RESUMEN
Viral infections have haunted humankind since times immemorial. Overpopulation, globalization, and extensive deforestation have created an ideal environment for a viral spread with unknown and multiple shedding routes. Many viruses can infect the male reproductive tract, with potential adverse consequences to male reproductive health, including infertility and cancer. Moreover, some genital tract viral infections can be sexually transmitted, potentially impacting the resulting offspring's health. We have summarized the evidence concerning the presence and adverse effects of the relevant viruses on the reproductive tract (mumps virus, human immunodeficiency virus, herpes virus, human papillomavirus, hepatitis B and C viruses, Ebola virus, Zika virus, influenza virus, and coronaviruses), their routes of infection, target organs and cells, prevalence and pattern of virus shedding in semen, as well as diagnosis/testing and treatment strategies. The pathophysiological understanding in the male genital tract is essential to assess its clinical impact on male reproductive health and guide future research.
Asunto(s)
Salud Reproductiva/tendencias , Virosis/complicaciones , Hepatitis B/complicaciones , Hepatitis B/fisiopatología , Hepatitis C/complicaciones , Hepatitis C/fisiopatología , Herpes Genital/complicaciones , Herpes Genital/fisiopatología , Humanos , Masculino , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/fisiopatología , Virosis/fisiopatología , Infección por el Virus Zika/complicaciones , Infección por el Virus Zika/fisiopatologíaRESUMEN
ETHNOPHAMACOLOGICAL RELEVANCE: The Chinese herbal prescription JieZe-1 (JZ-1) is based on the modification of Yihuang Tang, which was first described in Fu Qingzhu Nvke by the famous Qing Dynasty doctor Shan Fu as a treatment for leukorrheal diseases. As an in-hospital preparation, JZ-1 has been used in Tongji Hospital for many years to treat various infectious diseases of the lower female genital tract, including cervicitis, vaginitis, genital herpes and condyloma acuminatum. Our previous studies have shown that JZ-1 has curative effects on Candida albicans, Trichomonas vaginalis and Ureaplasma urealyticum infections. AIM OF THE STUDY: Genital herpes is among the most common sexually transmitted diseases (STDs) worldwide and is mainly caused by herpes simplex virus type-2 (HSV-2). Current therapies can relieve symptoms in patients but do not cure or prevent the spread of the virus. This study was designed to investigate the effect of JZ-1 on HSV-2 infection and its mechanism, which is based on autophagy induction, to provide new ideas and a basis for the study of antiviral drugs. MATERIALS AND METHODS: Evaluation of the antiviral activity of JZ-1 was conducted by MTT assay and western blotting. Then, Western blot and immunofluorescence analyses, observations through transmission electron microscopy and experiments with the recombinant lentivirus vector mRFP-GFP-LC3B were used to monitor autophagic flux in VK2/E6E7 cells. To explore the mechanism by which JZ-1 regulates autophagy, western blotting and real-time quantitative PCR (qRT-PCR) were used to determine the expression of phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway proteins and to detect changes in critical molecules in the pathway after the application of a PI3K inhibitor. Additionally, the mRNA expression levels of inflammatory cytokines, namely, IL-6, IFN-α, IFN-ß and TNF-α, were measured with qRT-PCR. RESULTS: HSV-2 infection inhibited autophagy in the VK2/E6E7 cells. Further study revealed that the activation of the PI3K/Akt/mTOR pathway induced by HSV-2 infection may result in the blocked autophagic flux and inhibited autophagosome and autolysosome formation. JZ-1 exhibited significant antiviral activity in the VK2/E6E7 cells, which showed increased cell vitality and reduced viral protein expression, namely, earliest virus-specific infected cell polypeptides 5 (ICP5) and glycoprotein D (gD). We found that JZ-1 treatment inhibited the upregulation of the PI3K/Akt/mTOR pathway proteins and promoted autophagy to combat HSV-2 infection, while PI3K inhibitor pretreatment prevented the enhanced autophagy induced by JZ-1. Moreover, JZ-1 attenuated the increase in inflammatory cytokines that had been induced HSV-2 infection. CONCLUSION: Our results showed that JZ-1 protects against HSV-2 infection, and this beneficial effect may be mediated by inducing autophagy via inhibition of the PI3K/Akt/mTOR signaling axis.
