ABSTRACT
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.
Subject(s)
Reproductive Health/trends , Virus Diseases/complications , Hepatitis B/complications , Hepatitis B/physiopathology , Hepatitis C/complications , Hepatitis C/physiopathology , Herpes Genitalis/complications , Herpes Genitalis/physiopathology , Humans , Male , Papillomavirus Infections/complications , Papillomavirus Infections/physiopathology , Virus Diseases/physiopathology , Zika Virus Infection/complications , Zika Virus Infection/physiopathologyABSTRACT
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.
Subject(s)
Autophagy/physiology , Drugs, Chinese Herbal/pharmacology , Herpes Genitalis/prevention & control , Herpesvirus 2, Human/physiology , Phosphatidylinositol 3-Kinases/biosynthesis , Proto-Oncogene Proteins c-akt/biosynthesis , TOR Serine-Threonine Kinases/biosynthesis , Antiviral Agents/pharmacology , Cells, Cultured , Epithelial Cells/metabolism , Female , Herpes Genitalis/metabolism , Herpes Genitalis/physiopathology , Humans , Inflammation Mediators/metabolism , Signal Transduction/drug effectsABSTRACT
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.
Subject(s)
Genitalia, Female/pathology , Herpes Genitalis/physiopathology , Hormonal Contraception , Menstrual Cycle , Virus Shedding , Adult , DNA, Viral/analysis , Female , Genitalia, Female/virology , Herpes Genitalis/virology , Herpesvirus 2, Human/genetics , Herpesvirus 2, Human/physiology , Humans , Middle Aged , Statistics, Nonparametric , Young AdultABSTRACT
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.
Subject(s)
Cervical Length Measurement , Herpes Genitalis/pathology , Herpesvirus 2, Human/pathogenicity , Premature Birth , Animals , Escherichia coli Infections/complications , Escherichia coli Infections/physiopathology , Female , Herpes Genitalis/complications , Herpes Genitalis/physiopathology , Humans , Mice , Mice, Inbred C57BL , Models, Animal , PregnancyABSTRACT
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.
Subject(s)
Encephalitis, Herpes Simplex/chemically induced , Herpes Genitalis/drug therapy , Sildenafil Citrate/adverse effects , Blood-Brain Barrier/physiopathology , Encephalitis, Herpes Simplex/physiopathology , Encephalitis, Herpes Simplex/virology , Herpes Genitalis/physiopathology , Herpes Genitalis/virology , Humans , Male , Middle Aged , Permeability , Sildenafil Citrate/administration & dosageABSTRACT
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.
Subject(s)
Herpes Genitalis/physiopathology , Herpesvirus 2, Human/physiology , Interleukin-17/physiology , Keratinocytes/metabolism , Peripheral Nervous System/virology , Animals , Herpes Genitalis/virology , Humans , Keratinocytes/virology , Neurites/physiology , Neuroblastoma/physiopathology , Peripheral Nervous System/physiopathology , Virus Activation/physiologyABSTRACT
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.
Subject(s)
Herpesvirus 2, Human/physiology , Pregnancy Complications, Infectious , Sexually Transmitted Diseases , Virus Shedding , Adolescent , Adult , Ambulatory Care Facilities , Chlamydia Infections/epidemiology , Chlamydia Infections/microbiology , Chlamydia Infections/physiopathology , Female , Gonorrhea/epidemiology , Gonorrhea/microbiology , Gonorrhea/physiopathology , HIV Infections/epidemiology , HIV Infections/physiopathology , HIV Infections/virology , Herpes Genitalis/epidemiology , Herpes Genitalis/physiopathology , Herpes Genitalis/virology , Herpes Simplex/epidemiology , Herpes Simplex/physiopathology , Herpes Simplex/virology , Herpesvirus 2, Human/growth & development , Humans , Point-of-Care Testing , Pregnancy , Pregnancy Complications, Infectious/epidemiology , Pregnancy Complications, Infectious/microbiology , Pregnancy Complications, Infectious/physiopathology , Pregnancy Complications, Infectious/virology , Pregnancy Outcome , Randomized Controlled Trials as Topic , Retrospective Studies , Sexually Transmitted Diseases/epidemiology , Sexually Transmitted Diseases/microbiology , Sexually Transmitted Diseases/virology , South Africa , Young AdultABSTRACT
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.
Subject(s)
Genitalia/innervation , Genitalia/virology , Herpes Genitalis/physiopathology , Herpesvirus 2, Human/physiology , T-Lymphocytes, Regulatory/virology , Virus Activation/physiology , Virus Shedding/physiology , Female , Humans , Male , WashingtonABSTRACT
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.
