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1.
Neuroimaging Clin N Am ; 33(1): 207-224, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36404044

RESUMO

This article highlights the changing profile of the pediatric patient with central nervous system infection as countries develop and the roles of different imaging modalities such as cranial ultrasound, MR imaging, and computed tomography. It discusses the commonly encountered congenital toxoplasmosis, rubella, cytomegalovirus, herpes simplex (TORCH) infections, Group B Streptococcal and Escherichia coli infections in the neonatal period, and disease outbreaks affecting children. Iatrogenic, opportunistic, and immune-mediated changes as well as long-term effects of infection and mimics of infection are also discussed. Variety of images is provided to show the range of neuroimaging findings encountered, particularly on cranial ultrasound and MR imaging.


Assuntos
Infecções do Sistema Nervoso Central , Herpes Simples , Recém-Nascido , Humanos , Criança , Infecções do Sistema Nervoso Central/diagnóstico por imagem , Herpes Simples/congênito , Imageamento por Ressonância Magnética , Neuroimagem , Tomografia Computadorizada por Raios X
2.
Biol Pharm Bull ; 45(3): 360-363, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-34937813

RESUMO

In this study, we investigated the effects of fosphenytoin (fPHT), a water-soluble prodrug of phenytoin, on the pain responses of a mouse herpes zoster (HZ) pain model. Transdermal herpes simplex virus type 1 (HSV-1) inoculation induced mechanical allodynia and hyperalgesia of the hind paw and spontaneous pain-like behaviors, such as licking the affected skin. Intravenous injection of fPHT (15 and 30 mg/kg) alleviated HSV-1-induced provoked pain (allodynia and hyperalgesia). The suppressive effects of fPHT on provoked pain were weaker than those of diclofenac and pregabalin which were used as positive controls. fPHT, diclofenac, and pregabalin significantly suppressed HSV-1-induced spontaneous pain-like behaviors. Among them, high-dose fPHT (30 mg/kg) showed the strongest suppression. Intravenous fPHT may become a viable option for an acute HZ pain, especially for spontaneous pain.


Assuntos
Herpes Simples , Herpesvirus Humano 1 , Animais , Herpes Simples/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Camundongos , Dor/tratamento farmacológico , Fenitoína/análogos & derivados , Fenitoína/farmacologia , Fenitoína/uso terapêutico
4.
Front Cell Infect Microbiol ; 12: 949036, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36325470

RESUMO

Type I interferons (IFNs) present the first line of defense against viral infections, providing antiviral, immunomodulatory and antiproliferative effects. The type I IFN family contains 12 IFNα subtypes and IFNß, and although they share the same receptor, they are classified as non-redundant, capable to induce a variety of different IFN-stimulated genes. However, the biological impact of individual subtypes remains controversial. Recent data propose a subtype-specificity of type I IFNs revealing unique effector functions for different viruses and thus expanding the implications for IFNα-based antiviral immunotherapies. Despite extensive research, drug-resistant infections with herpes simplex virus type 1 (HSV-1), which is the common agent of recurrent orogenital lesions, are still lacking a protective or curing therapeutic. However, due to the risk of generalized infections in immunocompromised hosts as well as the increasing incidence of resistance to conventional antiherpetic agents, HSV infections raise major health concerns. Based on their pleiotropic effector functions, the application of type I IFNs represents a promising approach to inhibit HSV-1 replication, to improve host immunity and to further elucidate their qualitative differences. Here, selective IFNα subtypes and IFNß were evaluated for their therapeutic potential in genital HSV-1 infections. Respective in vivo studies in mice revealed subtype-specific differences in the reduction of local viral loads. IFNß had the strongest antiviral efficacy against genital HSV-1 infection in mice, whereas IFNα1, IFNα4, and IFNα11 had no impact on viral loads. Based on flow cytometric analyses of underlying immune responses at local and peripheral sites, these differences could be further assigned to specific modulations of the antiviral immunity early during HSV-1 infection. IFNß led to enhanced systemic cytokine secretion and elevated cytotoxic responses, which negatively correlated with viral loads in the vaginal tract. These data provide further insights into the diversity of type I IFN effector functions and their impact on the immunological control of HSV-1 infections.