Asunto(s)
Autofagia/fisiología , Medicamentos Herbarios Chinos/farmacología , Herpes Genital/prevención & control , Herpesvirus Humano 2/fisiología , Fosfatidilinositol 3-Quinasas/biosíntesis , Proteínas Proto-Oncogénicas c-akt/biosíntesis , Serina-Treonina Quinasas TOR/biosíntesis , Antivirales/farmacología , Células Cultivadas , Células Epiteliales/metabolismo , Femenino , Herpes Genital/metabolismo , Herpes Genital/fisiopatología , Humanos , Mediadores de Inflamación/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: The effect of female sex hormones on herpes simplex virus (HSV)-2 shedding and lesion frequency is poorly understood. Previous studies suggest that hormonal contraception may increase the frequency of HSV-2 shedding. METHODS: We studied HSV-2 seropositive women who performed daily genital swabbing for HSV DNA and completed diaries for genital lesions and menses. We used Poisson mixed effects models to determine if HSV detection varied throughout the menstrual cycle, or in response to hormonal contraception. We used the Wilcoxon signed-rank test and rank-sum test to determine if lesion frequency differed by cycle phase or hormonal contraceptive use. RESULTS: In 189 women aged 19 to 46 years who collected swabs on 10,715 days and were not using hormonal contraception, HSV-2 DNA was detected on 20.9% of days in the follicular phase and 17.8% of days in the luteal phase (rate ratio, 1.19; 95% confidence interval, 1.03-1.37, P = 0.02). Genital lesions did not differ in the follicular versus luteal phase (12.8% vs. 10.7%, P = 0.07). In analyses of hormonal contraception, including 244 women, HSV-2 DNA was detected on 19.0% of days for women not using hormonal contraception and 18.3% of days for those using hormonal contraception (P = 0.50). Lesions were present on 11.1% of days for women not using hormonal contraception, and 8.7% of days for those using hormonal contraception (P = 0.66). CONCLUSIONS: In women with genital HSV-2 infection who are not using hormonal contraception, the follicular phase of the cycle may be associated with a higher frequency of HSV-2 shedding compared to the luteal phase. Lesion frequency is similar during the 2 menstrual phases. Hormonal contraception use was not observed to affect genital HSV-2 DNA detection or lesions.
Asunto(s)
Genitales Femeninos/patología , Herpes Genital/fisiopatología , Anticoncepción Hormonal , Ciclo Menstrual , Esparcimiento de Virus , Adulto , ADN Viral/análisis , Femenino , Genitales Femeninos/virología , Herpes Genital/virología , Herpesvirus Humano 2/genética , Herpesvirus Humano 2/fisiología , Humanos , Persona de Mediana Edad , Estadísticas no Paramétricas , Adulto JovenRESUMEN
Preterm birth (PTB), or birth before 37 weeks gestation, is the leading cause of neonatal mortality worldwide. Cervical viral infections have been established as risk factors for PTB in women, although the mechanism leading to increased risk is unknown. Using a mouse model of pregnancy, we determined that intra-vaginal HSV2 infection caused increased rates of preterm birth following an intra-vaginal bacterial infection. HSV2 infection resulted in histological changes in the cervix mimicking cervical ripening, including significant collagen remodeling and increased hyaluronic acid synthesis. Viral infection also caused aberrant expression of estrogen and progesterone receptor in the cervical epithelium. Further analysis using human ectocervical cells demonstrated a role for Src kinase in virus-mediated changes in estrogen receptor and hyaluronic acid expression. In conclusion, HSV2 affects proteins involved in tissue hormone responsiveness, causes significant changes reminiscent of premature cervical ripening, and increases risk of preterm birth. Studies such as this improve our chances of identifying clinical interventions in the future.
Asunto(s)
Medición de Longitud Cervical , Herpes Genital/patología , Herpesvirus Humano 2/patogenicidad , Nacimiento Prematuro , Animales , Infecciones por Escherichia coli/complicaciones , Infecciones por Escherichia coli/fisiopatología , Femenino , Herpes Genital/complicaciones , Herpes Genital/fisiopatología , Humanos , Ratones , Ratones Endogámicos C57BL , Modelos Animales , EmbarazoRESUMEN
Herpes simplex encephalitis (HSE) is associated with significant mortality and morbidity. As a consequence of HSE, up to 75% of infected individuals die or experience irreversible neurological damage. While the pathogenesis of the disease is unknown, it is traditionally hypothesized that the viral infection occurs by neuronal transmission directly from peripheral sites. Non-neuronal modes of infection have generally been overlooked as the brain is protected by the blood-brain-barrier (BBB). The BBB poses an effective barrier to pathogens as well as to drugs such as chemotherapies. In the pursuit to deliver chemotherapeutic agents to the brain, several studies demonstrated that phosphodiesterase type 5 (PDE5) inhibitors, such as sildenafil, may increase the permeability of the BBB enabling successful delivery of chemotherapeutic agents to the brain. In this communication, we report a case of HSE infection in a 62-year-old man, which we suspect was facilitated by the use of sildenafil during a primary genital herpes simple virus (HSV) infection. Due to large number of patients treated with PDE5 inhibitors for erectile dysfunction and the high incidence of genital HSV infection in the general population, a larger study should examine the potential risk of developing HSE in patients treated with PDE5 inhibitors.
