Autoimunidade/imunologia , Feminino , Herpes Simples/imunologia , Herpesvirus Humano 1/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Pele/imunologia
16.
Cell Host Microbe ; 29(4): 579-593.e5, 2021 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-33857419

RESUMO

How helminths influence the pathogenesis of sexually transmitted viral infections is not comprehensively understood. Here, we show that an acute helminth infection (Nippostrongylus brasiliensis [Nb]) induced a type 2 immune profile in the female genital tract (FGT). This leads to heightened epithelial ulceration and pathology in subsequent herpes simplex virus (HSV)-2 infection. This was IL-5-dependent but IL-4 receptor alpha (Il4ra) independent, associated with increased FGT eosinophils, raised vaginal IL-33, and enhanced epithelial necrosis. Vaginal eosinophil accumulation was promoted by IL-33 induction following targeted vaginal epithelium damage from a papain challenge. Inhibition of IL-33 protected against Nb-exacerbated HSV-2 pathology. Eosinophil depletion reduced IL-33 release and HSV-2 ulceration in Nb-infected mice. These findings demonstrate that Nb-initiated FGT eosinophil recruitment promotes an eosinophil, IL-33, and IL-5 inflammatory circuit that enhances vaginal epithelial necrosis and pathology following HSV-2 infection. These findings identify a mechanistic framework as to how helminth infections can exacerbate viral-induced vaginal pathology.


Assuntos
Eosinófilos/imunologia , Helmintíase/imunologia , Herpes Simples/imunologia , Receptores de Superfície Celular/imunologia , Vagina/imunologia , Doenças Vaginais/imunologia , Animais , Eosinófilos/patologia , Feminino , Helmintíase/complicações , Helmintos , Herpes Simples/complicações , Herpes Simples/patologia , Herpes Simples/virologia , Herpesvirus Humano 2/imunologia , Imunidade , Interleucina-33 , Interleucina-5 , Necrose , Nippostrongylus , Receptores de Superfície Celular/genética , Vagina/patologia , Vagina/virologia , Doenças Vaginais/parasitologia , Doenças Vaginais/virologia
17.
Front Immunol ; 12: 635257, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33679788

RESUMO

Multiple sclerosis (MS) is an increasingly prevalent progressive autoimmune and debilitating chronic disease that involves the detrimental recognition of central nervous system (CNS) antigens by the immune system. Although significant progress has been made in the last decades on the biology of MS and the identification of novel therapies to treat its symptoms, the etiology of this disease remains unknown. However, recent studies have suggested that viral infections may contribute to disease onset. Interestingly, a potential association between herpes simplex virus type 1 (HSV-1) infection and MS has been reported, yet a direct relationship among both has not been conclusively demonstrated. Experimental autoimmune encephalomyelitis (EAE) recapitulates several aspects of MS in humans and is widely used to study this disease. Here, we evaluated the effect of asymptomatic brain infection by HSV-1 on the onset and severity of EAE in C57BL/6 mice. We also evaluated the effect of infection with an HSV-1-mutant that is attenuated in neurovirulence and does not cause encephalitis. Importantly, we observed more severe EAE in mice previously infected either, with the wild-type (WT) or the mutant HSV-1, as compared to uninfected control mice. Also, earlier EAE onset was seen after WT virus inoculation. These findings support the notion that a previous exposure to HSV-1 can accelerate and enhance EAE, which suggests a potential contribution of asymptomatic HSV-1 to the onset and severity of MS.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Herpes Simples/imunologia , Herpesvirus Humano 1/imunologia , Animais , Anticorpos Antivirais/sangue , Doenças Assintomáticas , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/virologia , Permeabilidade Capilar , Citocinas/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/virologia , Feminino , Herpes Simples/genética , Herpes Simples/metabolismo , Herpes Simples/virologia , Herpesvirus Humano 1/patogenicidade , Mediadores da Inflamação/metabolismo , Camundongos Endogâmicos C57BL , Mutação , Índice de Gravidade de Doença , Fatores de Tempo , Virulência
18.
Int J Cancer ; 149(1): 214-227, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33687756