Assuntos
Herpes Genital , Herpes Simples , Herpesvirus Humano 1 , Interferon Tipo I , Feminino , Camundongos , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Herpes Genital/tratamento farmacológico , Herpes Genital/patologia , Interferon beta , Interferon-alfa , Genitália/patologia , Replicação Viral
5.
J Vis Exp ; (188)2022 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-36342164

RESUMO

The kinase Receptor-interacting serine/threonine protein kinase 3 (RIPK3) and its substrate mixed lineage kinase domain-like (MLKL) are critical regulators of necroptosis, an inflammatory form of cell death with important antiviral functions. Autophosphorylation of RIPK3 induces phosphorylation and activation of the pore-forming executioner protein of necroptosis MLKL. Trafficking and oligomerization of phosphorylated MLKL at the cell membrane results in cell lysis, characteristic of necroptotic cell death. The nucleic acid sensor ZBP1 is activated by binding to left-handed Z-form double-stranded RNA (Z-RNA) after infection with RNA and DNA viruses. ZBP1 activation restricts virus infection by inducing regulated cell death, including necroptosis, of infected host cells. Immunofluorescence microscopy permits the visualization of different signaling steps downstream of ZBP1-mediated necroptosis on a per-cell basis. However, the sensitivity of standard fluorescence microscopy, using current commercially available phospho-specific antibodies against human RIPK3 and MLKL, precludes reproducible imaging of these markers. Here, we describe an optimized staining procedure for serine (S) phosphorylated RIPK3 (S227) and MLKL (S358) in human HT-29 cells infected with herpes simplex virus 1 (HSV-1). The inclusion of a tyramide signal amplification (TSA) step in the immunofluorescent staining protocol allows the specific detection of S227 phosphorylated RIPK3. Moreover, TSA greatly increases the sensitivity of the detection of S358 phosphorylated MLKL. Together, this method enables the visualization of these two critical signaling events during the induction of ZBP1-induced necroptosis.


Assuntos
Herpes Simples , Infecções por Herpesviridae , Herpesvirus Humano 1 , Humanos , Fosforilação , Herpesvirus Humano 1/genética , Proteínas Quinases/metabolismo , RNA de Cadeia Dupla , Serina/metabolismo , Coloração e Rotulagem , Apoptose , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo
6.
Antiviral Res ; 208: 105454, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36334637

RESUMO

Herpes simplex virus type-1 (HSV1) exploits cellular machinery for its own replicative advantage. Current treatment modalities against HSV1 cause toxicity and drug resistance issues. In the search for alternative forms of treatment, we have uncovered a small molecule, BX795, as a candidate drug with strong antiviral potential owing to its multitargeted mode of action. In this study, we show that in addition to a previously known mechanism of action, BX795 can directly interact with the proviral host factor protein kinase C (PKC) in silico. When administered to HSV1 or mock infected human corneal epithelial (HCE) cells, BX795 significantly reduces the protein level and perinuclear localization of proviral PKC-α and PKC-ζ isoforms. This activity closely mimics that of a known PKC inhibitor, Bisindolylmaleimide I (BIM I), which also inhibits viral replication. Taken together our studies demonstrate a previously unknown mechanism by which BX795 exerts its antiviral potential.


Assuntos
Herpes Simples , Infecções por Herpesviridae , Herpesvirus Humano 1 , Humanos , Herpes Simples/tratamento farmacológico , Infecções por Herpesviridae/tratamento farmacológico , Antivirais/uso terapêutico , Proteína Quinase C/metabolismo
7.
Int J Mol Sci ; 23(21)2022 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-36362429