Subject(s)
Cell Transplantation/methods , Herpes Genitalis/physiopathology , Infertility, Male/therapy , Orchitis/etiology , Spermatogenesis , Testis/transplantation , Acyclovir/adverse effects , Acyclovir/therapeutic use , Animals , Animals, Newborn , Antiviral Agents/adverse effects , Antiviral Agents/therapeutic use , Cell Transplantation/adverse effects , Combined Modality Therapy/adverse effects , Herpes Genitalis/drug therapy , Herpes Genitalis/immunology , Herpes Genitalis/virology , Immunohistochemistry , Infertility, Male/etiology , Infertility, Male/pathology , Infertility, Male/prevention & control , Kinetics , Male , Mice, Inbred C57BL , Mice, Transgenic , Orchitis/immunology , Orchitis/metabolism , Orchitis/prevention & control , Seminiferous Tubules/drug effects , Seminiferous Tubules/immunology , Seminiferous Tubules/metabolism , Seminiferous Tubules/pathology , Sertoli Cells/drug effects , Sertoli Cells/immunology , Sertoli Cells/metabolism , Sertoli Cells/pathology , Simplexvirus/drug effects , Simplexvirus/immunology , Simplexvirus/isolation & purification , Spermatids/drug effects , Spermatids/immunology , Spermatids/metabolism , Spermatids/pathology , Spermatogenesis/drug effects , Testis/drug effects , Testis/metabolism , Testis/pathologyABSTRACT
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.
Subject(s)
Acyclovir/analogs & derivatives , Fetal Membranes, Premature Rupture/diagnosis , Herpes Genitalis , Papanicolaou Test/methods , Pregnancy Complications, Infectious , Uterine Cervicitis , Valine/analogs & derivatives , Acyclovir/administration & dosage , Adult , Amniotic Fluid , Antiviral Agents/administration & dosage , Diagnosis, Differential , Female , Gynecological Examination/methods , Herpes Genitalis/diagnosis , Herpes Genitalis/drug therapy , Herpes Genitalis/physiopathology , Humans , Pregnancy , Pregnancy Complications, Infectious/diagnosis , Pregnancy Complications, Infectious/drug therapy , Pregnancy Complications, Infectious/etiology , Pregnancy Complications, Infectious/physiopathology , Pregnancy Outcome , Reproducibility of Results , Uterine Cervicitis/diagnosis , Uterine Cervicitis/drug therapy , Uterine Cervicitis/etiology , Uterine Cervicitis/physiopathology , Valacyclovir , Valine/administration & dosageABSTRACT
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.
Subject(s)
Coinfection/virology , Disease Susceptibility/physiopathology , HIV Infections/physiopathology , Herpes Genitalis/complications , Herpesvirus 2, Human/physiology , Integrins/metabolism , Simian Acquired Immunodeficiency Syndrome/physiopathology , Animals , CD11c Antigen/metabolism , CD4-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/pathology , Coinfection/pathology , Coinfection/physiopathology , Dendritic Cells/metabolism , Dendritic Cells/pathology , Disease Models, Animal , Disease Susceptibility/metabolism , Female , HIV/isolation & purification , HIV/physiology , HIV Infections/metabolism , HIV Infections/pathology , Herpes Genitalis/metabolism , Herpes Genitalis/physiopathology , Herpesvirus 2, Human/isolation & purification , Macaca mulatta , Simian Acquired Immunodeficiency Syndrome/metabolism , Simian Acquired Immunodeficiency Syndrome/pathology , Simian Immunodeficiency Virus/isolation & purification , Simian Immunodeficiency Virus/physiology , Up-Regulation , Vagina/metabolism , Vagina/pathology , Vagina/virologyABSTRACT
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.
Subject(s)
Herpes Genitalis/pathology , Herpesvirus 1, Human , Testis/pathology , Testis/virology , Animals , Cell Death , Herpes Genitalis/physiopathology , Herpes Genitalis/virology , Herpesvirus 1, Human/isolation & purification , Herpesvirus 1, Human/pathogenicity , Herpesvirus 1, Human/physiology , Immunohistochemistry , Male , Mice , Mice, Inbred C57BL , Microscopy, Confocal , Real-Time Polymerase Chain Reaction , Seminal Vesicles/pathology , Seminal Vesicles/virology , Sertoli Cells/pathology , Sertoli Cells/virology , Spermatogenesis/physiology , Viral Proteins/metabolism , Viral TropismABSTRACT
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.
