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1.
Infect Genet Evol ; 96: 105136, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34775078

RESUMO

Sexually transmitted diseases (STDs) have a profound effect on reproductivity and sexual health worldwide. According to world health organization (WHO) 375 million new case of STD, including chlamydia trachomatis (chlamydia), Neisseria gonorrhoeae, HSV, HPV has been reported in 2016. More than 30 diverse pathogenesis have identified to be transmitted through sexual intercourse. Of these, viral infections (hepatitis B, herpes simplex virus (HSV or herpes), HIV, and human papillomavirus (HPV) are incurable. However, symptoms caused by the incurable viral infections can be alleviated through treatment. Antimicrobial resistance (AMR) of sexually transmitted infections (STIs) to antibiotics has increased recent years, in this regard, vaccination is proposed as an important strategy for prevention or treatment of STDs. Vaccine against HPV 16 and 18 suggests a new approach for controlling STDs but until now, there is no prophylactic or therapeutic vaccine have been approved for HSV-2 and Chlamydia trachomatis (CT); in this reason, developing an efficient vaccine is inevitable. Recently, different combinatorial forms of subunit vaccines against two or three type of bacteria have been designed. In this study, to design a combinatorial vaccine against HSV, CT, and HPV, the E7 and L2 from HPV, glycoprotein D from HSV-2 and ompA from CT were selected as final antigens. Afterward, the immunodominant helper T lymphocytes (HTLs) and cytolytic T lymphocytes (CTLs) epitopes were chosen from aforesaid antigens. P30 (tetanus toxoid epitope) as universal T-helper were also added to the vaccine. Moreover, flagellin D1/D0 as TLR5 agonist and the RS09 as a TLR4 ligand were incorporated to N and C-terminals of peptide vaccine, respectively. Finally, all selected parts were fused together by appropriate linkers to enhance vaccine efficiency. The physicochemical, structural, and immunological properties of the designed vaccine protein were assessed. To achieve the best 3D model of the protein vaccine, modeling, refinement, and validation of modeled structures were also done. Docking evaluation demonstrated suitable interaction between the vaccine and TLR5. Moreover, molecular dynamics (MD) studies showed an appropriate and stable structure of protein and TLR5. Based on immunoinformatic analysis, our vaccine candidate could potentially incite humoral and cellular immunities, which are critical for protection against HPV, HSV-2, and chlamydia trachomatis. It should be noted that, experimental studies are needed to confirm the efficacy of the designed vaccine.


Assuntos
Vacinas Bacterianas/imunologia , Chlamydia trachomatis/imunologia , Herpesvirus Humano 2/imunologia , Papillomaviridae/imunologia , Doenças Sexualmente Transmissíveis/prevenção & controle , Vacinas Virais/imunologia , Infecções por Chlamydia/prevenção & controle , Epitopos de Linfócito B/imunologia , Herpes Simples/prevenção & controle , Humanos , Infecções por Papillomavirus/prevenção & controle , Vacinas de Subunidades/imunologia
2.
J Clin Invest ; 131(23)2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34618692

RESUMO

Nucleoside-modified mRNA vaccines have gained global attention because of COVID-19. We evaluated a similar vaccine approach for preventing a chronic, latent genital infection rather than an acute respiratory infection. We used animal models to compare an HSV-2 trivalent nucleoside-modified mRNA vaccine with the same antigens prepared as proteins, with an emphasis on antigen-specific memory B cell responses and immune correlates of protection. In guinea pigs, serum neutralizing-antibody titers were higher at 1 month and declined far less by 8 months in mRNA- compared with protein-immunized animals. Both vaccines protected against death and genital lesions when infected 1 month after immunization; however, protection was more durable in the mRNA group compared with the protein group when infected after 8 months, an interval representing greater than 15% of the animal's lifespan. Serum and vaginal neutralizing-antibody titers correlated with protection against infection, as measured by genital lesions and vaginal virus titers 2 days after infection. In mice, the mRNA vaccine generated more antigen-specific memory B cells than the protein vaccine at early times after immunization that persisted for up to 1 year. High neutralizing titers and robust B cell immune memory likely explain the more durable protection by the HSV-2 mRNA vaccine.


Assuntos
Herpes Genital , Herpesvirus Humano 2/imunologia , Memória Imunológica , RNA Viral/imunologia , Vacinas Sintéticas/imunologia , Vacinas Virais/imunologia , Animais , COVID-19/imunologia , COVID-19/prevenção & controle , Modelos Animais de Doenças , Feminino , Cobaias , Herpes Genital/imunologia , Herpes Genital/prevenção & controle , SARS-CoV-2/imunologia
3.
Front Immunol ; 12: 724618, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34484233

RESUMO

Herpes simplex virus type 2 (HSV-2) infection is one of the most prevalent sexually transmitted infections that disproportionately impacts women worldwide. Currently, there are no vaccines or curative treatments, resulting in life-long infection. The mucosal environment of the female reproductive tract (FRT) is home to a complex array of local immune defenses that must be carefully coordinated to protect against genital HSV-2 infection, while preventing excessive inflammation to prevent disease symptoms. Crucial to the defense against HSV-2 infection in the FRT are three classes of highly related and integrated cytokines, type I, II, and III interferons (IFN). These three classes of cytokines control HSV-2 infection and reduce tissue damage through a combination of directly inhibiting viral replication, as well as regulating the function of resident immune cells. In this review, we will examine how interferons are induced and their critical role in how they shape the local immune response to HSV-2 infection in the FRT.


