Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.206
Filtrar
1.
Life Sci ; 274: 119313, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33667511

RESUMO

AIMS: To design and evaluate a novel AWRK6 peptide-based long-acting GLP-1 receptor agonist (GLP-1RA) conjugated a recombinant polyethylene glycol mimetic (XTEN protein) with significant therapeutic potential on type 2 diabetes mellitus (T2DM) alone as well as Herpes simplex virus type 2 (HSV-2) infection in combination with double shRNA. MAIN METHODS: First, four AWRK6 analogs (termed XA-1 to XA-4) were designed and produced by solid phase synthesis strategy. Further surface plasmon resonance (SPR) measurement and in vitro cAMP accumulation assay were performed to detect the GLP-1R binding affinities and GLP-1R activation, respectively. The in vivo efficacy evaluation including pharmacokinetic test, oral glucose tolerance test (OGTT), hypoglycemic duration test and chronic pharmacodynamics study in rodent animals were all carefully performed. KEY FINDINGS: Four XA peptides were synthesized with purity >99%. High binding affinity as well as activation potency of XA-4 for GLP-1R were demonstrated by SPR and cell-based luciferase reporter assay, respectively. Additionally, XA-4 exhibited the long-lasting antidiabetic effects in the multiple OGTTs, hypoglycemic duration test and chronic study in mice. Furthermore, combined treatment of XA-4 and double shRNA (D-shRNA) achieved potent antiviral effects in HSV-2 infected HEK293 cells. SIGNIFICANCE: XA-4 exhibited promising pharmaceutical potential to be a therapeutic drug for treating T2D, and also held potential to against the HSV-2 infection, which is really an accidental discovery. The strategy of recombinant XTENylation can also be applied to other peptides or small molecules for the development of long-acting therapeutic drugs.


Assuntos
Diabetes Mellitus Experimental/terapia , Herpes Simples/terapia , Herpesvirus Humano 2/efeitos dos fármacos , Obesidade/complicações , Fragmentos de Peptídeos/farmacologia , Peptídeos/farmacologia , RNA Interferente Pequeno/administração & dosagem , Animais , Terapia Combinada , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/patologia , Dieta Hiperlipídica/efeitos adversos , Herpes Simples/genética , Herpes Simples/virologia , Herpesvirus Humano 2/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Fragmentos de Peptídeos/química , Peptídeos/química , RNA Interferente Pequeno/genética
2.
Viruses ; 13(2)2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33546431

RESUMO

Nuclear domains 10 (ND10), a.k.a. promyelocytic leukemia nuclear bodies (PML-NBs), are membraneless subnuclear domains that are highly dynamic in their protein composition in response to cellular cues. They are known to be involved in many key cellular processes including DNA damage response, transcription regulation, apoptosis, oncogenesis, and antiviral defenses. The diversity and dynamics of ND10 residents enable them to play seemingly opposite roles under different physiological conditions. Although the molecular mechanisms are not completely clear, the pro- and anti-cancer effects of ND10 have been well established in tumorigenesis. However, in herpesvirus research, until the recently emerged evidence of pro-viral contributions, ND10 nuclear bodies have been generally recognized as part of the intrinsic antiviral defenses that converge to the incoming viral DNA to inhibit the viral gene expression. In this review, we evaluate the newly discovered pro-infection influences of ND10 in various human herpesviruses and analyze their molecular foundation along with the traditional antiviral functions of ND10. We hope to shed light on the explicit role of ND10 in both the lytic and latent cycles of herpesvirus infection, which is imperative to the delineation of herpes pathogenesis and the development of prophylactic/therapeutic treatments for herpetic diseases.


Assuntos
Herpes Simples/metabolismo , Herpesviridae/fisiologia , Proteínas Nucleares/metabolismo , Carcinogênese , Herpes Simples/virologia , Herpesviridae/classificação , Herpesviridae/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Proteínas Virais/metabolismo , Latência Viral , Replicação Viral
3.
Nat Microbiol ; 6(2): 234-245, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33432153

