HSV Type Research Articles

Israeli neonatal herpes simplex infection: Unique epidemiology and clinical profile

AbstractTo gather national level data on Israeli neonatal HSV (NHSV) infection and to evaluate the distinct clinical characteristics of NHSV and neonatal enteroviral meningitis (NEM). Israeli NHSV patients, hospitalized between January 2015 and April 2022 in 22 medical centers were assessed, together with NEM patients, hospitalized at Sheba Medical Center during the same period. NHSV demographic and clinical characteristics were documented and compared to those of NEM. Eighty‐five NHSV (73% males) and 130 NEM (62% males) patients were included. The incidence of NHSV was 5.9/100 000 live births, the common phenotype and HSV type were SEM (53%) and HSV1 (91%), respectively. Horizontal transmission was suspected in 50% cases (of which 67% underwent a Jewish ritual circumcision with direct wound sucking, 33% had relatives with highly suspicious herpetic lesions). Compared with NEM, NHSV tends to present with rash (14% vs. 60%, p‐value < 0.01) and seizures (0% vs. 6%, p‐value 0.02), while fever, irritability and poor feeding appear more frequently in NEM (94% vs. 18%, p‐value < 0.01; 37% vs. 1%, p‐value < 0.01; 25% vs. 1%, p‐value < 0.01 respectively). Of NEM patients, 28% were treated with acyclovir. Our results mark a decrease in the incidence rate of NHSV in Israel and a prominent mode of horizontal infection acquisition. We underscore the unique localized phenotype of NHSV, in contrast to enterovirus, which tends to cause a systemic disease with constitutional symptoms. These findings should be considered when evaluating the need for comprehensive empirical treatment for HSV in the context of neonatal fever, or according to a certain clinical presentation.

Herpes Simplex Type 1 as the Predominant Cause of Genital Herpes in College Students.

Genital herpes etiology has been shifting to include a greater proportion of herpes simplex virus type 1 (HSV-1) infection in the last few decades. A prior study published in 2003 found that 48.9% of infections in a college health population were HSV-1. We evaluated the number of positive HSV polymerase chain reaction test results obtained from anogenital sites from undergraduate and graduate students from 2013 to 2022 in a college health clinic setting and analyzed the number caused by HSV-1 and HSV type 2 and compared by sex. This was then compared with the prior study from 1993 to 2001. We received 691 (of 2685 samples) positive polymerase chain reaction results for HSV of both types in the period analyzed. Overall, 600 (86.8%) of these were HSV-1, and 520 (75.2%) were in female patients. The prior study in 1993 to 2001 found that 48.9% (244 of 675) of all positive test results were HSV-1; we observed an increase in the percentage of positive HSV-1 over all positive test results of 1.8 ( χ2 = 16.548; P < 0.001). Our study shows that 86.8% of the positive genital HSV test results from 2013 to 2022 were HSV-1. This shows that most positive HSV test results in this setting are now HSV-1, a substantial increase from the previous study in our clinic.

Effect of acyclovir therapy on the outcome of mechanically ventilated patients with lower respiratory tract infection and detection of herpes simplex virus in bronchoalveolar lavage: protocol for a multicentre, randomised controlled trial (HerpMV)

IntroductionHerpes simplex virus (HSV) is frequently detected in the respiratory tract of mechanically ventilated patients and is associated with a worse outcome. The aim of this study is to determine...

Rational approaches to therapy for combined urogenital infections in married couples

The purpose of the study. The aim of the study was to evaluate the effectiveness of antiviral therapy in urogenital infection caused by the herpes simplex virus in combination with human papillomavirus (HSV‑1, -2 and HPV) in couples with impaired reproductive function.Materials and methods. The study included 149 married couples with complaints about the absence or pathological course of pregnancy with termination in the first trimester. Urogenital infection caused by the herpes simplex virus was detected in 80 couples. A combination with human papillomavirus was detected in 36 cases. The effectiveness of antiviral therapy was evaluated.Results. After the first course of treatment with the use of an antiherpetic drug in 80 couples who had manifestations of active herpes infection, pregnancy and the birth of a healthy child were registered in 44 cases (55%). Combination therapy with acyclovir or valacyclovir and inosine pranobex was required, which led to a positive dynamic of indicators in case of a combined infection. The onset and normal course of pregnancy were registered after treatment in 33% of couples in this group.Conclusions. A possible cause of reproductive dysfunction with the absence or termination of pregnancy in the early stages may be a urogenital infection caused by HSV types 1, 2. In most cases, antiviral therapy promotes the birth of a healthy child. The ineffectiveness of therapy may be associated with the simultaneous presence of two or more infectious significant agents. For the treatment of couples who have an active persistence of HSV‑1, -2 in combination with HPV, the appointment of inosine pranobex in combination with acyclovir or valacyclovir is recommended.

