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1.
J Immunol ; 207(11): 2673-2680, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34732469

RESUMO

Stimulator of IFN genes (STING) is a key molecule that binds to cyclic dinucleotides produced by the cyclic GMP-AMP synthase to activate IFN expression and autophagy in the fight against microbial infection. The regulation of STING in the activation of IFN expression has been extensively reported, whereas the regulation of STING in the initiation of autophagy is still insufficiently determined. IFN-inducible guanylate-binding proteins (GBPs) are central to the cell-autonomous immunity in defending a host against viral, bacterial, and protozoan infections. In this study using the Chinese tree shrew (Tupaia belangeri chinensis), which is genetically close to primates, we found that Tupaia GBP1 (tGBP1) combines with Tupaia STING (tSTING), promotes autophagy, and moderately inhibits HSV type 1 (HSV-1) infection. The antiviral effects of tGBP1 are IFN independent. Mechanistically, tGBP1 interacted with tSTING, Tupaia sequestosome 1, and Tupaia microtubule associated protein 1 L chain 3, forming a complex which promotes autophagy in response to HSV-1 infection. This function of tGBP1 against HSV-1 infection was lost in tSTING knockout cells. Overexpression of either tSTING or its mutant tSTING-ΔCTT that can only activate autophagy rescued the anti-HSV-1 activity of tGBP1 in tSTING knockout cells. Our study not only elucidated the underlying mechanism of tGBP1 antiviral activity against HSV-1 infection, but also uncovered the regulation of tSTING in the initiation of autophagy in response to HSV-1 infection.


Assuntos
Autofagia/imunologia , Proteínas de Ligação ao GTP/imunologia , Herpes Simples/imunologia , Herpesvirus Humano 1/imunologia , Animais , Células HEK293 , Humanos , Tupaia
2.
Nat Med ; 27(10): 1789-1796, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34608333

RESUMO

Talimogene laherparepvec (T-VEC) is a herpes simplex virus type 1-based intralesional oncolytic immunotherapy approved for the treatment of unresectable melanoma. The present, ongoing study aimed to estimate the treatment effect of neoadjuvant T-VEC on recurrence-free survival (RFS) of patients with advanced resectable melanoma. An open-label, phase 2 trial (NCT02211131) was conducted in 150 patients with resectable stage IIIB-IVM1a melanoma who were randomized to receive T-VEC followed by surgery (arm 1, n = 76) or surgery alone (arm 2, n = 74). The primary endpoint was a 2-year RFS in the intention-to-treat population. Secondary and exploratory endpoints included overall survival (OS), pathological complete response (pCR), safety and biomarker analyses. The 2-year RFS was 29.5% in arm 1 and 16.5% in arm 2 (overall hazard ratio (HR) = 0.75, 80% confidence interval (CI) = 0.58-0.96). The 2-year OS was 88.9% for arm 1 and 77.4% for arm 2 (overall HR = 0.49, 80% CI = 0.30-0.79). The RFS and OS differences between arms persisted at 3 years. In arm 1, 17.1% achieved a pCR. Increased CD8+ density correlated with clinical outcomes in an exploratory analysis. Arm 1 adverse events were consistent with previous reports for T-VEC. The present study met its primary endpoint and estimated a 25% reduction in the risk of disease recurrence for neoadjuvant T-VEC plus surgery versus upfront surgery for patients with resectable stage IIIB-IVM1a melanoma.


Assuntos
Produtos Biológicos/administração & dosagem , Imunoterapia , Melanoma/terapia , Terapia Neoadjuvante , Adulto , Idoso , Produtos Biológicos/imunologia , Terapia Combinada , Intervalo Livre de Doença , Feminino , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/imunologia , Humanos , Masculino , Melanoma/genética , Melanoma/patologia , Melanoma/virologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Recidiva Local de Neoplasia/virologia , Estadiamento de Neoplasias , Terapia Viral Oncolítica/tendências , Vírus Oncolíticos/genética , Vírus Oncolíticos/imunologia
3.
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
4.
PLoS Pathog ; 17(10): e1009999, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34653236