RESUMO

Intrinsic antiviral host factors confer cellular defence by limiting virus replication and are often counteracted by viral countermeasures. We reasoned that host factors that inhibit viral gene expression could be identified by determining proteins bound to viral DNA (vDNA) in the absence of key viral antagonists. Herpes simplex virus 1 (HSV-1) expresses E3 ubiquitin-protein ligase ICP0 (ICP0), which functions as an E3 ubiquitin ligase required to promote infection. Cellular substrates of ICP0 have been discovered as host barriers to infection but the mechanisms for inhibition of viral gene expression are not fully understood. To identify restriction factors antagonized by ICP0, we compared proteomes associated with vDNA during HSV-1 infection with wild-type virus and a mutant lacking functional ICP0 (ΔICP0). We identified the cellular protein Schlafen family member 5 (SLFN5) as an ICP0 target that binds vDNA during HSV-1 ΔICP0 infection. We demonstrated that ICP0 mediates ubiquitination of SLFN5, which leads to its proteasomal degradation. In the absence of ICP0, SLFN5 binds vDNA to repress HSV-1 transcription by limiting accessibility of RNA polymerase II to viral promoters. These results highlight how comparative proteomics of proteins associated with viral genomes can identify host restriction factors and reveal that viral countermeasures can overcome SLFN antiviral activity.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Regulação Viral da Expressão Gênica , Herpes Simples/virologia , Interações Hospedeiro-Patógeno , Simplexvirus/genética , Transcrição Genética , Animais , Proteínas de Ciclo Celular/genética , Chlorocebus aethiops , DNA Viral/metabolismo , Células HEK293 , Células HeLa , Herpes Simples/metabolismo , Humanos , Proteínas Imediatamente Precoces/genética , Proteínas Imediatamente Precoces/metabolismo , Regiões Promotoras Genéticas , Proteômica , RNA Polimerase II/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação , Células Vero
4.
Viruses ; 13(1)2021 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-33435520

RESUMO

Herpes simplex virus type 1 (HSV-1) causes a lifelong latent infection with an estimated global prevalence of 66%. Primary and recurrent HSV infections are characterized by a tingling sensation, followed by an eruption of vesicles, which can cause painful erosions. Commonly used antiviral drugs against HSV infection are nucleoside analogues including acyclovir (ACV), famciclovir, and valacyclovir. Although these nucleoside analogues reduce morbidity and mortality in immunocompetent individuals, ACV-resistant HSV strains (ACVR-HSV) have been isolated from immunocompromised patients. Thus, ACVR-HSV infection poses a critical emerging public health concern. Recently, we reported that ginkgolic acid (GA) inhibits HSV-1 by disrupting viral structure, blocking fusion, and inhibiting viral protein synthesis. Additionally, we showed GA affords a broad spectrum of fusion inhibition of all three classes of fusion proteins, including those of HIV, Ebola, influenza A and Epstein Barr viruses. Here we report GA's antiviral activity against HSV-1 skin infection in BALB/cJ mice. GA-treated mice demonstrated a significantly reduced mortality rate and decreased infection scores compared to controls treated with dimethylsulfoxide (DMSO)-vehicle. Furthermore, GA efficiently inhibited ACVR-HSV-1 strain 17+ in vitro and in vivo. Since GA's mechanism of action includes virucidal activity and fusion inhibition, it is expected to work alone or synergistically with other anti-viral drugs, and we anticipate it to be effective against additional cutaneous and potentially systemic viral infections.


Assuntos
Antivirais/farmacologia , Dermatite/virologia , Herpes Simples/virologia , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 1/fisiologia , Salicilatos/farmacologia , Animais , Linhagem Celular , Chlorocebus aethiops , Dermatite/tratamento farmacológico , Modelos Animais de Doenças , Herpes Simples/tratamento farmacológico , Herpes Simples/transmissão , Camundongos , Células Vero , Ensaio de Placa Viral , Replicação Viral/efeitos dos fármacos
5.
BMJ Case Rep ; 14(1)2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33431534

RESUMO

A man in his late 30s presented with a several-day history of rectal pain, discharge and bleeding associated with systemic upset. Sexual history revealed receptive anal sex with several male partners in the 2 weeks preceding his clinic visit. Examination of the perianal area was unremarkable. Proctoscopy showed evidence of non-ulcerative proctitis. Microscopy for Gram stain showed pus cells plus extracellular Gram-negative diplococci. The patient was treated for presumptive gonorrhoea and chlamydial infection with ceftriaxone, azithromycin and doxycycline. The patient failed to improve with this treatment regimen. Rectal swab results at 48 hours confirmed the causative agent to be herpes simplex virus (HSV) type 2. The patient was recalled and treated successfully with valaciclovir. This case serves as a useful reminder to clinicians to consider HSV in the differential diagnosis of sexually transmitted proctitis, in the absence of perianal or anorectal ulceration.