P30 Blisters in a newborn: all that glitters is not gold

Abstract Mastocytosis is a rare and clinically heterogeneous disease characterized by abnormal accumulation of mast cells in various tissues. There are three major types of cutaneous mastocytosis (CM): diffuse cutaneous mastocytosis (DCM), urticaria pigmentosa and solitary mastocytoma, which is the most common form before the age of 3 months: 90% of CM cases present before 2 years of age, and congenital mastocytosis has been described in 23% of those. Solitary mastocytoma has been associated with a mutation of the KIT gene. A male infant was born at 39 weeks, with a large, indurated, blistering, ulcerated plaque containing yellow serous fluid affecting half his right calf. His nails and oral mucosa were normal. Our centre was contacted on suspected diagnosis of inherited epidermolysis bullosa (EB). There was no family history of EB, and the parents were not related. Initial testing showed a PCR positive for HSV type 1 and treatment with aciclovir and cefotaxime was initiated. There was no improvement after 2 weeks of treatment. Viral and bacterial skin swab were negative. A skin biopsy and ultrasound were performed showing extensive superficial hypoechoic lesion and reactive popliteal lymph nodes and the biopsy confirmed the diagnosis of mastocytoma. Bloods including tryptase level and abdominal ultrasound were normal. The lesion healed within 4 weeks with dressings and topical steroids. This case of a single isolated congenital mastocytoma shows the broad differential diagnoses that must be considered in the evaluation of bullous lesions in a newborn. It is key to biopsy early and always exclude ­infection.

Mucosal CCL28 Chemokine Improves Protection against Genital Herpes through Mobilization of Antiviral Effector Memory CCR10+CD44+ CD62L-CD8+ T Cells and Memory CCR10+B220+CD27+ B Cells into the Infected Vaginal Mucosa.

Four major mucosal-associated chemokines, CCL25, CCL28, CXCL14, and CXCL17, play an important role in protecting mucosal surfaces from infectious pathogens. However, their role in protection against genital herpes remains to be fully explored. The CCL28 is a chemoattractant for the CCR10 receptor-expressing immune cells and is produced homeostatically in the human vaginal mucosa (VM). In this study, we investigated the role of the CCL28/CCR10 chemokine axis in mobilizing protective antiviral B and T cell subsets into the VM site of herpes infection. We report a significant increase in the frequencies of HSV-specific memory CCR10+CD44+CD8+ T cells, expressing high levels of CCR10, in herpes-infected asymptomatic (ASYMP) women compared with symptomatic women. Similarly, a significant increase in the CCL28 chemokine (a ligand of CCR10), was detected in the VM of herpes-infected ASYMP C57BL/6 mice, associated with the mobilization of high frequencies of HSV-specific effector memory CCR10+CD44+CD62L-CD8+ TEM cells and memory CCR10+B220+CD27+ B cells in the VM of HSV-infected ASYMP mice. Inversely, compared with wild-type C57BL/6 mice, the CCL28 knockout (CCL28-/-) mice (1) appeared to be more susceptible to intravaginal infection and reinfection with HSV type 2, and (2) exhibited a significant decrease in the frequencies of HSV-specific effector memory CCR10+CD44+CD62L-CD8+ TEM cells and of memory CD27+B220+ B cells in the infected VM. These findings suggest a critical role of the CCL28/CCR10 chemokine axis in the mobilization of antiviral memory B and T cells within the VM to protect against genital herpes infection and disease.

Detection of herpes simplex virus in oral tongue squamous cell carcinoma.

Introduction: Oral tongue squamous cell carcinoma (OTSCC) is the most common cancer of the oral cavity. Contradictory results have been observed on the involvement of herpes simplex virus 1 (HSV-1) in oral squamous cell carcinomas. Here, we aimed to study the predominance of HSV-1 or HSV-2 in oral HSV infections and to investigate the presence of HSV-1 in OTSCC and its effect on carcinoma cell viability and invasion. Methods: The distribution of HSV types one and two in diagnostic samples taken from suspected oral HSV infections was determined from the Helsinki University Hospital Laboratory database. We then analysed 67 OTSCC samples for HSV-1 infection using immunohistochemical staining. We further tested the effects of HSV-1 using six concentrations (0.00001-1.0 multiplicity of infection [MOI]) on viability and two concentrations (0.001 and 0.1 MOI) on invasion of highly invasive metastatic HSC-3 and less invasive primary SCC-25 OTSCC cell lines using MTT and Myogel-coated Transwell invasion assays. Results: Altogether 321 oropharyngeal samples were diagnosed positive for HSV during the study period. HSV-1 was the predominant (97.8%) HSV type compared with HSV-2 (detected in 2.2% of samples). HSV-1 was also detected in 24% of the OTSCC samples and had no association with patient survival or recurrence. OTSCC cells were viable even after 6days with low viral load (0.00001, 0.0001, 0.001 MOI) of HSV-1. In both cell lines, 0.001 MOI did not affect cell invasion. However, 0.1 MOI significantly reduced cell invasion in HSC-3 cells. Discussion: HSV-1 infection is predominant compared with HSV-2 in the oral cavity. HSV-1 is detected in OTSCC samples without clinical significance, and OTSCC cell survival or invasion was not affected at low doses of HSV-1.