RESUMO

Herpes simplex virus type 1 (HSV-1) is a neurotropic virus that occasionally may spread to the central nervous system (CNS), being the most common cause of sporadic encephalitis. One of the main neurovirulence factors of HSV-1 is the protein ICP34.5, which although it initially seems to be relevant only in neuronal infections, it can also promote viral replication in non-neuronal cells. New ICP34.5 functions have been discovered during recent years, and some of them have been questioned. This review describes the mechanisms of ICP34.5 to control cellular antiviral responses and debates its most controversial functions. One of the most discussed roles of ICP34.5 is autophagy inhibition. Although autophagy is considered a defense mechanism against viral infections, current evidence suggests that this antiviral function is only one side of the coin. Different types of autophagic pathways interact with HSV-1 impairing or enhancing the infection, and both the virus and the host cell modulate these pathways to tip the scales in its favor. In this review, we summarize the recent progress on the interplay between autophagy and HSV-1, focusing on the intricate role of ICP34.5 in the modulation of this pathway to fight the battle against cellular defenses.


Assuntos
Herpes Simples , Herpesvirus Humano 1 , Humanos , Herpesvirus Humano 1/fisiologia , Proteínas Virais/metabolismo , Autofagia/fisiologia , Replicação Viral , Antivirais/metabolismo , Herpes Simples/metabolismo
8.
Molecules ; 27(21)2022 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-36363990

RESUMO

DNA nanostructures are well-established vectors for packaging diversified payloads for targeted cellular delivery. Here, DNA origami rectangular sheets were combined with Herpes Simplex Virus 1 (HSV1) capsids to demonstrate surface coverage of the particle via electrostatic interactions. The optimized origami:HSV1 molar ratios led to characteristic packaging geometries ranging from dispersed "HSV1 pockets" to agglomerated "HSV1 sleeves". "Pockets" were disguised from cells in HeLa and B16F10 cells and were 44.2% less infective than naked HSV1 particles. However, the pockets were 117% more infective than naked HSV1 particles when the origami sheets were coated with folic acid. We observed infectivity from naked origami, but they are 99.1% less infective with respect to HSV1 and 99.6% less infective with respect to the pocket complexes. This work suggests that DNA origami can selectively modulate virus infectivity.


Assuntos
Herpes Simples , Herpesvirus Humano 1 , Humanos , Virulência , Capsídeo , DNA/genética , Proteínas do Capsídeo/química
9.
Sci Rep ; 12(1): 20325, 2022 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-36434126

RESUMO

There are 150 million women worldwide using combined or progestogen-only hormonal contraceptive methods who may be at risk of sexually transmitted infections (STIs). Previous systematic reviews that have sought to establish whether there is an aetiological association between hormonal contraceptive methods/use and STIs have been limited in their methods and have mixed findings. We sought to update these reviews using appropriate control groups. We undertook a systematic review following the PRISMA guidelines and meta-analysis to examine the association between the use of all hormonal contraceptive methods and the acquisition of STIs (Neisseria gonorrhoeae, syphilis/Treponema pallidum, Chlamydia trachomatis, herpes simplex virus, and Trichomonas vaginalis) and/or bacterial vaginosis in literature published between 2005 and 2020. We analysed the effect of hormonal contraceptive methods/use separately on the prevalence, incidence and recurrence of STIs. A total of 37 studies were included in this review that reported 61 associations, in which 27 prevalence, eight incidence and two recurrence studies provided 43, 16, and two associations, respectively. We observed a positive association between hormonal contraceptive methods/use and the risk of chlamydia and herpes but a negative association for trichomoniasis and vaginosis. A negative but statistically insignificant association was observed between hormonal contraceptive methods/use and gonorrhoea. Hormonal contraceptive methods/use influences a woman's risk of STIs/ bacterial vaginosis, but the risk may differ depending on the type of STI. These findings should be contextualized carefully, particularly when formulating practice guidelines and policy, as the effects of hormonal contraceptive methods/use on the risk of STIs varied in direction when analysed separately by STI.