Asunto(s)
Encefalitis por Herpes Simple/inducido químicamente , Herpes Genital/tratamiento farmacológico , Citrato de Sildenafil/efectos adversos , Barrera Hematoencefálica/fisiopatología , Encefalitis por Herpes Simple/fisiopatología , Encefalitis por Herpes Simple/virología , Herpes Genital/fisiopatología , Herpes Genital/virología , Humanos , Masculino , Persona de Mediana Edad , Permeabilidad , Citrato de Sildenafil/administración & dosificaciónRESUMEN
Despite frequent herpes simplex virus (HSV) reactivation, peripheral nerve destruction and sensory anesthesia are rare. We discovered that skin biopsies obtained during asymptomatic human HSV-2 reactivation exhibit a higher density of nerve fibers relative to biopsies during virological and clinical quiescence. We evaluated the effects of HSV infection on keratinocytes, the initial target of HSV replication, to better understand this observation. Keratinocytes produced IL-17c during HSV-2 reactivation, and IL-17RE, an IL-17c-specific receptor, was expressed on nerve fibers in human skin and sensory neurons in dorsal root ganglia. In ex vivo experiments, exogenous human IL-17c provided directional guidance and promoted neurite growth and branching in microfluidic devices. Exogenous murine IL-17c pretreatment reduced apoptosis in HSV-2-infected primary neurons. These results suggest that IL-17c is a neurotrophic cytokine that protects peripheral nerve systems during HSV reactivation. This mechanism could explain the lack of nerve damage from recurrent HSV infection and may provide insight to understanding and treating sensory peripheral neuropathies.
Asunto(s)
Herpes Genital/fisiopatología , Herpesvirus Humano 2/fisiología , Interleucina-17/fisiología , Queratinocitos/metabolismo , Sistema Nervioso Periférico/virología , Animales , Herpes Genital/virología , Humanos , Queratinocitos/virología , Neuritas/fisiología , Neuroblastoma/fisiopatología , Sistema Nervioso Periférico/fisiopatología , Activación Viral/fisiologíaRESUMEN
OBJECTIVES: Genital herpes simplex virus-2 (HSV-2) shedding in pregnant women in association with neonatal herpes infection has been widely studied but there is limited evidence of its association with pregnancy outcomes. METHODS: In this retrospective observational study, we included a subgroup of pregnant women who were enrolled in a randomized control behavioural intervention study that was conducted in South Africa in 2008-2010. In pregnancy, women had a HIV rapid test done and a genital swab taken to test for curable STIs and HSV-2 DNA. Subsequent visits were scheduled for 6, 10, 14 weeks and 9 months post-delivery. Pregnancy outcomes were documented at the 6-week or 10-week postpartum visit. Women were treated syndromically for curable STIs. RESULTS: Among 615 women included in this data analysis, 36.6% (n=225) tested HIV positive and 8.3% (n=51) tested positive for genital HSV-2 shedding during pregnancy. Women <24 years and HIV-1 seropositive women were 1.5 and 2.5 times more likely to test positive for HSV-2 genital shedding respectively. STI treatment records were available for 158/205 (77.1%) women; all 87 women with symptomatic STIs were treated the same day, and 50/71 (70.4%) asymptomatic women received treatment at the subsequent visit. Remaining 21 (29.6%) asymptomatic women did not receive treatment because they failed to return for antenatal follow-up. In a multivariable regression analysis, genital HSV-2 shedding, HIV-1, Neisseria gonorrhoea, Chlamydia trachomatis and Trichomanas vaginalis were not associated with preterm deliveries, still births and low birth weight. However with stratification by treatment for a STI, asymptomatic women who were not treated were 3.3 times more likely to deliver prematurely (33.3%; n=6/18) when compared to women who were treated during pregnancy (13.2%; n=15/114) (p=0.042). CONCLUSIONS: Genital HSV-2 shedding in pregnancy does not appear to alter pregnancy outcomes. Untreated curable STIs (T.vaginalis, C.trachomatis, N.gonorrhoea) were more likely associated with preterm births.