Prevalence of herpes simplex viruses types 1 and 2 infections among suspected children of encephalitis in Kermanshah, Iran.

Various infectious and non-infectious factors can cause encephalitis in the central nervous system (CNS), the most important of which are viruses. Herpes viruses are one of the most important causes of encephalitis worldwide. PCR detected the virus on the cerebrospinal fluid (CSF) sample. The aim of this study was to set up an in-house PCR to identify herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) and determine the prevalence of these viruses in suspected children of encephalitis. This cross-sectional study was conducted on 160 suspected children with encephalitis cases referred to Dr. Kermanshahi Children Hospital, Kermanshah, Iran, from April to March 2021. CSF samples were extracted using a viral extraction kit, and a PCR was performed. The level of glucose and total protein of the samples was measured. The total prevalence of HSV was 16.25%. 17 samples were positive for HSV-1 (10.6%), and 9 samples for HSV-2 (5.6%). There was a significant correlation between glucose, total protein, and HSV PCR positive, but no significant correlation between age and HSV PCR positive results. Rapid diagnosis of a virus may reduce the hospitalization rate and the use of unnecessary therapies and crease mortality, morbidity, and disability in children. Results in this study show that the distribution of HSV types in children with encephalitis predominantly was type 1 compared with type 2.

THE CLINICAL CASE OF GENERALIZED CONGENITAL HERPESVIRUS INFECTION IN NEWBORNS, AS A RESULT OF PRIMARY ASYMPTOMATIC INFECTION OF THE MOTHER WITH HSV TYPE 2 DURING PREGNANCY

The article presents a clinical case of generalized congenital herpesvirus infection with manifestation on the fourth day of life due to asymptomatic primary infection of the mother with HSV type 2 during pregnancy, complicated by early neonatal bacterial sepsis. The features of the clinic, diagnostics, principles of treatment and follow-up data of the child are presented. Clinical manifestation of congenital herpes infection took place on the 4th day of life. Laboratory confirmed by the detection of DNA of the herpes simplex virus type 2 in the blood, followed by determination of the quantitative level of this indicator and subsequent clinical and laboratory dynamics. Cancellation of specific therapy after 21 days due to the end of the course. Continuation up to 1 year 2 months of a course of specific mmunosuppressive therapy with acyclovir with increased therapy in case of recurrence of local manifestations. At the age of 1 year and 2 months, the withdrawal of specific immunosuppressive therapy. During the next year of life, 4 episodes of recurrence of herpes infection, in the form of local skin lesions. The child was vaccinated according to the calendar, additional vaccination against chickenpox, hepatitis A, pneumococcus, rotavirus infection, seasonal flu. Now the child is 2.4 years old. The child's condition is satisfactory. Development by age. The publication of materials was agreed with the Bioethics Commission of the National Bohomolets Medical University. All anamnestic data, examination results and photo materials were published upon written consent of the parents of the newborn child.Conclusions. Neonatal herpes infection can lead to significant morbidity, mortality, and adverse long-term outcomes. Despiteadequate therapy, vesicular rash recurrences in the first years of life are very common. Given the high rate of herpes simplex virus infection in the population, especially in pregnant women, all children should be considered potentially prone to herpes infection. Determination of maternal immune status, early diagnosis of clinical signs with verification of the causative agent, and timely and adequate specific antiviral therapy are essential to improve prognosis and reduce disability in later years of life.