Assuntos
Gonorreia , Herpes Simples , Infecções Sexualmente Transmissíveis , Tricomoníase , Vaginose Bacteriana , Humanos , Feminino , Vaginose Bacteriana/epidemiologia , Infecções Sexualmente Transmissíveis/epidemiologia , Gonorreia/epidemiologia , Anticoncepcionais
10.
Cells ; 11(22)2022 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-36428968

RESUMO

Intrauterine infections during pregnancy by herpes simplex virus (HSV) can cause significant neurodevelopmental deficits in the unborn/newborn, but clinical studies of pathogenesis are challenging, and while animal models can model some aspects of disease, in vitro studies of human neural cells provide a critical platform for more mechanistic studies. We utilized a reductionist approach to model neurodevelopmental outcomes of HSV-1 infection of neural rosettes, which represent the in vitro equivalent of differentiating neural tubes. Specifically, we employed early-stage brain organoids (ES-organoids) composed of human induced pluripotent stem cells (hiPSCs)-derived neural rosettes to investigate aspects of the potential neuropathological effects induced by the HSV-1 infections on neurodevelopment. To allow for the long-term differentiation of ES-organoids, viral infections were performed in the presence of the antiviral drug acyclovir (ACV). Despite the antiviral treatment, HSV-1 infection caused organizational changes in neural rosettes, loss of structural integrity of infected ES-organoids, and neuronal alterations. The inability of ACV to prevent neurodegeneration was associated with the generation of ACV-resistant mutants during the interaction of HSV-1 with differentiating neural precursor cells (NPCs). This study models the effects of HSV-1 infection on the neuronal differentiation of NPCs and suggests that this environment may allow for accelerated development of ACV-resistance.


Assuntos
Herpes Simples , Herpesvirus Humano 1 , Células-Tronco Pluripotentes Induzidas , Células-Tronco Neurais , Animais , Recém-Nascido , Humanos , Organoides , Aciclovir/farmacologia , Aciclovir/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , Encéfalo
11.
Cells ; 11(22)2022 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-36429022

RESUMO

Non-essential proteins for viral replication affect host cell metabolism, while the function of the UL43 protein of herpes simplex virus 1 (HSV-1) is not clear. Herein, we performed a comprehensive microarray analysis of HUVEC cells infected with HSV-1 and its UL43-deficient mutant and found significant variation in genes associated with cellular energy metabolic pathways. The localization of UL43 protein in host cells and how it affects cellular energy metabolism pathways were further investigated. Internalization analysis showed that the UL43 protein could be endocytosis-mediated by YPLF motif (aa144-147) and localized to mitochondria. At the same time, more ATP was produced by coupling with mitochondrial small G protein ARF-like 2 (ARL2) GTPase, which triggered the phosphorylation of ANT1 (SLC25A4) to affect the opening degree of mitochondrial permeability transition pore (mPTP), and significantly promoted the aerobic oxidation and oxidative phosphorylation of glucose. Our study shows that UL43 mediates the improvement of host cell metabolism after HSV-1 infection. Additionally, UL43 protein could be a valuable ATP-stimulating factor for mammalian cells.


Assuntos
Herpes Simples , Herpesvirus Humano 1 , Animais , Proteínas de Membrana/metabolismo , Herpesvirus Humano 1/metabolismo , Metabolismo Energético , Fosforilação Oxidativa , Trifosfato de Adenosina/metabolismo , Mamíferos/metabolismo
12.
BMC Infect Dis ; 22(1): 817, 2022 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-36335305

RESUMO

BACKGROUND: Herpes simplex virus (HSV) rarely causes organ-invasive infection. Diagnosis and treatment for such infections are often delayed, and mortality is high. We present the first reported case of disseminated HSV-1 infection in an adult causing liver failure, myocarditis, and encephalitis in a patient who recovered after receiving parenteral acyclovir treatment. CASE PRESENTATION: A 46-year-old female presented with fever, chills, and malaise after 2 weeks of oral corticosteroid treatment for uveitis. She was diagnosed with disseminated HSV-1 infection with multi-organ involvement causing hepatitis, encephalitis, and myocarditis. Diagnosis was made timely using serum polymerase chain reaction (PCR) for HSV DNA and the patient was given intravenous acyclovir treatment promptly, which led to her survival without significant morbidity. CONCLUSIONS: Clinicians should have a low threshold for suspecting HSV infection and ordering HSV PCR to decrease morbidity and mortality when there is a high clinical suspicion of systemic HSV infection with multi-organ involvement. Serum PCR for HSV DNA is an excellent modality for an initial diagnostic approach. Further research is warranted to elucidate causality between a course of corticosteroid therapy and systemic HSV-1 infection without major immunosuppressive comorbidities or treatments.