Assuntos
Herpes Genital/imunologia , Herpesvirus Humano 2/imunologia , Interferons/imunologia , Animais , Feminino , Humanos , Imunidade nas Mucosas , Camundongos , Membrana Mucosa/virologia
4.
Front Immunol ; 12: 735643, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34552595

RESUMO

Tissue-resident-memory T cells (TRM) populate the body's barrier surfaces, functioning as frontline responders against reencountered pathogens. Understanding of the mechanisms by which CD8TRM achieve effective immune protection remains incomplete in a naturally recurring human disease. Using laser capture microdissection and transcriptional profiling, we investigate the impact of CD8TRM on the tissue microenvironment in skin biopsies sequentially obtained from a clinical cohort of diverse disease expression during herpes simplex virus 2 (HSV-2) reactivation. Epithelial cells neighboring CD8TRM display elevated and widespread innate and cell-intrinsic antiviral signature expression, largely related to IFNG expression. Detailed evaluation via T-cell receptor reconstruction confirms that CD8TRM recognize viral-infected cells at the specific HSV-2 peptide/HLA level. The hierarchical pattern of core IFN-γ signature expression is well-conserved in normal human skin across various anatomic sites, while elevation of IFI16, TRIM 22, IFITM2, IFITM3, MX1, MX2, STAT1, IRF7, ISG15, IFI44, CXCL10 and CCL5 expression is associated with HSV-2-affected asymptomatic tissue. In primary human cells, IFN-γ pretreatment reduces gene transcription at the immediate-early stage of virus lifecycle, enhances IFI16 restriction of wild-type HSV-2 replication and renders favorable kinetics for host protection. Thus, the adaptive immune response through antigen-specific recognition instructs innate and cell-intrinsic antiviral machinery to control herpes reactivation, a reversal of the canonical thinking of innate activating adaptive immunity in primary infection. Communication from CD8TRM to surrounding epithelial cells to activate broad innate resistance might be critical in restraining various viral diseases.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Células Epiteliais/imunologia , Herpes Genital/imunologia , Herpesvirus Humano 2/imunologia , Imunidade Inata , Memória Imunológica , Pele/imunologia , Imunidade Adaptativa/genética , Adulto , Idoso , Antígenos Virais/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/virologia , Células Cultivadas , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Feminino , Perfilação da Expressão Gênica , Herpes Genital/genética , Herpes Genital/metabolismo , Herpes Genital/virologia , Herpesvirus Humano 2/patogenicidade , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata/genética , Interferon gama/genética , Interferon gama/metabolismo , Masculino , /virologia , Pessoa de Meia-Idade , Fenótipo , Pele/metabolismo , Pele/virologia , Transcriptoma
5.
Viruses ; 13(8)2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34452501

RESUMO

Diseases caused by human herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) affect millions of people worldwide and range from fatal encephalitis in neonates and herpes keratitis to orofacial and genital herpes, among other manifestations. The viruses can be shed efficiently by asymptomatic carriers, causing increased rates of infection. Viral transmission occurs through direct contact of mucosal surfaces followed by initial replication of the incoming virus in skin tissues. Subsequently, the viruses infect sensory neurons in the trigeminal and lumbosacral dorsal root ganglia, where they are primarily maintained in a transcriptionally repressed state termed "latency", which persists for the lifetime of the host. HSV DNA has also been detected in other sympathetic ganglia. Periodically, latent viruses can reactivate, causing ulcerative and often painful lesions primarily at the site of primary infection and proximal sites. In the United States, recurrent genital herpes alone accounts for more than a billion dollars in direct medical costs per year, while there are much higher costs associated with the socio-economic aspects of diseased patients, such as loss of productivity due to mental anguish. Currently, there are no effective FDA-approved vaccines for either prophylactic or therapeutic treatment of human herpes simplex infections, while several recent clinical trials have failed to achieve their endpoint goals. Historically, live-attenuated vaccines have successfully combated viral diseases, including polio, influenza, measles, and smallpox. Vaccines aimed to protect against the devastation of smallpox led to the most significant achievement in medical history: the eradication of human disease by vaccination. Recently, novel approaches toward developing safe and effective live-attenuated vaccines have demonstrated high efficacy in various preclinical models of herpetic disease. This next generation of live-attenuated vaccines has been tailored to minimize vaccine-associated side effects and promote effective and long-lasting immune responses. The ultimate goal is to prevent or reduce primary infections (prophylactic vaccines) or reduce the frequency and severity of disease associated with reactivation events (therapeutic vaccines). These vaccines' "rational" design is based on our current understanding of the immunopathogenesis of herpesviral infections that guide the development of vaccines that generate robust and protective immune responses. This review covers recent advances in the development of herpes simplex vaccines and the current state of ongoing clinical trials in pursuit of an effective vaccine against herpes simplex virus infections and associated diseases.