RESUMO

Oncolytic viruses (OVs) remodel the tumor microenvironment by switching a "cold" tumor into a "hot" tumor with high CD8+ T-cell infiltration. CD8+ T-cell activity plays an essential role in the antitumor efficacy of OVs. However, the activity of T cells is impaired by the programmed cell death protein-1/programmed cell death-ligand 1 (PD-1/PD-L1) interaction. To date, it remains unclear why OVs alone have a significant antitumor activity even when PD-L1 expression persists on tumor or immune cells. In this study, we found that canerpaturev (C-REV) treatment significantly suppressed tumor growth, even though it induced a significant increase in PD-L1 expression in tumors in vivo as well as persistence of high PD-L1 expression on antigen-presenting cells (macrophage and dendritic cells [DCs]). Surprisingly, we observed that C-REV treatment increased the abundance of activated CD8+ PD-1- tumor-infiltrating lymphocytes (TILs) in the tumor on both the injected and contralateral sides, although infiltration of CD8+ PD-1high TILs into the tumor was observed in the control group. Moreover, the difference in PD-1 expression was observed only in tumors after treatment with C-REV, whereas most CD8+ T cells in the spleen, tumor-draining lymph nodes and blood were PD-1-negative, and this did not change after C-REV treatment. In addition, changes in expression of T-cell immunoglobulin and mucin-domain containing-3 and T-cell immune-receptor with Ig and ITIM domains were not observed on CD8+ TILs after C-REV treatment. Taken together, our findings may reveal mechanisms that allow OVs to trigger an antitumor immune response, irrespective of a PD-L1-enriched tumor microenvironment, by recruitment of CD8+ PD-1- TILs.


Assuntos
Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Escamosas/imunologia , Herpes Simples/imunologia , Neoplasias Pancreáticas/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Microambiente Tumoral/imunologia , Animais , Antígeno B7-H1/imunologia , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Feminino , Herpes Simples/virologia , Humanos , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Receptor de Morte Celular Programada 1/imunologia , Simplexvirus/fisiologia
19.
Viruses ; 13(3)2021 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-33668777

RESUMO

Tissue-resident memory T cells (TRM) were first described in 2009. While initially the major focus was on CD8+ TRM, there has recently been increased interest in defining the phenotype and the role of CD4+ TRM in diseases. Circulating CD4+ T cells seed CD4+ TRM, but there also appears to be an equilibrium between CD4+ TRM and blood CD4+ T cells. CD4+ TRM are more mobile than CD8+ TRM, usually localized deeper within the dermis/lamina propria and yet may exhibit synergy with CD8+ TRM in disease control. This has been demonstrated in herpes simplex infections in mice. In human recurrent herpes infections, both CD4+ and CD8+ TRM persisting between lesions may control asymptomatic shedding through interferon-gamma secretion, although this has been more clearly shown for CD8+ T cells. The exact role of the CD4+/CD8+ TRM axis in the trigeminal ganglia and/or cornea in controlling recurrent herpetic keratitis is unknown. In HIV, CD4+ TRM have now been shown to be a major target for productive and latent infection in the cervix. In HSV and HIV co-infections, CD4+ TRM persisting in the dermis support HIV replication. Further understanding of the role of CD4+ TRM and their induction by vaccines may help control sexual transmission by both viruses.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/imunologia , Herpes Simples/imunologia , Memória Imunológica/imunologia , Animais , Coinfecção/imunologia , Coinfecção/virologia , Infecções por HIV/virologia , Herpes Simples/virologia , Humanos
20.
J Clin Invest ; 131(9)2021 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-33784252

RESUMO

Tissue-based T cells are important effectors in the prevention and control of mucosal viral infections; less is known about tissue-based B cells. We demonstrate that B cells and antibody-secreting cells (ASCs) are present in inflammatory infiltrates in skin biopsy specimens from study participants during symptomatic herpes simplex virus 2 (HSV-2) reactivation and early healing. Both CD20+ B cells, most of which are antigen inexperienced based on their coexpression of IgD, and ASCs - characterized by dense IgG RNA expression in combination with CD138, IRF4, and Blimp-1 RNA - were found to colocalize with T cells. ASCs clustered with CD4+ T cells, suggesting the potential for crosstalk. HSV-2-specific antibodies to virus surface antigens were also present in tissue and increased in concentration during HSV-2 reactivation and healing, unlike in serum, where concentrations remained static over time. B cells, ASCs, and HSV-specific antibody were rarely detected in biopsies of unaffected skin. Evaluation of samples from serial biopsies demonstrated that B cells and ASCs followed a more migratory than resident pattern of infiltration in HSV-affected genital skin, in contrast to T cells. Together, these observations suggest the presence of distinct phenotypes of B cells in HSV-affected tissue; dissecting their role in reactivation may reveal new therapeutic avenues to control these infections.


Assuntos
Anticorpos Antivirais/imunologia , Linfócitos B/imunologia , Herpes Simples/imunologia , Herpesvirus Humano 2/fisiologia , Imunoglobulina D/imunologia , Imunoglobulina G/imunologia , Pele/imunologia , Ativação Viral/imunologia , Adulto , Linfócitos B/patologia , Linfócitos T CD4-Positivos , Feminino , Herpes Simples/patologia , Humanos , Masculino , Pele/patologia , Pele/virologia
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