Assuntos
Herpes Simples/diagnóstico , Herpesvirus Humano 2/isolamento & purificação , Proctite/diagnóstico , Doenças Sexualmente Transmissíveis/diagnóstico , Adulto , Antivirais/uso terapêutico , DNA Viral/isolamento & purificação , Diagnóstico Diferencial , Gonorreia/diagnóstico , Herpes Simples/tratamento farmacológico , Herpes Simples/transmissão , Herpes Simples/virologia , Herpesvirus Humano 2/genética , Humanos , Doenças Inflamatórias Intestinais/diagnóstico , Mucosa Intestinal/virologia , Masculino , Proctite/tratamento farmacológico , Proctite/virologia , Reto/virologia , Comportamento Sexual , Doenças Sexualmente Transmissíveis/tratamento farmacológico , Doenças Sexualmente Transmissíveis/transmissão , Doenças Sexualmente Transmissíveis/virologia , Valaciclovir/uso terapêutico
6.
Med Hypotheses ; 146: 110447, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33383524

RESUMO

The pathogen burden, defined by the frequency of antibodies to several viruses and a parasite, is greater in Hispanic whites and black populations than it is in non-Hispanic whites, in the USA. The poor and those without higher education also have higher pathogen burdens. The most frequent pathogen that was measured, was the Herpes simplex virus type 1 (HSV-1). This virus can inactivate most of the elements in the immune system, that are designed to protect against the incursions of viruses, bacteria and other pathogens. HSV-1 can also damage the blood brain barrier (BBB), which prevents the entry of pathogens into the central nervous system. Without the help of HSV-1, the COVID-19 virus may not be able to cause serious illness or death in humans. A prophylactic treatment to contain HSV-1, could be vital in the fight against COVID-19.


Assuntos
/epidemiologia , Grupos Étnicos , Herpes Simples/epidemiologia , Herpesvirus Humano 1/patogenicidade , Modelos Biológicos , Afro-Americanos , Barreira Hematoencefálica , /virologia , Grupo com Ancestrais do Continente Europeu , Herpes Simples/prevenção & controle , Herpes Simples/virologia , Hispano-Americanos , Interações entre Hospedeiro e Microrganismos , Humanos , Pandemias , Estados Unidos/epidemiologia
7.
Viruses ; 12(12)2020 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-33322225

RESUMO

Acyclovir is the drug of choice for the treatment of herpes simplex virus (HSV) infections. Acyclovir-resistant HSV strains may emerge, especially during long-term drug use, and subsequently cause difficult-to-treat exacerbations. Previously, we set up a novel treatment approach, based on enzymatically synthesized pools of siRNAs, or siRNA swarms. These swarms can cover kilobases-long target sequences, reducing the likelihood of resistance to treatment. Swarms targeting the UL29 essential gene of HSV-1 have demonstrated high efficacy against HSV-1 in vitro and in vivo. Here, we assessed the antiviral potential of a UL29 siRNA swarm against circulating strains of HSV-1, in comparison with acyclovir. All circulating strains were sensitive to both antivirals, with the half-maximal inhibitory concentrations (IC50) in the range of 350-1911 nM for acyclovir and 0.5-3 nM for the UL29 siRNA swarm. Additionally, we showed that an acyclovir-resistant HSV-1, devoid of thymidine kinase, is highly sensitive to UL29 siRNA treatment (IC50 1.0 nM; Imax 97%). Moreover, the detected minor variations in the RNAi target of the HSV strains had no effect on the potency or efficacy of UL29 siRNA swarm treatment. Our findings support the development of siRNA swarms for the treatment of HSV-1 infections, in order to circumvent any potential acyclovir resistance.


Assuntos
Aciclovir/farmacologia , Proteínas de Ligação a DNA/genética , Herpes Simples/virologia , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 1/genética , Interferência de RNA , RNA Interferente Pequeno/genética , Proteínas Virais/genética , Aciclovir/uso terapêutico , Animais , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Farmacorresistência Viral/efeitos dos fármacos , Farmacorresistência Viral/genética , Herpes Simples/terapia , Herpesvirus Humano 1/classificação , Herpesvirus Humano 1/isolamento & purificação , Humanos , Concentração Inibidora 50 , Células Vero
8.
Viruses ; 12(12)2020 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-33322659

RESUMO

Glycoprotein G (gG) from herpes simplex virus type 1 and 2 (HSV-1 and HSV-2, respectively) functions as a viral chemokine binding protein (vCKBP). Soluble recombinant forms of gG of HSV-1 and HSV-2 (SgG1 and SgG2, respectively) enhance chemokine-mediated leukocyte migration, in contrast to most known vCKBPs, including those from animal alpha-herpesviruses. Furthermore, both proteins bind to nerve growth factor (NGF), but only SgG2 enhances NGF-dependent neurite outgrowth. The basis and implications of this functional difference between the two proteins are still unknown. While gG1 and gG2 are positional homologues in the genome, they share very limited sequence homology. In fact, US4, the open reading frame encoding gG is the most divergent genetic locus between these viruses. Full-length gG1 and gG2 are type I transmembrane proteins located on the plasma membrane of infected cells and at the viral envelope. However, gG2 is larger than gG1 and is cleaved during protein maturation, secreting the N-terminal domain to the supernatant of infected cells, whereas gG1 is not. The enzyme involved in gG2 cleavage and the functional relevance of gG2 cleavage and secretion are unknown. We aim to identify the gG2 sequence required for cleavage to determine its functional role in future experiments. Our results prove the existence of at least two cleavage motifs in gG2 within the amino acid region 314-343. Transfer of this sequence to a fusion protein results in cleavage. Finally, we show that propeptide convertases like furin are responsible for gG2 cleavage.