Asunto(s)
Herpesvirus Humano 2/fisiología , Complicaciones Infecciosas del Embarazo , Enfermedades de Transmisión Sexual , Esparcimiento de Virus , Adolescente , Adulto , Instituciones de Atención Ambulatoria , Infecciones por Chlamydia/epidemiología , Infecciones por Chlamydia/microbiología , Infecciones por Chlamydia/fisiopatología , Femenino , Gonorrea/epidemiología , Gonorrea/microbiología , Gonorrea/fisiopatología , Infecciones por VIH/epidemiología , Infecciones por VIH/fisiopatología , Infecciones por VIH/virología , Herpes Genital/epidemiología , Herpes Genital/fisiopatología , Herpes Genital/virología , Herpes Simple/epidemiología , Herpes Simple/fisiopatología , Herpes Simple/virología , Herpesvirus Humano 2/crecimiento & desarrollo , Humanos , Pruebas en el Punto de Atención , Embarazo , Complicaciones Infecciosas del Embarazo/epidemiología , Complicaciones Infecciosas del Embarazo/microbiología , Complicaciones Infecciosas del Embarazo/fisiopatología , Complicaciones Infecciosas del Embarazo/virología , Resultado del Embarazo , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Retrospectivos , Enfermedades de Transmisión Sexual/epidemiología , Enfermedades de Transmisión Sexual/microbiología , Enfermedades de Transmisión Sexual/virología , Sudáfrica , Adulto JovenRESUMEN
BACKGROUND: Herpes simplex virus type 2 (HSV-2) reactivation is accompanied by a sustained influx of CD4(+) and CD8(+) T cells that persist in genital tissue for extended periods. While CD4(+) T cells have long been recognized as being present in herpetic ulcerations, their role in subclinical reactivation and persistence is less well known, especially the role of CD4(+) regulatory T cells (Tregs). METHODS: We characterized the Treg (CD4(+)Foxp3(+)) population during human HSV-2 reactivation in situ in sequential genital skin biopsy specimens obtained from HSV-2-seropositive subjects at the time of lesion onset up to 8 weeks after healing. RESULTS: High numbers of Tregs infiltrated to the site of viral reactivation and persisted in proximity to conventional CD4(+) T cells (Tconvs) and CD8(+) T cells. Treg density peaked during the lesion stage of the reactivation. The number of Tregs from all time points (lesion, healed, 2 weeks after healing, 4 weeks after healing, and 8 weeks after healing) was significantly higher than in control biopsy specimens from unaffected skin. There was a direct correlation between HSV-2 titer and Treg density. CONCLUSIONS: The association of a high Treg to Tconv ratio with high viral shedding suggests that the balance between regulatory and effector T cells influences human HSV-2 disease.
Asunto(s)
Genitales/inervación , Genitales/virología , Herpes Genital/fisiopatología , Herpesvirus Humano 2/fisiología , Linfocitos T Reguladores/virología , Activación Viral/fisiología , Esparcimiento de Virus/fisiología , Femenino , Humanos , Masculino , WashingtónRESUMEN
Genital tract infection and inflammation may affect male fertility, causing germ and Sertoli cell loss. We determined if testicular cell transplantation is effective at repairing testicular injury induced by herpes simplex virus (HSV) orchitis. ROSA26 mice were used as donors and the recipients were C57BL/6 mice after HSV testicular inoculation; some of the recipients were treated with the antiviral drug acyclovir (ACV). ACV reduced the amount of HSV antigen in testes on Day 3 after transplantation and enhanced the efficacy of transplantation at Day 30. In recipient testes, donor Sertoli cells formed new seminiferous tubules; significantly more new tubules were observed in the testes of ACV-treated mice compared with mice not treated with ACV (17.8% vs 3.6%). Over half (50.4%) of new tubules in ACV-treated testes contained germ cells and round spermatids were detected in 14.2% of new tubules compared with 15.9% and 5.3% in testes not treated with ACV, respectively. At Day 150 the seminiferous epithelium was completely recovered in some donor tubules and elongated spermatids were observed inside it. Thus, our findings reveal the effectiveness of the combination of antiviral therapy with neonatal testis-cell transplantation for the restoration of spermatogenesis damaged by viral infection.