Assuntos
Herpes Simples/prevenção & controle , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 2/imunologia , Vacinas Atenuadas/administração & dosagem , Vacinas Virais/administração & dosagem , Animais , Desenho de Fármacos , Herpes Simples/imunologia , Herpes Simples/virologia , Herpesvirus Humano 1/genética , Herpesvirus Humano 2/genética , Humanos , Vacinas Atenuadas/imunologia , Vacinas Virais/imunologia
6.
J Reprod Immunol ; 146: 103342, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34102513

RESUMO

This study evaluated the impact of the TLR7 Gln11Leu (rs179008) and TLR9 -1237 T/C (rs5743836) single nucleotide polymorphisms (SNPs) on susceptibility to placental infections and pregnancy complications in 455 Brazilian women. Demographic, socioeconomic, gynecological, and clinical characteristics of the women were collected. Placental tissues were sampled from pregnant women and human and viral DNA was extracted. Human alphaherpesvirus 1 (Herpes simplex virus type 1, HSV-1), Human alphaherpesvirus 2 (Herpes simplex virus type 2, HSV-2) and Human betaherpesvirus 5 (Human cytomegalovirus, HCMV) were detected by nested PCR. TLR9 and TLR7 SNPs were genotyped by PCR amplification of bi-directional specific alleles (Bi-PASA) and restriction fragment length polymorphism (RFLP), respectively. Infections at the time of birth were detected in 45.71 % of women. The presence of the TT genotype (recessive model) of the TLR7 SNP was associated with increased susceptibility to HSV-1 infection (O.R. = 2.23, p = 0.05). The presence of the C allele of the TLR9 SNP, in heterozygosis or homozygosis (dominant model), decreased the infection risk by HCMV (O.R. = 0.31, p-mod<0.05). The TT genotype (recessive model) of the TLR7 SNP was significantly associated (p < 0.05) with increased occurrence of pre-treated hypertension. The codominant model of the TLR9 SNP was significantly associated (p < 0.05) with reduced risk of hospitalization during pregnancy. In combination, the AA/CT (TLR7-TLR9) genotypes significantly decreased the risk of placental infection by HSV-1 and/or HSV-2 (O.R. = 0.47, p = 0.02), the susceptibility to all infectious agents considered in combination (O.R. = 0.4, p = 0.00), and the need of hospitalization (O.R. = 0.48, p = 0.02). In conclusion, TLR7 and TLR9 SNPs are potential modulating factors for the risk of placental infections and pregnancy complications.


Assuntos
Infecções por Citomegalovirus/genética , Herpes Simples/genética , Complicações Infecciosas na Gravidez/genética , Receptor 7 Toll-Like/genética , Receptor Toll-Like 9/genética , Adolescente , Adulto , Alelos , Brasil , Estudos de Casos e Controles , Citomegalovirus/imunologia , Citomegalovirus/isolamento & purificação , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/virologia , Epistasia Genética/imunologia , Feminino , Predisposição Genética para Doença , Herpes Simples/imunologia , Herpes Simples/virologia , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 1/isolamento & purificação , Herpesvirus Humano 2/imunologia , Herpesvirus Humano 2/isolamento & purificação , Humanos , Placenta/imunologia , Placenta/virologia , Polimorfismo de Fragmento de Restrição , Polimorfismo de Nucleotídeo Único , Gravidez , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/virologia , Estudos Retrospectivos , Adulto Jovem
7.
JCI Insight ; 6(15)2021 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-34156975

RESUMO

The ectocervix is part of the lower female reproductive tract (FRT), which is susceptible to sexually transmitted infections (STIs). Comprehensive knowledge of the phenotypes and T cell receptor (TCR) repertoire of tissue-resident memory T cells (TRMs) in the human FRT is lacking. We took single-cell RNA-Seq approaches to simultaneously define gene expression and TCR clonotypes of the human ectocervix. There were significantly more CD8+ than CD4+ T cells. Unsupervised clustering and trajectory analysis identified distinct populations of CD8+ T cells with IFNGhiGZMBloCD69hiCD103lo or IFNGloGZMBhiCD69medCD103hi phenotypes. Little overlap was seen between their TCR repertoires. Immunofluorescence staining showed that CD103+CD8+ TRMs were preferentially localized in the epithelium, whereas CD69+CD8+ TRMs were distributed evenly in the epithelium and stroma. Ex vivo assays indicated that up to 14% of cervical CD8+ TRM clonotypes were HSV-2 reactive in HSV-2-seropositive persons, reflecting physiologically relevant localization. Our studies identified subgroups of CD8+ TRMs in the human ectocervix that exhibited distinct expression of antiviral defense and tissue residency markers, anatomic locations, and TCR repertoires that target anatomically relevant viral antigens. Optimization of the location, number, and function of FRT TRMs is an important approach for improving host defenses to STIs.