Assuntos
Herpes Simples/virologia , Herpesvirus Humano 2/fisiologia , Domínios e Motivos de Interação entre Proteínas , Proteínas do Envelope Viral/metabolismo , Motivos de Aminoácidos , Sequência de Aminoácidos , Animais , Linhagem Celular , Cromatografia Líquida , Expressão Gênica , Genes Reporter , Humanos , Espectrometria de Massas , Proteólise
9.
PLoS Pathog ; 16(12): e1009166, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33370402

RESUMO

Herpes simplex virus 1 (HSV-1) infects skin and mucosal epithelial cells and then travels along axons to establish latency in the neurones of sensory ganglia. Although viral gene expression is restricted during latency, the latency-associated transcript (LAT) locus encodes many RNAs, including a 2 kb intron known as the hallmark of HSV-1 latency. Here, we studied HSV-1 infection and the role of the LAT locus in human skin xenografts in vivo and in cultured explants. We sequenced the genomes of our stock of HSV-1 strain 17syn+ and seven derived viruses and found nonsynonymous mutations in many viral proteins that had no impact on skin infection. In contrast, deletions in the LAT locus severely impaired HSV-1 replication and lesion formation in skin. However, skin replication was not affected by impaired intron splicing. Moreover, although the LAT locus has been implicated in regulating gene expression in neurones, we observed only small changes in transcript levels that were unrelated to the growth defect in skin, suggesting that its functions in skin may be different from those in neurones. Thus, although the LAT locus was previously thought to be dispensable for lytic infection, we show that it is a determinant of HSV-1 virulence during lytic infection of human skin.


Assuntos
Herpes Simples/virologia , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/patogenicidade , MicroRNAs/genética , Pele/virologia , Virulência/genética , Animais , Xenoenxertos , Humanos , Camundongos , Fatores de Virulência/genética
10.
Viruses ; 13(1)2020 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-33374862

RESUMO

Viruses encode for structural proteins that participate in virion formation and include capsid and envelope proteins. In addition, viruses encode for an array of non-structural accessory proteins important for replication, spread, and immune evasion in the host and are often linked to virus pathogenesis. Most virus accessory proteins are non-essential for growth in cell culture because of the simplicity of the infection barriers or because they have roles only during a state of the infection that does not exist in cell cultures (i.e., tissue-specific functions), or finally because host factors in cell culture can complement their absence. For these reasons, the study of most nonessential viral factors is more complex and requires development of suitable cell culture systems and in vivo models. Approximately half of the proteins encoded by the herpes simplex virus 1 (HSV-1) genome have been classified as non-essential. These proteins have essential roles in vivo in counteracting antiviral responses, facilitating the spread of the virus from the sites of initial infection to the peripheral nervous system, where it establishes lifelong reservoirs, virus pathogenesis, and other regulatory roles during infection. Understanding the functions of the non-essential proteins of herpesviruses is important to understand mechanisms of viral pathogenesis but also to harness properties of these viruses for therapeutic purposes. Here, we have provided a comprehensive summary of the functions of HSV-1 non-essential proteins.


Assuntos
Regulação Viral da Expressão Gênica , Herpes Simples/virologia , Herpesvirus Humano 1/fisiologia , Interações Hospedeiro-Patógeno , Proteínas Virais/genética , Proteínas Virais/metabolismo , Replicação Viral , Animais , Endonucleases/genética , Endonucleases/metabolismo , Inativação Gênica , Herpes Simples/imunologia , Herpes Simples/metabolismo , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Ácidos Nucleicos/metabolismo , Fosfotransferases/genética , Fosfotransferases/metabolismo , Transativadores , Proteínas Virais Reguladoras e Acessórias/genética , Proteínas Virais Reguladoras e Acessórias/metabolismo , Virulência
11.
BMC Infect Dis ; 20(1): 832, 2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-33176697