Assuntos
Encefalite por Herpes Simples , Encefalite , Herpes Simples , Herpesvirus Humano 1 , Miocardite , Humanos , Adulto , Feminino , Pessoa de Meia-Idade , Herpesvirus Humano 1/genética , Miocardite/tratamento farmacológico , Herpes Simples/diagnóstico , Herpes Simples/tratamento farmacológico , Aciclovir/uso terapêutico , Corticosteroides/uso terapêutico , Antivirais/uso terapêutico , Encefalite por Herpes Simples/tratamento farmacológico
13.
PLoS Pathog ; 18(11): e1010969, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36374856

RESUMO

During virion morphogenesis herpes simplex virus nucleocapsids transit from the nucleoplasm to the cytoplasm, through a process called nuclear egress, where the final stages of virion assembly occur. Coupled to nuclear egress is a poorly understood quality-control mechanism that preferentially selects genome-containing C-capsids, rather than A- and B-capsids that lack genomes, for transit to the cytoplasm. We and others have reported that cells infected with HSV strains deleted for the tegument protein pUL21 accumulate both empty A-capsids and C-capsids in the cytoplasm of infected cells. Quantitative microscopy experiments indicated that C-capsids were preferentially selected for envelopment at the inner nuclear membrane and that nuclear integrity remained intact in cells infected with pUL21 mutants, prompting alternative explanations for the accumulation of A-capsids in the cytoplasm. More A-capsids were also found in the nuclei of cells infected with pUL21 mutants compared to their wild type (WT) counterparts, suggesting pUL21 might be required for optimal genome packaging or genome retention within capsids. In support of this, more viral genomes were prematurely released into the cytoplasm during pUL21 mutant infection compared to WT infection and led to enhanced activation of cellular cytoplasmic DNA sensors. Mass spectrometry and western blot analysis of WT and pUL21 mutant capsids revealed an increased association of the known pUL21 binding protein, pUL16, with pUL21 mutant capsids, suggesting that premature and/or enhanced association of pUL16 with capsids might result in capsid destabilization. Further supporting this idea, deletion of pUL16 from a pUL21 mutant strain rescued genome retention within capsids. Taken together, these findings suggest that pUL21 regulates pUL16 addition to nuclear capsids and that premature, and/or, over-addition of pUL16 impairs HSV genome retention within capsids.


Assuntos
Herpes Simples , Herpesvirus Humano 1 , Humanos , Capsídeo/metabolismo , Herpesvirus Humano 1/genética , Montagem de Vírus/genética , Genoma Viral
14.
Georgian Med News ; (328-329): 43-46, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36318840

RESUMO

The purpose of the study - the establishment of serological prevalence of Herpes simplex 1 (HSV-1) и Herpes simplex 2 (HSV-2) in male and female prisoners as well as the analysis of separate psychosocial aspects of the spread of the infection in prisons in Ukraine. Herpes simplex virus markers, specifically class M and G immunoglobulins (IgM and IgG), have been identified (HSV-1 и HSV-2 in the blood serum in 80 prisoners from the prisons in Ukraine (40 men, average age 38.2 years and 40 women, average age 35.9 years), as well as some social characteristics of the convicts have been analysed. 43 men and 47 women patients of the institute made up the control group. The markers IgG to HSV-1 were diagnosed in 92.5% of cases compared to 97.7% in the control group in male prisoners, and IgG to HSV-2 in 50.0% and 18.6%, respectively. The markers IgG to HSV-1 were diagnosed in 97.5% of cases compared to 91.5% in the control group in imprisoned women, and IgG to HSV-2 in 72.5% and 28.8%, respectively. The Serological markers of IgG to HSV-2 were detected in women 1.5 times more often than in men. Only in the group of prisoners IgM were detected for both types of HSV (in women in 5.0% and in men in 7.5%). The prevalence of IgG antibodies to herpes simplex viruses (HSV-1 and HSV-2) among prisoners in Ukraine is quite high (95%). The presence of IgG to HSV-1 practically did not differ from the control levels in the population. IgG to HSV-2 were detected 2.5 times more often than in the general population and 1.5 times more often in women than in men. IgM to both types of HSV were detected only in the group of prisoners. Active herpetic manifestations in the genital area were diagnosed in 17% of the abovementioned patients. However, only 2.5% of prisoners reported a history of herpes in the anamnesis. The risk factors for having HSV-2 were: female gender, age over 35, HIV infection, risky sexual behaviour, drug abuse (up to 80%) and alcoholism (up to 30%), second incarceration, and extensive tattoos (97.5%).