A REVIEW: ZINC AS AN ANTIVIRUS ALTERNATIVE TREATMENT FOR HERPES SIMPLEX VIRUS INFECTION

This study aimed to review zinc's effectiveness as an antivirus in treating herpes simplex virus infection. The authors use international journals published from 2000-2022, and use search engines such as Google Scholar, PubMed, and Science Direct with the keywords "zinc and herpes simplex virus". The herpes simplex virus that often causes symptoms in humans are HSV type 1 and type 2. The lesions appear as vesicles which then rupture into ulcers. Zinc is one of the most abundant nutrients or metals in the human body besides iron. Studies about the effects of zinc on HSV have shown that it has the function of inhibiting the viral life cycle. HSV attaches to the host cells to replicate and synthesize new viral proteins. Zinc can inhibit this process by depositing on the surface of the virion and inactivating the enzymatic function which is required for the attachment to the host cell, disrupting the surface glycoprotein of the viral membrane so it could not adhere and carry out the next life cycle, it can also inhibit the function of DNA polymerase that works for viral replication in the host cell. This article showed that zinc has effectiveness as an antivirus against the herpes simplex virus, therefore, patients infected with HSV can be treated with zinc as an alternative to an antivirus drug.

Serological Evidence of Herpes Simplex Virus-1 (HSV-1) Infection among Humans from Bandung, West Java Province, Indonesia

BACKGROUND: Toxoplasma gondii, Rubella virus, Cytomegalovirus, and herpes simplex virus (TORCH) infection is still a significant burden in developing countries since they potentially increase perinatal death and decrease life quality by causing congenital disorders. As part of TORCH and as one of the most common infections in humans, HSV Type 1 infection also should receive attention. HSV-1 infection induces an immediate reactive oxygen species (ROS) production, indicate that ROS plays beneficial effects in several biological functions, including innate immunity and antiviral responses. HSV-1 preferentially replicate and establish latency in different subtypes of sensory neurons and in neurons of the autonomic nervous system that are highly responsive to stress hormones, including cortisol. AIM: The objective of the study was to detect the latent HSV-1 infection in adults population and its effect on ROS and cortisol levels. PATIENTS AND METHODS: Subjects were enrolled with consecutive-sampling methods among the adults population age 18–40 years old, with no health complaints. We collected their blood to examined IgG HSV-1, ROS, and cortisol levels. RESULTS: A total of 57 subjects with 27 subjects were reactive IgG HSV-1 (herpes group) and 30 subjects were non-reactive IgG HSV-1 (non herpes groups). Mean of cortisol and ROS was 223.2904 nmol/L and 2.23337 IU/mL, respectively. There was a very weak correlation between HSV-1 infection with ROS and cortisol. CONCLUSION: There is a positive effect of latent HSV-1 infection in the adult population on cortisol ROS levels.

Molecular Epidemiology and Risk Factors of Herpes Simplex Virus Type 2 in Pregnant Women

Background: Herpes simplex virus type 2 (HSV-2) infection is the main cause of genital and neonatal herpes infections. It has considerable public health importance among women as the virus may lead to adverse outcomes in pregnancy and neonatal infection. This study determines the molecular epidemiology and risk factors of HSV-2 infection among pregnant women. Methods: In this cross-sectional study, all pregnant women admitted to three university hospitals for natural birth and Caesarean sections were enrolled. HSV detection and typing were carried out based on PCR and reverse dot blotting method, respectively. ANOVA and bivariate correlations were used to analyze the data. Results: In this study, the prevalence of genital herpes infection was 5.7%. A significant positive correlation was found between age group &lt; 25 years and HSV-2 shedding (P = 0.026). Twelve participants (60%) with HSV-2 shedding were younger than 25. A significant correlation was found between the presence of genital lesion and HSV-2 (? = 0.02). Among participants with HSV-2 infection, the use of condom was low. Neonatal complications were not seen in newborns from mothers with HSV-2 shedding. Conclusion: PCR assay may help in promoting early diagnosis and more effective treatment for patients. Also, it shortens hospital stay and enhances patients’ condition. HSV-2 transmission is rapid following the onset of sexual activity and likely to result in the significant prevalence of genital disease.

Seroprevalence Pattern of Herpes Simplex Viruses (HSV-1 &amp; 2) among STI Vulnerable Women Population