RESUMO

BACKGROUND: Carvacrol, as the major components of aromatic plants used for treating human skin diseases including origanum, Satureja, thymus, and coridothymus species, presented a kind of antiviral activity. To explore the mechanisms of carvacrol against herpes simplex virus (HSV) in vitro. METHOD: The BSC-1 cells model of HSV infection was established, and from the two aspects of viral replication level and cell death pathway, the antiviral effects of carvacrol on HSV infected cells were also evaluated by plaque assay under the three modes including prevention, treatment, and direct inactivation. RESULTS: In the three ways, the half-maximal effective concentration (EC50) of 2% true carvacrol solution on HSV-2 infected cells were severally 0.43, 0.19 and 0.51 mmol/L, and the corresponding therapeutic index (TI) were 4.02, 9.11 and 3.39, respectively. It's the opposite of the increased levels caused by HSV-2 infection, that both the expressions at the transcription genes and protein levels of virus own replication key factors (including ICP4, ICP27, VP16, gB, and UL30) and cytokines (including RIP3, TNF-α, and MLKL) of infected cells treated with carvacrol were dose-dependently inhibited. Besides, HSV-2 infection can cause the decrease of intracellular protein ubiquitination level, and carvacrol can reverse the ubiquitination decrease level caused by HSV-2 infection. CONCLUSION: Carvacrol exhibits significant antiviral activity by inhibiting the HSV-2 proliferation process and HSV-2-induced TNF-α increasing levels, decreasing RIP3 and MLKL protein expressions through the intracellular RIP3-mediated programmed cell necrosis pathway. In addition, carvacrol also may exhibit anti-HSV-2 activity by reversing the ubiquitination decrease level caused by HSV-2 infection on the ubiquitin-proteasome system, which provides insights into the molecular mechanism.


Assuntos
Antivirais/farmacologia , Apoptose/efeitos dos fármacos , Cimenos/farmacologia , Células Epiteliais/virologia , Herpes Simples/metabolismo , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Ubiquitina/metabolismo , Animais , Chlorocebus aethiops , Citocinas/metabolismo , Herpes Simples/virologia , Transdução de Sinais/efeitos dos fármacos , Células Vero , Replicação Viral/efeitos dos fármacos
12.
Nat Commun ; 11(1): 5536, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-33139700

RESUMO

MAVS and MITA are essential adaptor proteins mediating innate antiviral immune responses against RNA and DNA viruses, respectively. Here we show that RNF115 plays dual roles in response to RNA or DNA virus infections by catalyzing distinct types of ubiquitination of MAVS and MITA at different phases of viral infection. RNF115 constitutively interacts with and induces K48-linked ubiquitination and proteasomal degradation of homeostatic MAVS in uninfected cells, whereas associates with and catalyzes K63-linked ubiquitination of MITA after HSV-1 infection. Consistently, the protein levels of MAVS are substantially increased in Rnf115-/- organs or cells without viral infection, and HSV-1-induced aggregation of MITA is impaired in Rnf115-/- cells compared to the wild-type counterparts. Consequently, the Rnf115-/- mice exhibit hypo- and hyper-sensitivity to EMCV and HSV-1 infection, respectively. These findings highlight dual regulation of cellular antiviral responses by RNF115-mediated ubiquitination of MAVS and MITA and contribute to our understanding of innate immune signaling.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Infecções por Cardiovirus/imunologia , Herpes Simples/imunologia , Imunidade Inata , Proteínas de Membrana/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Infecções por Cardiovirus/patologia , Infecções por Cardiovirus/virologia , Modelos Animais de Doenças , Vírus da Encefalomiocardite/imunologia , Feminino , Células HEK293 , Herpes Simples/patologia , Herpes Simples/virologia , Herpesvirus Humano 1/imunologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Lisina/metabolismo , Macrófagos/imunologia , Macrófagos/virologia , Masculino , Camundongos , Camundongos Knockout , Cultura Primária de Células , Agregados Proteicos/imunologia , RNA Interferente Pequeno/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/fisiologia , Ubiquitinação/imunologia
13.
Cell Rep ; 33(5): 108339, 2020 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-33147451

RESUMO

Here, we report our studies of immune-mediated regulation of Zika virus (ZIKV), herpes simplex virus 1 (HSV-1), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the human cornea. We find that ZIKV can be transmitted via corneal transplantation in mice. However, in human corneal explants, we report that ZIKV does not replicate efficiently and that SARS-CoV-2 does not replicate at all. Additionally, we demonstrate that type III interferon (IFN-λ) and its receptor (IFNλR1) are expressed in the corneal epithelium. Treatment of human corneal explants with IFN-λ, and treatment of mice with IFN-λ eye drops, upregulates antiviral interferon-stimulated genes. In human corneal explants, blockade of IFNλR1 enhances replication of ZIKV and HSV-1 but not SARS-CoV-2. In addition to an antiviral role for IFNλR1 in the cornea, our results suggest that the human cornea does not support SARS-CoV-2 infection despite expression of ACE2, a SARS-CoV-2 receptor, in the human corneal epithelium.