Assuntos
Antígenos CD/análise , Antígenos de Diferenciação de Linfócitos T/análise , Linfócitos T CD8-Positivos/imunologia , Colo do Útero , Herpesvirus Humano 2 , Cadeias alfa de Integrinas/análise , Lectinas Tipo C/análise , Imunidade Adaptativa , Linfócitos T CD4-Positivos/imunologia , Colo do Útero/imunologia , Colo do Útero/patologia , Colo do Útero/virologia , Feminino , Genes Codificadores dos Receptores de Linfócitos T/imunologia , Herpesvirus Humano 2/imunologia , Herpesvirus Humano 2/isolamento & purificação , Humanos , Memória Imunológica , Imunofenotipagem/métodos , Membrana Mucosa/imunologia , Membrana Mucosa/patologia , Membrana Mucosa/virologia
8.
J Immunol ; 206(12): 2937-2948, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34088770

RESUMO

Tissue-resident memory CD8 T cells (CD8 TRM) are critical for maintaining barrier immunity. CD8 TRM have been mainly studied in the skin, lung and gut, with recent studies suggesting that the signals that control tissue residence and phenotype are highly tissue dependent. We examined the T cell compartment in healthy human cervicovaginal tissue (CVT) and found that most CD8 T cells were granzyme B+ and TCF-1- To address if this phenotype is driven by CVT tissue residence, we used a mouse model to control for environmental factors. Using localized and systemic infection models, we found that CD8 TRM in the mouse CVT gradually acquired a granzyme B+, TCF-1- phenotype as seen in human CVT. In contrast to CD8 TRM in the gut, these CD8 TRM were not stably maintained regardless of the initial infection route, which led to reductions in local immunity. Our data show that residence in the CVT is sufficient to progressively shape the size and function of its CD8 TRM compartment.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Colo do Útero/imunologia , Herpes Simples/imunologia , Vagina/imunologia , Adulto , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Colo do Útero/efeitos dos fármacos , Colo do Útero/virologia , Feminino , Herpes Simples/tratamento farmacológico , Herpes Simples/virologia , Herpesvirus Humano 2/efeitos dos fármacos , Herpesvirus Humano 2/imunologia , Humanos , Injeções Subcutâneas , Acetato de Medroxiprogesterona/administração & dosagem , Acetato de Medroxiprogesterona/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Vagina/efeitos dos fármacos , Vagina/virologia , Adulto Jovem
9.
Sex Transm Infect ; 97(7): 490-500, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34088792

RESUMO

OBJECTIVE: To characterise epidemiology of herpes simplex virus type 2 (HSV-2) in Latin America and the Caribbean. METHODS: HSV-2 reports were systematically reviewed and synthesised, and findings were reported following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Meta-analyses and metaregressions were conducted. FINDING: 102 relevant reports were identified including 13 overall incidence measures, 163 overall (and 402 stratified) seroprevalence measures, and 7 and 10 proportions of virus detection in genital ulcer disease and in genital herpes, respectively. Pooled mean seroprevalence was 20.6% (95% CI 18.7% to 22.5%) in general populations, 33.3% (95% CI 26.0% to 41.0%) in intermediate-risk populations, 74.8% (95% CI 70.6% to 78.8%) in female sex workers, and 54.6% (95% CI 47.4% to 61.7%) in male sex workers, men who have sex with men and transgender people. In general populations, seroprevalence increased from 9.6% (95% CI 7.1% to 12.4%) in those aged <20 years to 17.9% (95% CI 13.6% to 22.5%) in those aged 20-30, 27.6% (95% CI 21.4% to 34.2%) in those aged 30-40 and 38.4% (95% CI 32.8% to 44.2%) in those aged >40. Compared with women, men had lower seroprevalence with an adjusted risk ratio (ARR) of 0.68 (95% CI 0.60 to 0.76). Seroprevalence declined by 2% per year over the last three decades (ARR of 0.98, 95% CI 0.97 to 0.99). Pooled mean proportions of HSV-2 detection in GUD and genital herpes were 41.4% (95% CI 18.9% to 67.0%) and 91.1% (95% CI 82.7% to 97.2%), respectively. CONCLUSIONS: One in five adults is HSV-2 infected, a higher level than other world regions, but seroprevalence is declining. Despite this decline, HSV-2 persists as the aetiological cause of nearly half of GUD cases and almost all of genital herpes cases.


Assuntos
Herpes Genital/epidemiologia , Herpesvirus Humano 2/imunologia , Região do Caribe/epidemiologia , Feminino , Herpes Genital/imunologia , Herpesvirus Humano 2/patogenicidade , Homossexualidade Masculina/estatística & dados numéricos , Humanos , América Latina/epidemiologia , Masculino , Razão de Chances , Análise de Regressão , Fatores de Risco , Estudos Soroepidemiológicos , Profissionais do Sexo/estatística & dados numéricos , Comportamento Sexual
10.
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.


Herpes simplex virus (HSV) is a human pathogen that causes genital herpes, an incurable disease that results in recurrent sores and inflammation. Infection with HSV induces a strong antiviral immune response, which results in large numbers of immune cells arriving at these lesions. But while some of these cells help to control viral replication, others might contribute to the inflammation that drives the disease. One of the first immune cells to respond to infection are neutrophils. Although neutrophils are generally protective, especially against bacteria and fungi, they have also been implicated in tissue damage and severe inflammation during viral infections. But what determines whether a neutrophil will help to fight off an infection or increase disease severity is still an open question. To investigate this, Lebratti, Lim et al. studied mice that had been infected with the genital herpes virus HSV-2, which is known to cause significant amounts of inflammation in mice. The experiments revealed that a signaling molecule called type I interferon, which is thought to be antiviral, causes neutrophils at the site of the infection to produce proteins, such as IL-18, which trigger an inflammatory reaction. Lebratti, Lim et al. found that type I interferon and IL-18 had shifting roles during the course of infection. In the early stages, both molecules had a protective effect, confirming results from previous studies. However, as the infection progressed, sustained levels of type I interferon signaling in neutrophils led to excess amounts of IL-18. Lebratti, Lim et al. discovered that blocking interferon signaling or decreasing the levels of IL-18 later during infection unexpectedly reduced the severity of the disease and resulted in less genital tissue damage. Further experiments also showed that mice infected with another genital herpes virus called HSV-1 did not experience sustained levels of type I interferon. This may explain why this virus causes less severe disease in mice. Understanding how the immune system reacts to viruses could reveal new targets for treatments of genital herpes. At the moment, there is little information about IL-18 production during genital herpes in humans. So, the next step is to see whether neutrophils behave in the same way and whether IL-18 can be detected during human disease. It is possible that the same immune components could promote disease in other infections too. If so, this work may help uncover new drug targets for other viral diseases.