RESUMO

Ocular HSV-1 infection is a major cause of eye disease and innate and adaptive immunity both play a role in protection and pathology associated with ocular infection. Previously we have shown that M1-type macrophages are the major and earliest infiltrates into the cornea of infected mice. We also showed that HSV-1 infectivity in the presence and absence of M2-macrophages was similar to wild-type (WT) control mice. However, it is not clear whether the absence of M1 macrophages plays a role in protection and disease in HSV-1 infected mice. To explore the role of M1 macrophages in HSV-1 infection, we used mice lacking M1 activation (M1-/- mice). Our results showed that macrophages from M1-/- mice were more susceptible to HSV-1 infection in vitro than were macrophages from WT mice. M1-/- mice were highly susceptible to ocular infection with virulent HSV-1 strain McKrae, while WT mice were refractory to infection. In addition, M1-/- mice had higher virus titers in the eyes than did WT mice. Adoptive transfer of M1 macrophages from WT mice to M1-/- mice reduced death and rescued virus replication in the eyes of infected mice. Infection of M1-/- mice with avirulent HSV-1 strain KOS also increased ocular virus replication and eye disease but did not affect latency-reactivation seen in WT control mice. Severity of virus replication and eye disease correlated with significantly higher inflammatory responses leading to a cytokine storm in the eyes of M1-/- infected mice that was not seen in WT mice. Thus, for the first time, our study illustrates the importance of M1 macrophages specifically in primary HSV-1 infection, eye disease, and survival but not in latency-reactivation.


Assuntos
Síndrome da Liberação de Citocina/imunologia , Ceratite Herpética/imunologia , Macrófagos/imunologia , Animais , Herpesvirus Humano 1/imunologia , Camundongos , Ativação Viral/imunologia , Latência Viral/imunologia
5.
Nat Commun ; 12(1): 5908, 2021 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-34625564

RESUMO

Oncolytic herpes simplex virus-1 is capable of lysing tumor cells while alerting the immune system. CD47, in collaboration with SIRPα, represents an important immune checkpoint to inhibit phagocytosis by innate immune cells. Here we show locoregional control of glioblastoma by an oncolytic herpes virus expressing a full-length anti(α)-human CD47 IgG1 or IgG4 antibody. The antibodies secreted by the virus-infected glioblastoma cells block the CD47 'don't eat me' signal irrespective of the subclass; however, αCD47-IgG1 has a stronger tumor killing effect than αCD47-IgG4 due to additional antibody-dependent cellular phagocytosis by macrophages and antibody-dependent cellular cytotoxicity by NK cells. Intracranially injected αCD47-IgG1-producing virus continuously releases the respective antibody in the tumor microenvironment but not into systemic circulation; additionally, αCD47-IgG1-producing virus also improves the survival of tumor-bearing mice better than control oncolytic herpes virus combined with topical αCD47-IgG1. Results from immunocompetent mouse tumor models further confirm that macrophages, and to a lesser extent NK cells, mediate the anti-tumor cytotoxicity of antibody-producing oncolytic herpesviruses. Collectively, oncolytic herpes simplex virus-1 encoding full-length antibodies could improve immune-virotherapy for glioblastoma.


Assuntos
Anticorpos/farmacologia , Glioblastoma/imunologia , Glioblastoma/terapia , Imunidade Inata , Vírus Oncolíticos/imunologia , Animais , Anticorpos/imunologia , Citotoxicidade Celular Dependente de Anticorpos , Antígeno CD47 , Modelos Animais de Doenças , Feminino , Herpesvirus Humano 1/imunologia , Humanos , Imunoglobulina G , Imunoterapia , Células Matadoras Naturais , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Terapia Viral Oncolítica/métodos , Fagocitose , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
6.
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
7.
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
8.
Viruses ; 13(7)2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34372614

RESUMO

Oncolytic herpes simplex virus (oHSV) is a therapeutic modality that has seen substantial success for the treatment of cancer, though much remains to be improved. Commonly attenuated through the deletion or alteration of the γ134.5 neurovirulence gene, the basis for the success of oHSV relies in part on the malignant silencing of cellular pathways critical for limiting these viruses in healthy host tissue. However, only recently have the molecular mechanisms underlying the success of these treatments begun to emerge. Further clarification of these mechanisms can strengthen rational design approaches to develop the next generation of oHSV. Herein, we review our current understanding of the molecular basis for tumor susceptibility to γ134.5-attenuated oHSV, with particular focus on the malignant suppression of nucleic acid sensing, along with strategies meant to improve the clinical efficacy of these therapeutic viruses.