Assuntos
Betacoronavirus/fisiologia , Córnea/virologia , Infecções por Coronavirus/transmissão , Herpesvirus Humano 1/fisiologia , Interferons/imunologia , Pneumonia Viral/transmissão , Zika virus/fisiologia , Animais , Betacoronavirus/imunologia , Córnea/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Herpes Simples/imunologia , Herpes Simples/transmissão , Herpes Simples/virologia , Humanos , Camundongos , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Replicação Viral/fisiologia , Infecção por Zika virus/imunologia , Infecção por Zika virus/transmissão , Infecção por Zika virus/virologia
14.
Molecules ; 25(21)2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33105694

RESUMO

Viral infections and associated diseases are responsible for a substantial number of mortality and public health problems around the world. Each year, infectious diseases kill 3.5 million people worldwide. The current pandemic caused by COVID-19 has become the greatest health hazard to people in their lifetime. There are many antiviral drugs and vaccines available against viruses, but they have many disadvantages, too. There are numerous side effects for conventional drugs, and active mutation also creates drug resistance against various viruses. This has led scientists to search herbs as a source for the discovery of more efficient new antivirals. According to the World Health Organization (WHO), 65% of the world population is in the practice of using plants and herbs as part of treatment modality. Additionally, plants have an advantage in drug discovery based on their long-term use by humans, and a reduced toxicity and abundance of bioactive compounds can be expected as a result. In this review, we have highlighted the important viruses, their drug targets, and their replication cycle. We provide in-depth and insightful information about the most favorable plant extracts and their derived phytochemicals against viral targets. Our major conclusion is that plant extracts and their isolated pure compounds are essential sources for the current viral infections and useful for future challenges.


Assuntos
Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Herpes Simples/tratamento farmacológico , Influenza Humana/tratamento farmacológico , Compostos Fitoquímicos/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Antivirais/química , Antivirais/classificação , Antivirais/isolamento & purificação , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/patogenicidade , Betacoronavirus/fisiologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Descoberta de Drogas , HIV/efeitos dos fármacos , HIV/patogenicidade , HIV/fisiologia , Infecções por HIV/patologia , Infecções por HIV/virologia , Hepacivirus/efeitos dos fármacos , Hepacivirus/patogenicidade , Hepacivirus/fisiologia , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Herpes Simples/patologia , Herpes Simples/virologia , Humanos , Influenza Humana/patologia , Influenza Humana/virologia , Orthomyxoviridae/efeitos dos fármacos , Orthomyxoviridae/patogenicidade , Orthomyxoviridae/fisiologia , Pandemias , Compostos Fitoquímicos/química , Compostos Fitoquímicos/classificação , Compostos Fitoquímicos/isolamento & purificação , Plantas Medicinais , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Simplexvirus/efeitos dos fármacos , Simplexvirus/patogenicidade , Simplexvirus/fisiologia , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
15.
BMC Infect Dis ; 20(1): 782, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33081701

RESUMO

BACKGROUND: Primary herpetic gingivostomatitis (PHGS) in children, though usually self-limited, might mimic bacterial and enteroviral pharyngitis clinically. We conducted a study to define the clinical features of PHGS in children. METHODS: Between January 2012 and December 2016, 282 inpatients aged less than 19 years with cell culture-confirmed herpes simplex virus (HSV) infection in a medical center were identified from the virologic laboratory logbook. Clinical data were retrospectively collected. RESULTS: Among the 282 inpatients, 185 cases were considered as PHGS and were included for analysis. Fever was present in 99.5%. The mean duration of fever was 5.11 days (±2.24) with the longest being 17 days. Common oral manifestations included oral ulcers (84.3%), which equally resided in the anterior and posterior part of the oral cavity (65.4% vs. 63.2%), gum swelling and/or bleeding (67.6%), and exudate coated tonsils (16.8%). Leukocytosis (WBC count > 15,000/uL3) was noted in 52 patients (28.1%) and a serum C-reactive protein level > 40 mg/L in 55 patients (29.7%). Fixty-five patients (35%) were diagnosed with PHGS on admission and were significantly more likely to have ulcers over the anterior oral cavity (76.1% vs. 26.7%) and gum swelling/bleeding (76.2% vs. 7.5%, p-value all < 0.001) on admission and were significantly less likely to receive antibiotic treatment (16.9 vs. 36.7%, p-value < 0.01) than others. Forty-six patients (25%) undiagnosed as PHGS on discharge were significantly more likely to have exudate coated on the tonsils, to receive antibiotic treatment and significantly less likely to have gum swelling/bleeding and oral ulcers (all p-values < 0.01). CONCLUSIONS: Meticulously identifying specific oral manifestations of gum swelling/bleeding and ulcers over the anterior oral cavity in children can help making the diagnosis of PHGS earlier and subsequently reduce unnecessary prescription of antibiotics.