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
11.
J Immunol ; 206(12): 2852-2861, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34049972

RESUMO

NF-κB plays a crucial role in regulating cell proliferation, inflammation, apoptosis, and immune responses. HSV type 2 (HSV-2) is one of the most predominant sexually transmitted pathogens worldwide, and its infection increases the risk of HIV type 1 (HIV-1) acquisition and transmission. HSV-2 glycoprotein D (gD), highly homologous to HSV-1 gD, is essential for viral adhesion, fusion, entry, and spread. It is known that HSV-1 gD can bind herpesvirus entry mediator (HVEM) to trigger NF-κB activation and thereby facilitate viral replication at the early stage of infection. In this study, we found that purified HSV-2 gD triggered NF-κB activation at the early stage of infection, whereas ectopic expression of HSV-2 gD significantly downregulated TNF-α-induced NF-κB activity as well as TNF-α-induced IL-6 and IL-8 expression. Mechanistically, HSV-2 gD inhibited NF-κB, but not IFN-regulatory factor 3 (IRF3), activation and suppressed NF-κB activation mediated by overexpression of TNFR-associated factor 2 (TRAF2), IκB kinase α (IKKα), IKKß, or p65. Coimmunoprecipitation and binding kinetic analyses demonstrated that HSV-2 gD directly bound to the NF-κB subunit p65 and abolished the nuclear translocation of p65 upon TNF-α stimulation. Mutational analyses further revealed that HSV-2 gD interacted with the region spanning aa 19-187 of p65. Findings in this study together demonstrate that HSV-2 gD interacts with p65 to regulate p65 subcellular localization and thereby prevents NF-κB-dependent gene expression, which may contribute to HSV-2 immune evasion and pathogenesis.


Assuntos
Herpesvirus Humano 2/imunologia , Fator de Transcrição RelA/imunologia , Proteínas do Envelope Viral/imunologia , Células HEK293 , Células HeLa , Humanos
12.
J Immunother Cancer ; 9(4)2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33837053

RESUMO

BACKGROUND: OH2 is a genetically engineered oncolytic herpes simplex virus type 2 designed to selectively amplify in tumor cells and express granulocyte-macrophage colony-stimulating factor to enhance antitumor immune responses. We investigated the safety, tolerability and antitumor activity of OH2 as single agent or in combination with HX008, an anti-programmed cell death protein 1 antibody, in patients with advanced solid tumors. METHODS: In this multicenter, phase I/II trial, we enrolled patients with standard treatment-refractory advanced solid tumors who have injectable lesions. In phase I, patients received intratumoral injection of OH2 at escalating doses (106, 107 and 108CCID50/mL) as single agent or with fixed-dose HX008. The recommended doses were then expanded in phase II. Primary endpoints were safety and tolerability defined by the maximum-tolerated dose and dose-limiting toxicities (DLTs) in phase I, and antitumor activity assessed per Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) and immune-RECIST in phase II. RESULTS: Between April 17, 2019 and September 22, 2020, 54 patients with metastatic cancers were enrolled. Forty patients were treated with single agent OH2, and 14 with OH2 plus HX008. No DLTs were reported with single agent OH2 in phase I. Four patients, having metastatic mismatch repair-proficient rectal cancer or metastatic esophageal cancer, achieved immune-partial response, with two from the single agent cohort and two from the combination cohort. The duration of response were 11.25+ and 14.03+ months for the two responders treated with single agent OH2, and 1.38+ and 2.56+ months for the two responders in the combination cohort. The most common treatment-related adverse event (TRAE) with single agent OH2 was fever (n=18, 45.0%). All TRAEs were of grade 1-2, except one case of grade 3 fever in the 108CCID50/mL group. No treatment-related serious AEs occurred. Single agent OH2 induced alterations in the tumor microenvironment, with clear increases in CD3+ and CD8+ cell density and programmed death-ligand 1 expression in the patients' post-treatment biopsies relative to baseline. CONCLUSIONS: Intratumoral injection of OH2 was well-tolerated, and demonstrated durable antitumor activity in patients with metastatic esophageal and rectal cancer. Further clinical development of OH2 as single agent or with immune checkpoint inhibitors in selected tumor types is warranted.