Assuntos
Infecções por HIV , Herpes Simples , Humanos , Feminino , Masculino , Adulto , Prevalência , Infecções por HIV/epidemiologia , Anticorpos Antivirais , Herpesvirus Humano 2 , Imunoglobulina G , Imunoglobulina M
15.
BMJ Case Rep ; 15(11)2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36368731

RESUMO

An immunocompetent man in his 20s presented with a 24-hour history of severe odynophagia, nausea, vomiting and throat pain. Esophagogastroduodenoscopy (EGD) revealed severe esophagitis with ulcerated mucosa, exudative debris, haemorrhage and multiple erosions. Biopsy of the oesophageal tissue demonstrated marginated chromatin, multinucleated giant cells and molding of nuclei, consistent with herpes simplex virus esophagitis (HSE). Treatment with oral acyclovir led to the complete resolution of symptoms. The patient subsequently developed dysphagia again, 8 months later. EGD showed furrowing and concentric rings typical of eosinophilic esophagitis (EoE), a diagnosis confirmed by biopsy. Treatment with a proton pump inhibitor and swallowed topical corticosteroids led to symptomatic improvement. Thus, HSE can occur in immunocompetent hosts and on occasion, HSE may be a harbinger of EoE, as evidenced by our extensive literature review. Mechanical disruption of the mucosal barrier by viruses, facilitating food allergen penetration, and associated immunological signaling abnormalities may be responsible phenomena requiring further elucidation.


Assuntos
Transtornos de Deglutição , Esofagite Eosinofílica , Esofagite , Herpes Simples , Masculino , Adulto Jovem , Humanos , Esofagite Eosinofílica/complicações , Esofagite Eosinofílica/diagnóstico , Esofagite Eosinofílica/tratamento farmacológico , Esofagite/diagnóstico , Herpes Simples/complicações , Herpes Simples/diagnóstico , Herpes Simples/tratamento farmacológico , Simplexvirus , Dor
16.
J Neuroinflammation ; 19(1): 249, 2022 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-36203181

RESUMO

BACKGROUND: Trigeminal ganglia (TG) neurons are the main site of lifelong latent herpes simplex virus type 1 (HSV-1) infection. T-cells in ganglia contribute to long-term control of latent HSV-1 infection, but it is unclear whether these cells are bona fide tissue-resident memory T-cells (TRM). We optimized the processing of human post-mortem nervous tissue to accurately phenotype T-cells in human TG ex vivo and in situ. METHODS: Peripheral blood mononuclear cells (PBMC; 5 blood donors) were incubated with several commercial tissue digestion enzyme preparations to determine off-target effect on simultaneous detection of 15 specific T-cell subset markers by flow cytometry. Next, optimized enzymatic digestion was applied to ex vivo phenotype T-cells in paired PBMC, normal appearing white matter (NAWM) and TG of 8 deceased brain donors obtained < 9 h post-mortem by flow cytometry. Finally, the phenotypic and functional markers, and spatial orientation of T-cells in relation to neuronal somata, were determined in TG tissue sections of five HSV-1-latently infected individuals by multiparametric in situ analysis. RESULTS: Collagenase IV digestion of human nervous tissue was most optimal to obtain high numbers of viable T-cells without disrupting marker surface expression. Compared to blood, majority T-cells in paired NAWM and TG were effector memory T-cells expressing the canonical TRM markers CD69, CXCR6 and the immune checkpoint marker PD1, and about half co-expressed CD103. A trend of relatively higher TRM frequencies were detected in TG of latently HSV-1-infected compared to HSV-1 naïve individuals. Subsequent in situ analysis of latently HSV-1-infected TG showed the presence of cytotoxic T-cells (TIA-1+), which occasionally showed features of proliferation (KI-67+) and activation (CD137+), but without signs of degranulation (CD107a+) nor damage (TUNEL+) of TG cells. Whereas majority T-cells expressed PD-1, traits of T-cell senescence (p16INK4a+) were not detected. CONCLUSIONS: The human TG represents an immunocompetent environment in which both CD4 and CD8 TRM are established and retained. Based on our study insights, we advocate for TRM-targeted vaccine strategies to bolster local HSV-1-specific T-cell immunity, not only at the site of recurrent infection but also at the site of HSV-1 latency.