Assuntos
Gengivite/diagnóstico , Herpes Simples/diagnóstico , Herpesvirus Humano 1/imunologia , Úlceras Orais/diagnóstico , Faringite/diagnóstico , Estomatite Herpética/diagnóstico , Tonsilite/diagnóstico , Adolescente , Antibacterianos/uso terapêutico , Proteína C-Reativa/análise , Criança , Pré-Escolar , Diagnóstico Diferencial , Diagnóstico Precoce , Feminino , Febre , Herpes Simples/tratamento farmacológico , Herpes Simples/virologia , Herpesvirus Humano 1/isolamento & purificação , Humanos , Lactente , Leucocitose , Masculino , Estudos Retrospectivos , Estomatite Herpética/tratamento farmacológico , Estomatite Herpética/virologia
16.
PLoS Pathog ; 16(8): e1008703, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32776994

RESUMO

Herpes simplex virus type 1 (HSV1) is a complicated structural agent with a sophisticated transcription process and a high infection rate. A vaccine against HSV1 is urgently needed. As multiple viral-encoded proteins, including structural and nonstructural proteins, contribute to immune response stimulation, an attenuated or deficient HSV1 vaccine may be relatively reliable. Advances in genomic modification technologies provide reliable means of constructing various HSV vaccine candidates. Based on our previous work, an M6 mutant with mutations in the UL7, UL41, LAT, Us3, Us11 and Us12 genes was established. The mutant exhibited low proliferation in cells and an attenuated phenotype in an animal model. Furthermore, in mice and rhesus monkeys, the mutant can induce remarkable serum neutralizing antibody titers and T cell activation and protect against HSV1 challenge by impeding viral replication, dissemination and pathogenesis.


Assuntos
Vacinas contra o Vírus do Herpes Simples/imunologia , Herpes Simples/imunologia , Herpesvirus Humano 1/imunologia , Animais , Feminino , Herpes Simples/prevenção & controle , Herpes Simples/virologia , Vacinas contra o Vírus do Herpes Simples/administração & dosagem , Vacinas contra o Vírus do Herpes Simples/genética , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/fisiologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Mutação , Fenótipo , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/genética , Vacinas Atenuadas/imunologia , Proteínas Virais/administração & dosagem , Proteínas Virais/genética , Proteínas Virais/imunologia
17.
BMC Infect Dis ; 20(1): 605, 2020 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-32807089

RESUMO

BACKGROUND: Herpetic esophagitis (EH) usually affects those who are immunocompromised and is uncommon in immunocompetent patients. In these cases, EH may occasionally present as an acute and self-limited illness. Such cases are rare and only a few have beenreported and limited published reviews exist making the benefits of antiviral therapy in immunocompetent patients unknown. CASE PRESENTATION: We report four cases of young patients who presented dysphagia, odynophagia and epigastric pain. Endoscopic findings revealed lesions in the distal esophagus and histopathological changes compatible with herpes virus infection confirmed by viral DNA in every case. After treatment, every patient showed significant improvement and tolerated oral intake after discharge. CONCLUSIONS: In this publication, we present four immunocompetent patients with EH, without relevant alterations in laboratory workup and with negative HIV status. This disease is infrequent in patients with such characteristics and there are few cases published. In order to better understand this pathology, we present the symptoms, the endoscopic alterations and the clinical evolution with treatment. In our series, 50% of patients had serology compatible with acute HVS type 1 infection, 25% had a subacute infection pattern (IgM and IgG positive antibodies) and in another 25% of patients, serology was not done. No patient presented leukocyte alterations, while all patients presented with anatomopathological findings compatible with acute herpetic esophagitis and responded to acyclovir therapy.