Asunto(s)
Trasplante de Células/métodos , Herpes Genital/fisiopatología , Infertilidad Masculina/terapia , Orquitis/etiología , Espermatogénesis , Testículo/trasplante , Aciclovir/efectos adversos , Aciclovir/uso terapéutico , Animales , Animales Recién Nacidos , Antivirales/efectos adversos , Antivirales/uso terapéutico , Trasplante de Células/efectos adversos , Terapia Combinada/efectos adversos , Herpes Genital/tratamiento farmacológico , Herpes Genital/inmunología , Herpes Genital/virología , Inmunohistoquímica , Infertilidad Masculina/etiología , Infertilidad Masculina/patología , Infertilidad Masculina/prevención & control , Cinética , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Orquitis/inmunología , Orquitis/metabolismo , Orquitis/prevención & control , Túbulos Seminíferos/efectos de los fármacos , Túbulos Seminíferos/inmunología , Túbulos Seminíferos/metabolismo , Túbulos Seminíferos/patología , Células de Sertoli/efectos de los fármacos , Células de Sertoli/inmunología , Células de Sertoli/metabolismo , Células de Sertoli/patología , Simplexvirus/efectos de los fármacos , Simplexvirus/inmunología , Simplexvirus/aislamiento & purificación , Espermátides/efectos de los fármacos , Espermátides/inmunología , Espermátides/metabolismo , Espermátides/patología , Espermatogénesis/efectos de los fármacos , Testículo/efectos de los fármacos , Testículo/metabolismo , Testículo/patologíaRESUMEN
BACKGROUND: The diagnosis of preterm premature rupture of membranes (PROM) is based on pooling, ferning, and Nitrazine tests; definitive diagnosis is made with a blue dye test. CASE: A 21-year-old woman, gravida 1 para 0, at 25 5/7 weeks of gestation was admitted for preterm PROM with positive findings of pooling, Nitrazine, and ferning. Her cervix was bluish with white plaques. Amniotic fluid volume was normal. On hospital day 8, her discharge ceased; examination was negative for pooling, Nitrazine, and ferning. A blue dye tampon test was negative. A Pap test result from her hospitalization returned consistent with herpes infection. CONCLUSION: The diagnosis of preterm PROM should be constantly reevaluated in the setting of a normal amniotic fluid volume.
Asunto(s)
Aciclovir/análogos & derivados , Rotura Prematura de Membranas Fetales/diagnóstico , Herpes Genital , Prueba de Papanicolaou/métodos , Complicaciones Infecciosas del Embarazo , Cervicitis Uterina , Valina/análogos & derivados , Aciclovir/administración & dosificación , Adulto , Líquido Amniótico , Antivirales/administración & dosificación , Diagnóstico Diferencial , Femenino , Examen Ginecologíco/métodos , Herpes Genital/diagnóstico , Herpes Genital/tratamiento farmacológico , Herpes Genital/fisiopatología , Humanos , Embarazo , Complicaciones Infecciosas del Embarazo/diagnóstico , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Complicaciones Infecciosas del Embarazo/etiología , Complicaciones Infecciosas del Embarazo/fisiopatología , Resultado del Embarazo , Reproducibilidad de los Resultados , Cervicitis Uterina/diagnóstico , Cervicitis Uterina/tratamiento farmacológico , Cervicitis Uterina/etiología , Cervicitis Uterina/fisiopatología , Valaciclovir , Valina/administración & dosificaciónRESUMEN
The availability of highly susceptible HIV target cells that can rapidly reach the mucosal lymphoid tissues may increase the chances of an otherwise rare transmission event to occur. Expression of α4ß7 is required for trafficking of immune cells to gut inductive sites where HIV can expand and it is expressed at high level on cells particularly susceptible to HIV infection. We hypothesized that HSV-2 modulates the expression of α4ß7 and other homing receptors in the vaginal tissue and that this correlates with the increased risk of HIV acquisition in HSV-2 positive individuals. To test this hypothesis we used an in vivo rhesus macaque (RM) model of HSV-2 vaginal infection and a new ex vivo model of macaque vaginal explants. In vivo we found that HSV-2 latently infected RMs appeared to be more susceptible to vaginal SHIVSF162P3 infection, had higher frequency of α4ß7high CD4+ T cells in the vaginal tissue and higher expression of α4ß7 and CD11c on vaginal DCs. Similarly, ex vivo HSV-2 infection increased the susceptibility of the vaginal tissue to SHIVSF162P3. HSV-2 infection increased the frequencies of α4ß7high CD4+ T cells and this directly correlated with HSV-2 replication. A higher amount of inflammatory cytokines in vaginal fluids of the HSV-2 infected animals was similar to those found in the supernatants of the infected explants. Remarkably, the HSV-2-driven increase in the frequency of α4ß7high CD4+ T cells directly correlated with SHIV replication in the HSV-2 infected tissues. Our results suggest that the HSV-2-driven increase in availability of CD4+ T cells and DCs that express high levels of α4ß7 is associated with the increase in susceptibility to SHIV due to HSV-2. This may persists in absence of HSV-2 shedding. Hence, higher availability of α4ß7 positive HIV target cells in the vaginal tissue may constitute a risk factor for HIV transmission.