Assuntos
Herpes Simples , Infecções por Herpesviridae , Herpesvirus Humano 1 , Linfócitos T CD8-Positivos , Humanos , Antígeno Ki-67/metabolismo , Antígenos Comuns de Leucócito/metabolismo , Leucócitos Mononucleares , Células T de Memória , Receptor de Morte Celular Programada 1/metabolismo , Gânglio Trigeminal
17.
Front Immunol ; 13: 936235, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36211447

RESUMO

Herpes simplex viruses (HSV) types 1 and 2 are ubiquitous infections in humans. They cause orofacial and genital herpes with occasional severe complications. HSV2 also predisposes individuals to infection with HIV. There is currently no vaccine or immunotherapy for these diseases. Understanding the immunopathogenesis of HSV infections is essential to progress towards these goals. Both HSV viruses result in initial infections in two major sites - in the skin or mucosa, either after initial infection or recurrence, and in the dorsal root or trigeminal ganglia where the viruses establish latency. HSV1 can also cause recurrent infection in the eye. At all of these sites immune cells respond to control infection. T cells and resident dendritic cells (DCs) in the skin/mucosa and around reactivating neurones in the ganglia, as well as keratinocytes in the skin and mucosa, are major sources of cytokines and chemokines. Cytokines such as the Type I and II interferons synergise in their local antiviral effects. Chemokines such as CCL2, 3 and 4 are found in lesion vesicle fluid, but their exact role in determining the interactions between epidermal and dermal DCs and with resident memory and infiltrating CD4 and CD8 T cells in the skin/mucosa is unclear. Even less is known about these mechanisms in the ganglia. Here we review the data on known sources and actions of these cytokines and chemokines at cellular and tissue level and indicate their potential for preventative and therapeutic interventions.


Assuntos
Herpes Simples , Herpesvirus Humano 1 , Antivirais , Quimiocinas , Citocinas , Humanos , Interferons , Membrana Mucosa
18.
J Dtsch Dermatol Ges ; 20(10): 1327-1351, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36184818

RESUMO

Human herpes viruses belong to the DNA viruses and are among the most common viral pathogens. Currently, eight human herpes viruses have been characterized. Primary infection is typically followed by virus latency. Viral reactivations are more often symptomatic than primary infections and lead more often to medical consultation. In daily practice, infections with herpes simplex virus (HSV) and varicella zoster virus (VZV) are the most common. If HSV primary infections become clinically manifest, they are often accompanied by systemic symptoms whereas manifest HSV reactivations are usually harmless, self-limiting and present as grouped vesicles on an erythematous base (herpetiform). Primary VZV infection leads to the clinical picture of varicella (chickenpox). VZV reactivation manifests clinically as shingles and can be accompanied by severe acute neuralgiform pain. In immunosuppression, complicated (necrotizing, ulcerative, hemorrhagic, generalized) manifestations may occur. The diagnosis is usually made clinically. Therapeutic options include topical agents and systemic antivirals. Adequate therapeutic management includes the recognition and treatment of complications such as the possible involvement of other organ systems and pain. Infection during pregnancy may result in transmission to the unborn child.