Assuntos
Herpesvirus Humano 2/patogenicidade , Neoplasias/terapia , Terapia Viral Oncolítica , Vírus Oncolíticos/patogenicidade , Adulto , Idoso , China , Terapia Combinada , Feminino , Herpesvirus Humano 2/genética , Herpesvirus Humano 2/imunologia , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Masculino , Pessoa de Meia-Idade , Neoplasias/imunologia , Neoplasias/virologia , Terapia Viral Oncolítica/efeitos adversos , Vírus Oncolíticos/genética , Vírus Oncolíticos/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Critérios de Avaliação de Resposta em Tumores Sólidos , Fatores de Tempo , Resultado do Tratamento
13.
mSphere ; 6(2)2021 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-33910988

RESUMO

Potent systemic immunity is important for recalled mucosal immune responses, but in the defense against mucosal viral infections, it usually remains low at mucosal sites. Based on our previous findings that enhanced immune responses can be achieved by immunization with an immunogen in combination with a molecular adjuvant, here we designed chemokine-antigen (Ag) fusion constructs (CCL19- or CCL28-herpes simplex virus 2 glycoprotein D [HSV-2 gD]). After intramuscular (i.m.) immunization with different DNA vaccines in a prime and boost strategy, BALB/c mice were challenged with a lethal dose of HSV-2 through the genital tract. Ag-specific immune responses and chemokine receptor-specific lymphocytes were analyzed to determine the effects of CCL19 and CCL28 in strengthening humoral and cellular immunity. Both CCL19 and CCL28 were efficient in inducing long-lasting HSV-2 gD-specific systemic immunity. Compared to CCL19, less CCL28 was required to elicit HSV-2 gD-specific serum IgA responses, Th1- and Th2-like responses of immunoglobulin (Ig) subclasses and cytokines, and CCR3+ T cell enrichment (>8.5-fold) in spleens. These findings together demonstrate that CCL28 tends to assist an immunogen to induce more potently protective immunity than CCL19. This work provides information for the application potential of a promising vaccination strategy against mucosal infections caused by HSV-2 and other sexually transmitted viruses.IMPORTANCE An effective HSV-2 vaccine should induce antigen (Ag)-specific immune responses against viral mucosal infection. This study reveals that chemokine CCL19 or CCL28 enhanced HSV-2 glycoprotein D ectodomain (gD-306aa)-induced immune responses against vaginal virus challenge. In addition to eliciting robust humoral immune responses, the chemokine-Ag fusion construct also induced Th1- and Th2-like immune responses characterized by the secretion of multiple Ig subclasses and cytokines that were able to be recalled after HSV-2 challenge, while CCL28 appeared to be more effective than CCL19 in promoting gD-elicited immune responses as well as the migration of T cells to secondary lymph tissues. Of importance, both CCL19 and CCL28 significantly facilitated gD to induce protective mucosal immune responses in the genital tract. The above-described findings together highlight the potential of CCL19 or CCL28 in combination with gD as a vaccination strategy to control HSV-2 infection.


Assuntos
Anticorpos Antivirais/sangue , Quimiocina CCL19/imunologia , Quimiocinas CC/imunologia , Vacinas contra o Vírus do Herpes Simples/imunologia , Herpesvirus Humano 2/genética , Herpesvirus Humano 2/imunologia , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/imunologia , Adjuvantes Imunológicos/administração & dosagem , Animais , Quimiocina CCL19/genética , Quimiocinas CC/genética , Feminino , Vacinas contra o Vírus do Herpes Simples/administração & dosagem , Vacinas contra o Vírus do Herpes Simples/classificação , Imunidade nas Mucosas , Memória Imunológica , Camundongos , Camundongos Endogâmicos BALB C , Vacinação/métodos , Vagina/imunologia , Vagina/virologia
14.
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
15.
J Infect Dis ; 224(9): 1509-1519, 2021 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-33718970

RESUMO

Previous herpes simplex virus type 2 (HSV-2) vaccines have not prevented genital herpes. Concerns have been raised about the choice of antigen, the type of antibody induced by the vaccine, and whether antibody is present in the genital tract where infection occurs. We reported results of a trial of an HSV-2 replication-defective vaccine, HSV529, that induced serum neutralizing antibody responses in 78% of HSV-1-/HSV-2- vaccine recipients. Here we show that HSV-1-/HSV-2- vaccine recipients developed antibodies to epitopes of several viral proteins; however, fewer antibody epitopes were detected in vaccine recipients compared with naturally infected persons. HSV529 induced antibodies that mediated HSV-2-specific natural killer (NK) cell activation. Depletion of glycoprotein D (gD)-binding antibody from sera reduced neutralizing titers by 62% and NK cell activation by 81%. HSV-2 gD antibody was detected in cervicovaginal fluid at about one-third the level of that in serum. A vaccine that induces potent serum antibodies transported to the genital tract might reduce HSV genital infection.


Assuntos
Anticorpos Antivirais/sangue , Herpes Genital/prevenção & controle , Vacinas contra o Vírus do Herpes Simples/administração & dosagem , Herpes Simples/prevenção & controle , Herpesvirus Humano 2/imunologia , Proteínas do Envelope Viral/imunologia , Vacinas Virais/administração & dosagem , Epitopos , Vacinas contra o Vírus do Herpes Simples/imunologia , Herpesvirus Humano 1/imunologia , Humanos , Imunização
16.
J Acquir Immune Defic Syndr ; 87(2): 789-793, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33587502