Assuntos
Esofagite/diagnóstico , Herpes Simples/diagnóstico , Aciclovir/uso terapêutico , Adolescente , Antivirais/uso terapêutico , Endoscopia do Sistema Digestório , Esofagite/tratamento farmacológico , Esofagite/patologia , Esôfago/patologia , Feminino , Herpes Simples/tratamento farmacológico , Herpes Simples/virologia , Humanos , Hospedeiro Imunocomprometido , Masculino , Simplexvirus/isolamento & purificação , Adulto Jovem
18.
Andrologia ; 52(9): e13791, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32790205

RESUMO

Male infertility is linked to some viral infections including human papillomavirus (HPV), herpes simplex viruses (HSV) and human immunodeficiency viruses (HIVs). Almost nothing is known about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) effect on fertility. The possible risk factors of coronavirus disease 2019 (COVID-19) infection on fertility comes from the abundance of angiotensin-Converting Enzyme-2 (ACE2), receptor entry of the virus, on testes, a reduction in important sex hormone ratios and COVID-19-associated fever. Recent studies have shown a gender difference for COVID-19 rates and comorbidity. In this review, we will discuss the potential effect of COVID-19 on male fertility and talk about what needs to be done by the scientific community to tackle our limited understanding of the disease. On the other side, we will focus on what is known so far about the risk of COVID-19 on pregnancy, neonatal health and the vertical transfer of the virus between mothers and their neonates. Finally, because reproduction is a human right and infertility is considered a health disease, we will discuss how assisted reproductive clinics can cope with the pandemic and what guidelines they should follow to minimise the risk of viral transmission.


Assuntos
Infecções por Coronavirus/complicações , Transmissão Vertical de Doença Infecciosa , Infertilidade Masculina/virologia , Pneumonia Viral/complicações , Complicações Infecciosas na Gravidez/virologia , Saúde Reprodutiva , Betacoronavirus/isolamento & purificação , Betacoronavirus/metabolismo , Betacoronavirus/patogenicidade , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Feminino , Infecções por HIV/complicações , Infecções por HIV/transmissão , Infecções por HIV/virologia , Herpes Simples/complicações , Herpes Simples/transmissão , Herpes Simples/virologia , Humanos , Infertilidade Masculina/patologia , Masculino , Pandemias , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/transmissão , Infecções por Papillomavirus/virologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/epidemiologia , Pneumonia Viral/transmissão , Pneumonia Viral/virologia , Gravidez , Fatores de Risco , Glicoproteína da Espícula de Coronavírus/metabolismo , Testículo/metabolismo , Testículo/patologia
19.
BMC Infect Dis ; 20(1): 577, 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32758172

RESUMO

BACKGROUND: Despite the significant decline in the prevalence of HIV in Tanzania, the prevalence rates in Mbeya, Iringa, and Njombe regions are higher than the national average and have remained stable for years. The current stable HIV prevalence may be driven by factors such as a high incidence of sexually transmitted infections (STIs) and high-risk behaviours. In sub-Saharan Africa, it has previously been observed that up to 50% of HIV cases were attributed to herpes simplex type 2 (HSV-2) among low-risk populations. Because the proportion of sexually transmitted HSV-1 is rising, it is essential to study the interaction between HSV-1 and HIV infections. METHODS: We conducted a study in Mbeya region using the archived blood sera of participants from the recently completed EU-funded EMINI project. A specially designed questionnaire was used to obtain the social and demographic characteristics of the study participants in the database. We tested archived participants' sera for herpes simplex virus type 1 using Virotech HSV-1 (gG1) IgG ELISA (Enzygnost, Behring, Germany). Univariate and multivariate Poisson regression models were used to identify factors associated with HSV-1. RESULTS: A total of 640 adults were randomly recruited after stratification by HIV status (318 were HIV positive), age, and sex. The overall seroprevalence of HSV-1 in the study population was 92.1%. The extrapolated seroprevalence estimate of herpes simplex virus type 1 in the general population was 95.0% (96.0% in males versus 94.0% in females). Males and females were equally affected by HSV-1. HSV-1 was less prevalent in HIV-positive individuals than in HIV-negative individuals. CONCLUSION: People living with HIV were less likely to be HSV-1 seropositive. Further prospective studies are necessary to conclude a causal association.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/epidemiologia , HIV-1 , Herpes Simples/epidemiologia , Herpesvirus Humano 1/imunologia , Doenças Sexualmente Transmissíveis/epidemiologia , Infecções Oportunistas Relacionadas com a AIDS/sangue , Infecções Oportunistas Relacionadas com a AIDS/virologia , Adolescente , Adulto , Anticorpos Antivirais/sangue , Estudos de Coortes , Estudos Transversais , Feminino , Herpes Simples/sangue , Herpes Simples/virologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Estudos Soroepidemiológicos , Comportamento Sexual , Doenças Sexualmente Transmissíveis/sangue , Doenças Sexualmente Transmissíveis/virologia , Tanzânia/epidemiologia , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...