Asunto(s)
Coinfección/virología , Susceptibilidad a Enfermedades/fisiopatología , Infecciones por VIH/fisiopatología , Herpes Genital/complicaciones , Herpesvirus Humano 2/fisiología , Integrinas/metabolismo , Síndrome de Inmunodeficiencia Adquirida del Simio/fisiopatología , Animales , Antígeno CD11c/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/patología , Coinfección/patología , Coinfección/fisiopatología , Células Dendríticas/metabolismo , Células Dendríticas/patología , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades/metabolismo , Femenino , VIH/aislamiento & purificación , VIH/fisiología , Infecciones por VIH/metabolismo , Infecciones por VIH/patología , Herpes Genital/metabolismo , Herpes Genital/fisiopatología , Herpesvirus Humano 2/aislamiento & purificación , Macaca mulatta , Síndrome de Inmunodeficiencia Adquirida del Simio/metabolismo , Síndrome de Inmunodeficiencia Adquirida del Simio/patología , Virus de la Inmunodeficiencia de los Simios/aislamiento & purificación , Virus de la Inmunodeficiencia de los Simios/fisiología , Regulación hacia Arriba , Vagina/metabolismo , Vagina/patología , Vagina/virologíaRESUMEN
Herpes simplex virus (HSV) causes inflammatory diseases of the genitourinary system of males, infects male sex cells, and its presence in the ejaculate is associated with infertility. However, information on the pathways of HSV in the testicles, the extent of damage of spermatogenic tissue and the effect on spermatogenesis are insufficient. This work was aimed to the evaluation of effect of HSV on mice spermatogenesis in retrograde infection with the virus. Molecular (RT-PCR), virologic, morphological and immunohistochemical methods were used. Analysis showed that after virus inoculation directly into seminiferous tubules the viral protein is found in all layers of seminiferous epithelium. On the third day of infection the proportion of tubules containing HSV protein was 4.9%, reached a maximum on day 6 - 23,5 and 18% for the high and low doses of HSV, respectively, and then decreased; viral protein was not detected on 21th and 45th day. HSV DNA was detected in the testes at all stages of infection. Since the 14th day after infection, testes weight was significantly reduced compared to the control: 7,9-fold decrease at 45th day with a high dose of HSV, and 4,9-fold decrease with low dose. The infection with HSV led to the development of orchitis and considerable destructive changes in the spermatogenic tissue. The proportion of morphologically normal tubules was reduced to 6 and 15% at day 14 and remained at a low level up to 45th day. Approximately half of the seminiferous tubules (46.5%) at the 14th and 21th day had no somatic Sertoli cells needed for the restoration of spermatogenic tissue. These data suggests that retrograde infection of male gonads with HSV leads to the structure damage of testis and death of germ and somatic cells, indicating the irreversibility of degenerative changes in infected testes.
Asunto(s)
Herpes Genital/patología , Herpesvirus Humano 1 , Testículo/patología , Testículo/virología , Animales , Muerte Celular , Herpes Genital/fisiopatología , Herpes Genital/virología , Herpesvirus Humano 1/aislamiento & purificación , Herpesvirus Humano 1/patogenicidad , Herpesvirus Humano 1/fisiología , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos C57BL , Microscopía Confocal , Reacción en Cadena en Tiempo Real de la Polimerasa , Vesículas Seminales/patología , Vesículas Seminales/virología , Células de Sertoli/patología , Células de Sertoli/virología , Espermatogénesis/fisiología , Proteínas Virales/metabolismo , Tropismo ViralRESUMEN
Transgenic rats show spermatid-specific ectopic expression of the reporter gene, herpes simplex virus type1 thymidine kinase (HSV1-TK), in the testes and have demonstrated male infertility. However, the disruption of spermatogenesis and the underlying molecular mechanisms in these transgenic animals have not been well clarified. In this study, light and electron microscopic observations were performed to characterize the morphological changes in the testes. To explore the molecular mechanisms of male infertility in the HSV1-TK transgenic rat, cDNA microarray and quantitative real-time PCR analyses were performed. The seminiferous tubules of 3-month-old transgenic rats showed morphological alterations including seminiferous epithelial sloughing, vacuolization, and degeneration of spermatogenic cells, suggesting a failure of Sertoli-germ cell interaction. Components of the epididymal lumen from transgenic rats included abnormal spermatozoa, degenerating round spermatids and abnormal elongated spermatids indicating an appearance of direct impairment of spermiogenesis. cDNA microarray and real-time PCRanalyses revealed significant changes (P<0.05) in the gene expression level in six genes, testin, versican, mamdc1, fgf7, ostf1 and cnot7. Among them, testin drew most of our attention, since the testin gene is a sensitive marker for disruption of Sertoli-germ cell adhesion. Thus, our results suggest that the accumulation of HSV1-TK in the spermatids not only directly interferes with spermiogenesis but also disrupts spermatogenesis through a disruption of Sertoli-germ cell adhesions. It is important to explore the testicular actions of the HSV1-TK protein in transgenic experimental models and thereby gain clues to find an appropriate treatment for HSV-infected patients exhibiting human male infertility, as has been recently observed.