RESUMO

BACKGROUND: Herpes simplex virus type-2 (HSV-2) seropositive persons have a 3- to 5-fold higher risk of acquiring HIV, possibly because of HSV-2-induced inflammation and recruitment of susceptible immune cells to exposure sites. We hypothesized that cervical HSV-2 activation (ie, viral DNA shedding and/or ulcers) preceded HIV acquisition in the hormonal contraception and HIV cohort. METHODS: Zimbabwean women who acquired HIV were matched to HIV-negative women on visit, age, and bacterial sexually transmitted infections. Up to 5 cervical swabs bracketing first polymerase chain reaction detection of HIV DNA (the index visit) were selected (t-6months, t-3months, tindex, t+3months, t+6months). Women with HSV-2 immunoglobulin G+ before tindex were polymerase chain reaction tested for viral shedding. Self-reported and clinician-diagnosed ulcers were documented. Multivariable logistic regression, accounting for matching, estimated adjusted odds ratios (aOR) and 95% confidence intervals (CIs) at each visit. RESULTS: Of 387 HSV-2 seropositive women, most had prevalent as compared with incident HSV-2 (91% vs. 9%, respectively). HSV-2 viral shedding was more common among HIV seroconverters than HIV-negative women (26% vs. 14%, P < 0.01). Shedding occurred around HIV acquisition (t-3months aOR, 2.7; 95% CI, 0.8 to 8.8; tindex aOR, 2.6; 95% CI, 1.1 to 6.5; t+3months aOR, 2.6; 95% CI, 1.0 to 6.6). Genital ulcers were reported more often among HIV seroconverters than HIV-negative women (13% vs. 7%; P = 0.06) and detection was after HIV acquisition (t+6months aOR, 14.5; 95% CI, 1.6 to 133.9). CONCLUSIONS: HSV-2 shedding appeared synergistic with HIV acquisition followed by presentation of ulcers. Evaluating all sexually transmitted infections rather than HSV-2 alone may clarify the relationship between inflammation and HIV acquisition.


Assuntos
Anticorpos Antivirais/sangue , Infecções por HIV/epidemiologia , Herpes Genital/epidemiologia , Eliminação de Partículas Virais , Adolescente , Adulto , Feminino , Soropositividade para HIV/sangue , HIV-1/imunologia , Herpesvirus Humano 2/imunologia , Humanos , Úlcera/diagnóstico , Úlcera/virologia , Adulto Jovem , Zimbábue/epidemiologia
17.
Sex Transm Infect ; 97(6): 461-464, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-32938706

RESUMO

OBJECTIVE: Female sex workers (FSWs) are vulnerable to human alphaherpesvirus 2 (HSV-2) infection due to their high numbers of sexual partners. The objective of this study was to evaluate the seroprevalence and risk behaviours associated with HSV-2. METHODS: A cross-sectional study was conducted in Mato Grosso do Sul, Brazil. A total of 376 FSWs were recruited by respondent-driven sampling (RDS) methodology and answered an epidemiological questionnaire. Blood samples were collected to test for HSV-2 antibodies using commercial ELISA and for HSV-2 DNA using real-time PCR. RESULTS: The seropositivity was 47.3% (178/376) for HSV-2 IgG and 10.1% (38/376) for HSV-2 IgM. HSV-2 viraemia was detected in two infected FSWs with primary infections. In bivariate and multivariate analyses, the OR for HSV-2 IgG increased with age (OR=2.53-7.90, OR=2.66-6.37) and the number of sexual partners (OR=2.30-3.25). On the other hand, daily alcohol consumption (OR=0.10) and the use of condoms during the last intercourse (OR=0.47) were protective factors against HSV-2 acquisition. CONCLUSION: Despite the impact of FSWs in public health policies with the dissemination of sexually transmitted infections, there have been few studies performed regarding the prevalence of HSV-2 in Brazil, making it difficult to implement any control or preventative measures. The results produced here using an RDS methodology demonstrated a high prevalence, risk behaviours and primary infection among the FSWs. These results reinforce the need to implement control and preventative measures for HSV-2 infection in this population.


Assuntos
Herpesvirus Humano 2/imunologia , Profissionais do Sexo/estatística & dados numéricos , Doenças Sexualmente Transmissíveis/epidemiologia , Doenças Sexualmente Transmissíveis/imunologia , Adulto , Brasil/epidemiologia , Estudos Transversais , Feminino , Herpesvirus Humano 2/genética , Herpesvirus Humano 2/isolamento & purificação , Humanos , Prevalência , Fatores de Risco , Assunção de Riscos , Estudos Soroepidemiológicos , Comportamento Sexual/estatística & dados numéricos , Doenças Sexualmente Transmissíveis/sangue , Doenças Sexualmente Transmissíveis/virologia , Inquéritos e Questionários , Adulto Jovem
18.
J Med Virol ; 93(6): 3383-3388, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33174631

RESUMO

Pregnant women are an important group to be monitored for infection due to the risk of transmitting infections to their babies. Both herpes simples virus (HSV) and Zika virus (ZIKV) are neurotropic viruses that can be transmitted congenitally. In this study, the prevalence and risk factors of HSV among Zika-positive and -negative pregnant women from Rio de Janeiro, Brazil, were evaluated and compared. About 167 serum samples included in our study were from pregnant women with ZIKV infection symptoms, who were attended to in different hospitals in Rio de Janeiro between November 2015 to February 2016. Blood samples collected from 167 pregnant women were used for this study. The presence of HSV antibodies and viremia were evaluated by commercial ELISA and quantitative real-time polymerase chain reaction analyses, respectively. The data obtained from medical records were statistically analyzed. The HSV-1 and HSV-2 prevalence among pregnant women was 80.2% and 12.5% for Zika-positive women and 84.5% and 5.6% for Zika-negative women, respectively. None of the pregnant women exhibited HSV viremia. Age, trimester of gestation, and skin color were associated with HSV-1 and HSV-2 prevalence among the groups studied. HSV-2 was more prevalent in Zika-positive pregnant women than in Zika-negative pregnant women, and this simultaneous infection should be better investigated in future studies.