Assuntos
Varicela , Herpes Simples , Herpes Zoster , Antivirais/uso terapêutico , Varicela/tratamento farmacológico , Herpes Simples/diagnóstico , Herpes Simples/tratamento farmacológico , Herpes Zoster/diagnóstico , Herpes Zoster/tratamento farmacológico , Herpesvirus Humano 3 , Humanos , Dor
19.
Sci Data ; 9(1): 610, 2022 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-36209289

RESUMO

Viruses are genetically and structurally diverse, and outnumber cells by orders of magnitude. They can cause acute and chronic infections, suppress, or exacerbate immunity, or dysregulate survival and growth of cells. To identify chemical agents with pro- or antiviral effects we conducted arrayed high-content image-based multi-cycle infection screens of 1,280 mainly FDA-approved compounds with three human viruses, rhinovirus (RV), influenza A virus (IAV), and herpes simplex virus (HSV) differing in genome organization, composition, presence of an envelope, and tropism. Based on Z'-factors assessing screening quality and Z-scores ranking individual compounds, we identified potent inhibitors and enhancers of infection: the RNA mutagen 5-Azacytidine against RV-A16; the broad-spectrum antimycotic drug Clotrimazole inhibiting IAV-WSN; the chemotherapeutic agent Raltitrexed blocking HSV-1; and Clobetasol enhancing HSV-1. Remarkably, the topical antiseptic compound Aminacrine, which is clinically used against bacterial and fungal agents, inhibited all three viruses. Our data underscore the versatility and potency of image-based, full cycle virus propagation assays in cell-based screenings for antiviral agents.


Assuntos
Anti-Infecciosos Locais , Herpes Simples , Vírus da Influenza A , Aminacrina/uso terapêutico , Anti-Infecciosos Locais/uso terapêutico , Antivirais/farmacologia , Azacitidina/uso terapêutico , Clobetasol/uso terapêutico , Clotrimazol/uso terapêutico , Herpes Simples/tratamento farmacológico , Humanos , Mutagênicos/uso terapêutico , Rhinovirus
20.
Sci Rep ; 12(1): 16577, 2022 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-36195643

RESUMO

Halophilic archaea is considered an promising natural source of many important metabolites. This study focused on one of the surface-active biomolecules named biosurfactants produced by haloarchaeon Natrialba sp. M6. The production trend was optimized and the product was partially purified and identified using GC-Mass spectrometry. Sequential optimization approaches, Plackett-Burman (PB) and Box-Behnken Designs (BBD) were applied to maximize the biosurfactants production from M6 strain by using 14 factors; pH, NaCl, agitation and glycerol; the most significant factors that influenced the biosurfactant production were used for Response Surface Methodology (RSM). The final optimal production conditions were agitation (150 rpm), glycerol (3%), NaCl (20.8%), pH (12) and cultivation temperature (37°C). GC-Mass spectrometry for the recovered extract revealed the presence of a diverse group of bipolar nature, hydrophobic hydrocarbon chain and charged function group. The majority of these compounds are fatty acids. Based on results of GC-MS, compositional analysis content and Zetasizer, it was proposed that the extracted biosurfactant produced by haloarchaeon Natrialba sp. M6 could be a cationic lipoprotein. The antiviral activity of such biosurfactant was investigated against hepatitis C (HCV) and herpes simplex (HSV1) viruses at its maximum safe doses (20 µg/mL and 8 µg/mL, respectively). Its mode of antiviral action was declared to be primarily via deactivating viral envelopes thus preventing viral entry. Moreover, this biosurfactant inhibited RNA polymerase- and DNA polymerase-mediated viral replication at IC50 of 2.28 and 4.39 µg/mL, respectively also. Molecular docking studies showed that surfactin resided well and was bound to the specified motif with low and accepted binding energies (ΔG = - 5.629, - 6.997 kcal/mol) respectively. Therefore, such biosurfactant could be presented as a natural safe and effective novel antiviral agent.


Assuntos
Hepatite C , Herpes Simples , Antivirais/farmacologia , DNA Polimerase Dirigida por DNA , Ácidos Graxos , Glicerol , Halobacteriaceae , Hepacivirus/metabolismo , Humanos , Simulação de Acoplamento Molecular , Cloreto de Sódio , Tensoativos/química
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