Asunto(s)
Herpesvirus Humano 1/enzimología , Uniones Intercelulares/metabolismo , Células de Sertoli/metabolismo , Espermatogénesis , Espermatozoides/metabolismo , Timidina Quinasa/metabolismo , Proteínas Virales/metabolismo , Animales , Cruzamientos Genéticos , Epidídimo/metabolismo , Epidídimo/ultraestructura , Perfilación de la Expresión Génica , Herpes Genital/metabolismo , Herpes Genital/patología , Herpes Genital/fisiopatología , Herpes Genital/virología , Humanos , Infertilidad Masculina/etiología , Infertilidad Masculina/metabolismo , Infertilidad Masculina/patología , Uniones Intercelulares/ultraestructura , Masculino , Proteínas/genética , Proteínas/metabolismo , Ratas , Ratas Endogámicas F344 , Ratas Transgénicas , Proteínas Recombinantes/metabolismo , Células de Sertoli/ultraestructura , Espermatozoides/ultraestructura , Testículo/metabolismo , Testículo/ultraestructura , Timidina Quinasa/genética , Proteínas Virales/genéticaRESUMEN
Maternal exposure to genital and reproductive infections has been associated with schizophrenia in previous studies. Impairments in several neuropsychological functions, including verbal memory, working memory, executive function, and fine-motor coordination occur prominently in patients with schizophrenia. The etiologies of these deficits, however, remain largely unknown. We aimed to assess whether prospectively documented maternal exposure to genital/reproductive (G/R) infections was related to these neuropsychological deficits in offspring with schizophrenia and other schizophrenia spectrum disorders. The cases were derived from a population-based birth cohort; all cohort members belonged to a prepaid health plan. Cases were assessed for verbal memory, working memory, executive function, and fine-motor coordination. Compared to unexposed cases, patients exposed to maternal genital/reproductive infection performed more poorly on verbal memory, fine-motor coordination, and working memory. Stratification by race revealed associations between maternal G/R infection and verbal memory and fine-motor coordination for case offspring of African-American mothers, but not for case offspring of White mothers. Significant infection-by-race interactions were also observed. Although independent replications are warranted, maternal G/R infections were associated with verbal memory and motor function deficits in African-American patients with schizophrenia.
Asunto(s)
Herpes Genital/fisiopatología , Trastornos de la Memoria/etiología , Trastornos del Movimiento/etiología , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Esquizofrenia/complicaciones , Aprendizaje Verbal/fisiología , Adulto , Estudios de Cohortes , Ensayo de Inmunoadsorción Enzimática , Función Ejecutiva , Femenino , Humanos , Masculino , Persona de Mediana Edad , Destreza Motora/fisiología , Pruebas Neuropsicológicas , Embarazo , Adulto JovenRESUMEN
Type I interferon (IFN) signalling, NK cells and NK cell-derived IFN-γ are critical in the early control of genital HSV-2 infection. We have recently reported that NK cells are the source of early IFN-γ in the genital tract in response to HSV-2. However, the response of NK cells to genital HSV-2 infection is not well defined in the context of type I IFN signalling. Here we show that HSV-2 replication was significantly higher in mice deficient in the type I IFN receptor or NK cells compared to wild type controls. There was no detectable IFN-γ production in the genital washes from IFN-α/ßR(-/-) mice or NK cell depleted mice in response to HSV-2 infection compared to control mice. Absence of the type I IFN receptor does not alter homing of NK cells to the genital mucosa. Moreover, the absence of IL-12 had no significant effect on NK cell-derived IFN-γ. Surprisingly, IFN-α/ßR(-/-) mice had more IL-15 positive cells in the genital mucosa in response to HSV-2 infection compared to control mice. We then examined the expression of IL-15 receptors on NK cells. There was no significant differences in the levels of IL-15 receptor expression on NK cells from IFN-α/ßR(-/-) or control mice. Our data clearly suggest that type I IFN receptor signalling is essential for NK cell activation in response to genital HSV-2 infection, and propose that NK cell activation by IL-15 may involve type I IFNs.