Subject(s)
Herpesvirus 1, Human/enzymology , Intercellular Junctions/metabolism , Sertoli Cells/metabolism , Spermatogenesis , Spermatozoa/metabolism , Thymidine Kinase/metabolism , Viral Proteins/metabolism , Animals , Crosses, Genetic , Epididymis/metabolism , Epididymis/ultrastructure , Gene Expression Profiling , Herpes Genitalis/metabolism , Herpes Genitalis/pathology , Herpes Genitalis/physiopathology , Herpes Genitalis/virology , Humans , Infertility, Male/etiology , Infertility, Male/metabolism , Infertility, Male/pathology , Intercellular Junctions/ultrastructure , Male , Proteins/genetics , Proteins/metabolism , Rats , Rats, Inbred F344 , Rats, Transgenic , Recombinant Proteins/metabolism , Sertoli Cells/ultrastructure , Spermatozoa/ultrastructure , Testis/metabolism , Testis/ultrastructure , Thymidine Kinase/genetics , Viral Proteins/geneticsABSTRACT
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.
Subject(s)
Herpes Genitalis/physiopathology , Memory Disorders/etiology , Movement Disorders/etiology , Prenatal Exposure Delayed Effects/physiopathology , Schizophrenia/complications , Verbal Learning/physiology , Adult , Cohort Studies , Enzyme-Linked Immunosorbent Assay , Executive Function , Female , Humans , Male , Middle Aged , Motor Skills/physiology , Neuropsychological Tests , Pregnancy , Young AdultABSTRACT
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.
Subject(s)
Herpes Genitalis/immunology , Herpesvirus 2, Human , Killer Cells, Natural/immunology , Receptor, Interferon alpha-beta/immunology , Animals , Antiviral Agents/immunology , Female , Herpes Genitalis/physiopathology , Immunohistochemistry , Interleukin-15/metabolism , Mice , Mice, Inbred C57BL , Mice, KnockoutABSTRACT
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.
Subject(s)
Fas Ligand Protein/immunology , Herpes Genitalis/immunology , Herpesvirus 2, Human/physiology , Vagina/immunology , fas Receptor/immunology , Animals , Apoptosis , Disease Models, Animal , Epithelial Cells/cytology , Epithelial Cells/immunology , Epithelial Cells/virology , Fas Ligand Protein/genetics , Female , Herpes Genitalis/genetics , Herpes Genitalis/physiopathology , Herpes Genitalis/virology , Herpesvirus 2, Human/immunology , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Vagina/virology , fas Receptor/geneticsABSTRACT
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.
Subject(s)
Herpes Genitalis/immunology , Herpesvirus 2, Human/pathogenicity , Interferon Type I/metabolism , Leukemia Inhibitory Factor Receptor alpha Subunit/deficiency , Administration, Intravaginal , Animals , Female , Herpes Genitalis/physiopathology , Herpes Genitalis/virology , Herpes Simplex/virology , Herpesvirus 2, Human/metabolism , Humans , Leukemia Inhibitory Factor Receptor alpha Subunit/genetics , Mice , Mice, Inbred C57BL , Spinal Cord/immunology , Spinal Cord/virology , T-Lymphocytes, Cytotoxic/immunology , Vagina/immunology , Vagina/virology , Virus ReplicationABSTRACT
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.
Subject(s)
Infertility, Male , Simplexvirus , Spermatids , Spermatocytes , Spermatogenesis , Aged , Cells, Cultured , Herpes Genitalis/metabolism , Herpes Genitalis/physiopathology , Humans , Infertility, Male/metabolism , Infertility, Male/physiopathology , Infertility, Male/virology , Male , Sperm Motility , Spermatids/metabolism , Spermatids/virology , Spermatocytes/metabolism , Spermatocytes/virologyABSTRACT
El Herpes genital es una infección de transmisión sexual vírica que representa la causa más frecuente de úlcera genital en nuestro medio. Clínicamente, cursa con episodios recurrentes que pueden ser asintomáticos o con lesiones características vesículas-úlceras. Aunque existen pruebas serológicas que confirman el diagnóstico, así como el cultivo viral de las lesiones, en Atención Primaria el diagnóstico es eminentemente clínico. El tratamiento de elección consiste en fármacos antivirales sistémicos, que acortan el tiempo de eliminación del virus, aunque no evitan la recidiva. Es importante recordar su frecuente predisposición con otras infecciones de transmisión sexual y, en especial, con el VIH. Por ello, no debemos desaprovechar la ocasión para realizar su búsqueda. Presentamos el caso de un varón adulto de 36 años con lesiones características que acude a nuestra consulta (AU)
The genital herpes is an infection of viral sexual transmission that represents the most frequent reason of genital ulcer in our environment. Clinically it deals with recurrent episodes who can be asymptomatic or with typical injuries vesicles-ulcers. Though there are serologic tests that confirm the diagnosis, as well as viral culture of the injuries, at Primary Care the diagnosis is eminently clinical. The treatment of choice consists of antiviral systemic medicaments, wich they shorten the time of elimination of the virus though they do not avoid the recidivation. It is important to remember the frequent predisposition with other infections of sexual transmission especially with the HIV infection. So we must not fail to take advantage of the opportunity to do search it. We present a case of a 36 years old adult male with typical injuries that comes to our consultation (AU)