Assuntos
Anticorpos Antivirais/sangue , Herpes Simples/epidemiologia , Herpes Simples/imunologia , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 2/imunologia , Infecção por Zika virus/epidemiologia , Adolescente , Adulto , Brasil/epidemiologia , Criança , Coinfecção/sangue , Coinfecção/epidemiologia , Coinfecção/imunologia , Coinfecção/virologia , Feminino , Herpes Simples/sangue , Humanos , Gravidez , Complicações Infecciosas na Gravidez/epidemiologia , Complicações Infecciosas na Gravidez/virologia , Gestantes , Prevalência , Fatores de Risco , Estudos Soroepidemiológicos , Adulto Jovem , Zika virus/fisiologia , Infecção por Zika virus/sangue
19.
Front Immunol ; 12: 764861, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35069537

RESUMO

Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) infections are life-long and highly prevalent in the human population. These viruses persist in the host, eliciting either symptomatic or asymptomatic infections that may occur sporadically or in a recurrent manner through viral reactivations. Clinical manifestations due to symptomatic infection may be mild such as orofacial lesions, but may also translate into more severe diseases, such as ocular infections that may lead to blindness and life-threatening encephalitis. A key feature of herpes simplex viruses (HSVs) is that they have evolved molecular determinants that hamper numerous components of the host's antiviral innate and adaptive immune system. Importantly, HSVs infect and negatively modulate the function of dendritic cells (DCs), by inhibiting their T cell-activating capacity and eliciting their apoptosis after infection. Previously, we reported that HSV-2 activates the splicing of the mRNA of XBP1, which is related to the activity of the unfolded protein response (UPR) factor Inositol-Requiring Enzyme 1 alpha (IRE-1α). Here, we sought to evaluate if the activation of the IRE-1α pathway in DCs upon HSV infection may be related to impaired DC function after infection with HSV-1 or HSV-2. Interestingly, the pharmacological inhibition of the endonuclease activity of IRE-1α in HSV-1- and HSV-2-infected DCs significantly reduced apoptosis in these cells and enhanced their capacity to migrate to lymph nodes and activate virus-specific CD4+ and CD8+ T cells. These findings suggest that the activation of the IRE-1α-dependent UPR pathway in HSV-infected DCs may play a significant role in the negative effects that these viruses exert over these cells and that the modulation of this signaling pathway may be relevant for enhancing the function of DCs upon infection with HSVs.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Endorribonucleases/antagonistas & inibidores , Herpes Genital/imunologia , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 2/imunologia , Ativação Linfocitária , /antagonistas & inibidores , Animais , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/virologia , Chlorocebus aethiops , Células Dendríticas/virologia , Endorribonucleases/imunologia , Feminino , Camundongos , Células Vero
20.
Front Immunol ; 12: 758721, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35058919

RESUMO

Endogenous retroviruses (ERVs) are genomic sequences that originated from retroviruses and are present in most eukaryotic genomes. Both beneficial and detrimental functions are attributed to ERVs, but whether ERVs contribute to antiviral immunity is not well understood. Here, we used herpes simplex virus type 2 (HSV-2) infection as a model and found that Toll-like receptor 7 (Tlr7 -/-) deficient mice that have high systemic levels of infectious ERVs are protected from intravaginal HSV-2 infection and disease, compared to wildtype C57BL/6 mice. We deleted the endogenous ecotropic murine leukemia virus (Emv2) locus on the Tlr7 -/- background (Emv2 -/- Tlr7 -/-) and found that Emv2 -/- Tlr7 -/- mice lose protection against HSV-2 infection. Intravaginal application of purified ERVs from Tlr7-/- mice prior to HSV-2 infection delays disease in both wildtype and highly susceptible interferon-alpha receptor-deficient (Ifnar1- /-) mice. However, intravaginal ERV treatment did not protect Emv2-/-Tlr7-/- mice from HSV-2 disease, suggesting that the protective mechanism mediated by exogenous ERV treatment may differ from that of constitutively and systemically expressed ERVs in Tlr7-/- mice. We did not observe enhanced type I interferon (IFN-I) signaling in the vaginal tissues from Tlr7-/- mice, and instead found enrichment in genes associated with extracellular matrix organization. Together, our results revealed that constitutive and/or systemic expression of ERVs protect mice against vaginal HSV-2 infection and delay disease.


Assuntos
Retrovirus Endógenos/imunologia , Herpes Genital/imunologia , Herpes Genital/prevenção & controle , Herpesvirus Humano 2/imunologia , Doenças Vaginais/imunologia , Doenças Vaginais/prevenção & controle , Animais , Retrovirus Endógenos/genética , Feminino , Herpes Genital/genética , Herpesvirus Humano 2/genética , Camundongos , Camundongos Knockout , Doenças Vaginais/genética
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