Assuntos
Herpesvirus Humano 1/fisiologia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/fisiologia , Animais , Citocinas/imunologia , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Camundongos
9.
J Virol ; 95(19): e0103621, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34287036

RESUMO

Previously, we reported that herpes simplex virus type 1 (HSV-1) ICP22 binds to the CD80 promoter and suppresses its expression in vitro and in vivo. To better understand the impact of ICP22 binding to CD80 on HSV-1 infectivity and pathogenicity, we mapped the region of ICP22 required to bind the CD80 promoter to a 40-amino-acid (aa) region of ICP22. We constructed a recombinant HSV-1 expressing a truncated form of ICP22 that lacks these 40 aa, which does not bind to the CD80 promoter (KOS-ICP22Δ40) and retains the ability to replicate efficiently in rabbit skin cells, in contrast to ICP22-null virus. The replication of this recombinant virus in vitro and in vivo was higher than that of the ICP22-null virus, but virus replication kinetics were lower than those of the wild-type (WT) control virus. Similar to ICP22-null virus, the KOS-ICP22Δ40 mutant virus increased CD80 expression in dendritic cells (DCs) and interferon gamma (IFN-γ) expression in CD8+ T cells but not CD4+ T cells in infected mouse corneas. In contrast to the significantly reduced virus replication in the eyes of ocularly infected mice, the levels of latency reactivation were similar between KOS-ICP22Δ40 virus and WT virus. Thus, blocking ICP22 binding to the CD80 promoter using a recombinant virus expressing a truncated ICP22 that lacks CD80 promoter binding appears to reduce virus replication and enhance CD8+IFN-γ+ infiltrates in corneas of infected mice, with no effect on latency reactivation. IMPORTANCE Direct binding of HSV-1 ICP22 to the CD80 promoter downregulates the expression of the costimulatory molecule CD80 but not CD86. In this study, we fine mapped the region of ICP22 required for binding to the CD80 promoter and constructed a recombinant virus containing a deletion in ICP22 that failed to bind to the CD80 promoter. This recombinant virus replicated less efficiently in vitro and in vivo than did the WT control virus, although CD80-expressing CD11c+ cells and IFN-γ-expressing CD8+ T cells were increased. Interestingly, the levels of latency and reactivation in the two viruses were similar despite lower virus replication in the eyes of infected mice. Therefore, blocking the interaction of ICP22 with the CD80 promoter could be used to temper the immune response.


Assuntos
Antígeno B7-1/genética , Herpesvirus Humano 1/fisiologia , Proteínas Imediatamente Precoces/metabolismo , Interferon gama/metabolismo , Ceratite Herpética/virologia , Latência Viral , Animais , Antígeno B7-1/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular , Córnea/imunologia , Córnea/virologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/imunologia , Humanos , Proteínas Imediatamente Precoces/química , Proteínas Imediatamente Precoces/genética , Evasão da Resposta Imune , Interferon gama/genética , Camundongos , Camundongos Endogâmicos BALB C , Regiões Promotoras Genéticas , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Lágrimas/virologia , Regulação para Cima , Ativação Viral , Replicação Viral
10.
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
11.
J Immunol ; 207(2): 613-625, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34272232

RESUMO

Alphaherpesviruses are large dsDNA viruses with an ability to establish persistent infection in hosts, which rely partly on their ability to evade host innate immune responses, notably the type I IFN response. However, the relevant molecular mechanisms are not well understood. In this study, we report the UL42 proteins of alphaherpesvirus pseudorabies virus (PRV) and HSV type 1 (HSV1) as a potent antagonist of the IFN-I-induced JAK-STAT signaling pathway. We found that ectopic expression of UL42 in porcine macrophage CRL and human HeLa cells significantly suppresses IFN-α-mediated activation of the IFN-stimulated response element (ISRE), leading to a decreased transcription and expression of IFN-stimulated genes (ISGs). Mechanistically, UL42 directly interacts with ISRE and interferes with ISG factor 3 (ISGF3) from binding to ISRE for efficient gene transcription, and four conserved DNA-binding sites of UL42 are required for this interaction. The substitution of these DNA-binding sites with alanines results in reduced ISRE-binding ability of UL42 and impairs for PRV to evade the IFN response. Knockdown of UL42 in PRV remarkably attenuates the antagonism of virus to IFN in porcine kidney PK15 cells. Our results indicate that the UL42 protein of alphaherpesviruses possesses the ability to suppress IFN-I signaling by preventing the association of ISGF3 and ISRE, thereby contributing to immune evasion. This finding reveals UL42 as a potential antiviral target.