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Herpes Genital/inmunología , Herpesvirus Humano 2 , Células Asesinas Naturales/inmunología , Receptor de Interferón alfa y beta/inmunología , Animales , Antivirales/inmunología , Femenino , Herpes Genital/fisiopatología , Inmunohistoquímica , Interleucina-15/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
To assess the role of Fas in lesion development during genital HSV-2 infection, we used a well-established HSV-2 murine model applied to MRL-Fas(lpr)/J (Fas-/-) and C3-Fasl(gld)/J (FasL-/-) C57BL6 mice. In vitro infection of murine keratinocytes and epithelial cells was used to clarify molecular details of HSV-2 infection. Despite upregulation of Fas and FasL, HSV-2-infected keratinocytes and epithelial cells showed a moderate level of apoptosis due to upregulated expression of the anti-apoptotic factors Bcl-2, Akt kinase and NF-κB. Inflammatory lesions within the HSV-2-infected epithelium of C57BL6 mice consisted of infected cells upregulating Fas, FasL and Bcl-2, uninfected cells upregulating Fas and neutrophils expressing both Fas and FasL. Apoptosis was detected in HSV-2-infected cells and to even higher extent in non-infected cells surrounding HSV-2 infection sites. HSV-2 infection of Fas- and FasL-deficient mice led to increased apoptosis and stronger recruitment of neutrophils within the infection sites. We conclude that the Fas pathway participates in regulation of inflammatory response in the vaginal epithelium at the initial stage of HSV-2 infection.
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Proteína Ligando Fas/inmunología , Herpes Genital/inmunología , Herpesvirus Humano 2/fisiología , Vagina/inmunología , Receptor fas/inmunología , Animales , Apoptosis , Modelos Animales de Enfermedad , Células Epiteliales/citología , Células Epiteliales/inmunología , Células Epiteliales/virología , Proteína Ligando Fas/genética , Femenino , Herpes Genital/genética , Herpes Genital/fisiopatología , Herpes Genital/virología , Herpesvirus Humano 2/inmunología , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Vagina/virología , Receptor fas/genéticaRESUMEN
The mouse model of genital herpes relies on medoxyprogesterone treatment of female mice to render the vaginal lumen susceptible to inoculation with herpes simplex virus 2 (HSV-2). In the present study, we report that mice deficient in the A1 chain of the type I interferon receptor (CD118(-/-)) are susceptible to HSV-2 in the absence of medroxyprogesterone preconditioning. In the absence of hormone pretreatment, 2,000 PFU of a clinical isolate of HSV-2 was sufficient to establish a productive infection in the vagina of 75% ± 17% and in the spinal cord of 71% ± 14% of CD118(-/-) mice, whereas the same dose of HSV-2 replicated to detectable levels in only 13% ± 13% of vaginal samples and 0% of spinal cord samples from wild-type mice, as determined at day 5 postinfection. The susceptibility to HSV-2 infection in the CD118(-/-) mice was associated with a significant reduction in the infiltration of HSV-specific cytotoxic T lymphocytes into the vaginal tissue, the local production of gamma interferon (IFN-γ), and the expression of T cell-recruiting chemokines CCL5, CXCL9, and CXCL10. Collectively, the results underscore the significant contribution of type I IFNs in resistance to genital HSV-2 infection.
Asunto(s)
Herpes Genital/inmunología , Herpesvirus Humano 2/patogenicidad , Interferón Tipo I/metabolismo , Subunidad alfa del Receptor del Factor Inhibidor de Leucemia/deficiencia , Administración Intravaginal , Animales , Femenino , Herpes Genital/fisiopatología , Herpes Genital/virología , Herpes Simple/virología , Herpesvirus Humano 2/metabolismo , Humanos , Subunidad alfa del Receptor del Factor Inhibidor de Leucemia/genética , Ratones , Ratones Endogámicos C57BL , Médula Espinal/inmunología , Médula Espinal/virología , Linfocitos T Citotóxicos/inmunología , Vagina/inmunología , Vagina/virología , Replicación ViralRESUMEN
To investigate the effect of Herpes Simplex virus (HSV) on spermatogenesis, HSV in ejaculate was detected by a rapid cultural method in 268 infertile males and 47 healthy ones. The number of mobile spermatozoa in HSV infected samples was less than in non-infected samples (21 mln/mlversus 40 mln/ml, p = 0.0001). The relative number of morphologically normal gametes was 13% versus 19% (p = 0.002), respectively. The quantitative karyological test discovered that males with HSV-infected ejaculate have more degenerating sex cells while in high virus contamination (more than 10 virus particles in 1 ml) the number of spermatides and spermatocytes of the 1 order at diploten stage is low. Organic testicular culture was used for more detailed study of pathogenetic mechanisms of HSV impact on spermatogenesis. Testicular explants infection was associated with reduction in the number of spermatogones, spermatocytes and spermatides on culturing week 2. The above findings reveal some pathogenetic mechanisms underling fertility disorders in males with HSV infection: a gametotoxic effect of the virus reducing populations of spermatogones, spermatocytes and spermatide; affected mobility and morphological characteristics of spermatozoa. Detection of the mechanisms of HSV action on spermatogenesis opens a perspective of antivirus drug administration in combined treatment of male infertility.