Assuntos
DNA Polimerase Dirigida por DNA/imunologia , Exodesoxirribonucleases/imunologia , Herpesvirus Suídeo 1/imunologia , Interferon Tipo I/imunologia , Fator Gênico 3 Estimulado por Interferon, Subunidade gama/imunologia , Proteínas Virais/imunologia , Animais , Linhagem Celular , Linhagem Celular Tumoral , Células HEK293 , Células HeLa , Herpesvirus Humano 1/imunologia , Humanos , Evasão da Resposta Imune/imunologia , Imunidade Inata/imunologia , Pseudorraiva/imunologia , Elementos de Resposta/imunologia , Transdução de Sinais/imunologia , Suínos , Transcrição Genética/imunologia
12.
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
13.
Cells ; 10(5)2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-34064516

RESUMO

Sphingolipids are important structural membrane components and, together with cholesterol, are often organized in lipid rafts, where they act as signaling molecules in many cellular functions. They play crucial roles in regulating pathobiological processes, such as cancer, inflammation, and infectious diseases. The bioactive metabolites ceramide, sphingosine-1-phosphate, and sphingosine have been shown to be involved in the pathogenesis of several microbes. In contrast to ceramide, which often promotes bacterial and viral infections (for instance, by mediating adhesion and internalization), sphingosine, which is released from ceramide by the activity of ceramidases, kills many bacterial, viral, and fungal pathogens. In particular, sphingosine is an important natural component of the defense against bacterial pathogens in the respiratory tract. Pathologically reduced sphingosine levels in cystic fibrosis airway epithelial cells are normalized by inhalation of sphingosine, and coating plastic implants with sphingosine prevents bacterial infections. Pretreatment of cells with exogenous sphingosine also prevents the viral spike protein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) from interacting with host cell receptors and inhibits the propagation of herpes simplex virus type 1 (HSV-1) in macrophages. Recent examinations reveal that the bactericidal effect of sphingosine might be due to bacterial membrane permeabilization and the subsequent death of the bacteria.


Assuntos
Infecções Bacterianas/imunologia , Micoses/imunologia , Transdução de Sinais/imunologia , Esfingosina/metabolismo , Viroses/imunologia , Animais , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/metabolismo , Infecções Bacterianas/microbiologia , Parede Celular/efeitos dos fármacos , Ceramidas/metabolismo , Modelos Animais de Doenças , Herpesvirus Humano 1/imunologia , Humanos , Lisofosfolipídeos/metabolismo , Microdomínios da Membrana/imunologia , Microdomínios da Membrana/metabolismo , Micoses/tratamento farmacológico , Micoses/metabolismo , Micoses/microbiologia , SARS-CoV-2/imunologia , Esfingolipídeos/metabolismo , Esfingosina/análogos & derivados , Esfingosina/farmacologia , Esfingosina/uso terapêutico , Viroses/tratamento farmacológico , Viroses/metabolismo , Viroses/virologia
14.
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
15.
Elife ; 102021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-34047696

RESUMO

Neutrophil responses against pathogens must be balanced between protection and immunopathology. Factors that determine these outcomes are not well-understood. In a mouse model of genital herpes simplex virus-2 (HSV-2) infection, which results in severe genital inflammation, antibody-mediated neutrophil depletion reduced disease. Comparative single-cell RNA-sequencing analysis of vaginal cells against a model of genital HSV-1 infection, which results in mild inflammation, demonstrated sustained expression of interferon-stimulated genes (ISGs) only after HSV-2 infection primarily within the neutrophil population. Both therapeutic blockade of IFNα/ß receptor 1 (IFNAR1) and genetic deletion of IFNAR1 in neutrophils concomitantly decreased HSV-2 genital disease severity and vaginal IL-18 levels. Therapeutic neutralization of IL-18 also diminished genital inflammation, indicating an important role for this cytokine in promoting neutrophil-dependent immunopathology. Our study reveals that sustained type I interferon (IFN) signaling is a driver of pathogenic neutrophil responses and identifies IL-18 as a novel component of disease during genital HSV-2 infection.


Assuntos
Herpes Genital/virologia , Herpesvirus Humano 2/patogenicidade , Imunidade nas Mucosas , Interferon Tipo I/metabolismo , Interleucina-18/metabolismo , Membrana Mucosa/virologia , Ativação de Neutrófilo , Neutrófilos/virologia , Vagina/virologia , Animais , Anticorpos/farmacologia , Chlorocebus aethiops , Modelos Animais de Doenças , Feminino , Herpes Genital/imunologia , Herpes Genital/metabolismo , Herpes Genital/prevenção & controle , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 1/patogenicidade , Herpesvirus Humano 2/imunologia , Interações Hospedeiro-Patógeno , Imunidade nas Mucosas/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Membrana Mucosa/efeitos dos fármacos , Membrana Mucosa/inervação , Membrana Mucosa/metabolismo , Ativação de Neutrófilo/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Receptor de Interferon alfa e beta/antagonistas & inibidores , Receptor de Interferon alfa e beta/metabolismo , Transdução de Sinais , Vagina/efeitos dos fármacos , Vagina/imunologia , Vagina/metabolismo , Células Vero
16.
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
17.
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
18.
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
19.
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
20.
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
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