Background: Genital infections caused by Herpes Simplex viruses are viewed as the indicators of sexual network in the society. Most of the infections caused by these viruses are asymptomatic and underdiagnosed.&#x0D; Aim: To investigate the seroprevalences of HSV-1 and HSV-2 among the STI vulnerable women and correlate them with clinical infections and other co-viral STIs.&#x0D; Study design: A cross sectional retrospective study was conducted on female contacts of HIV / STI positive male partners, who were consulting the STD clinics of NGOs and OP section of STD department of Government hospital in Chennai, India between October 2006 and September 2008.&#x0D; Methodology: The study included 138 STI vulnerable women along with age matched control group from whom socio-demographic and clinical data were collected. Serological screening was performed using ELISA for detection of IgM and IgG antibodies to HSV types 1 and 2 and co-positivities to HIV, HBV, HCV and CMV. Statistical analysis of results was carried out using Chi-square test.&#x0D; Results: Overall seroprevalences of 79.71% and 74.32% were recorded respectively for HSV-1 and HSV-2 among the study group. Proportionate increase in symptomatic cases were observed with individuals showing seropositivities to anti-HSV-1/2 IgM, IgM+IgG (combined) and IgG antibodies, which correlated respectively with primary, reactivated and episodic infections. Observation of symptomatic cases among HSV-1 (48.0% vs. 4.05%) and HSV-2 (68.29% vs. 25.0%) IgG positive study and control groups corroborated the sexual transmission of these viruses. Significant percentages of co-positivities to other viral STIs were recorded with higher preponderance among HSV-2 seropositive individuals than those of HSV-1.&#x0D; Conclusion: Comprehensive serological screening and its correlation with the clinical data would be very helpful in demonstrating the impact of HSV infections. Wide screening of STI vulnerable women is necessary to estimate the actual burden of STIs and to adopt preventive intervention.

Molecular diagnosis of Herpes virus type 1 by glycoprotein receptor primers

BackgroundHerpes simplex virus 1 (HSV-1) is considered the primary cause of Labial herpes. The primary diagnostic approach for HSV type is polymerase chain reaction (PCR), sequencing, and commercial qPCR, in which fluorescent-labeled probes are used for detection. ObjectiveThis study aimed to use a sequencing method to detect novel HSV-1 genotypes, which are anticipated to grow as the number of HSV-1 labials infected increases. MethodsHSV-1 genomes were amplified and sequenced from 50 patient swabs in the Babylon province of Iraq, The group patients comprised male and female aged 1–78 years diagnosed with HSV-1 infection. ResultsSequencing showed about 20% (10 out of 50 samples) of patients as positive, 30% (3 out of 10) of positive samples have been recorded for the first time as new isolates. Subsequently, the three novel isolates were registered in the National Center for Biotechnology Information database with ID: MW916900, MW940838, and MZ020781. ConclusionSequencing assay provides a powerful and low-cost tool for HSV-1 detection. Hence, it can be used as a routine in the diagnosis of clinical samples. Moreover, the significance of this tool is distinguish HSV-1 from other Herpeviridae species.

Lyme Borreliosis Associated with Ramsay-Hunt Syndrome: A Case Presentation of Bilateral Facial Nerve Palsy in a 14-Year-Old Patient

Background: In children, facial neuropathy is the most common disease that occurs due to the damage of the cranial nerves. Facial nerve palsy (FNP) in children can be congenital or acquired. Congenital FNP may occur at birth due to the trauma and with certain genetic syndromes. Acquired FNP can be caused by HSV types 1,2, HHV-6, cytomegalovirus, EBV, VZV, bacterium B. burgdorferi or can result from inflammatory diseases, trauma and tumors. Unilateral or bilateral FNP is the most common complication of Lyme disease in children. The study that was conducted by Furuta Y. et al. indicates that reactivation of VZV infection is an important cause of acute peripheral FNP in children aged 6-15 years. Case Report: We have described a rare clinical case of bilateral peripheral FNP in a 14-year-old child with a confirmed diagnosis of Lyme disease and reactivation of VZV infection. Conclusions: Prescribed therapy with doxycycline for 21 days and valaciclovir for 7 days made it possible to achieve functional recovery of nerve on both sides.

Herpetic gingivostomatitis in a young adult.

An 18-year-old woman presented with a 7-day history of fever up to 39.2°C followed by painful oral enanthema. She had taken acetaminophen as a palliative medicine. Her past history was unremarkable. Physical examination showed hemorrhagic crusts and necrotic ulcers on the lips. Prominent swelling with dilated capillaries and white sloughs of the attached gingiva over the teeth were observed (A, B). Laboratory investigations were unremarkable, except for elevated C-reactive protein at 3.81 mg per deciliter (reference < 0.30). Serum anti-herpes simplex virus (HSV) IgM was positive, but IgG was negative. The Tzanck test was positive, and polymerase chain reaction detected HSV type 1 (HSV-1) DNA. Primary HSV-1-induced herpetic gingivostomatitis were diagnosed. She was treated with oral valacyclovir, and the lesion completely resolved in 10 days.

Intrinsic Antiviral Activity of Optineurin Prevents Hyperproliferation of a Primary Herpes Simplex Virus Type 2 Infection.

Very little knowledge exists on virus-specific host cell intrinsic mechanisms that prevent hyperproliferation of primary HSV type 2 (HSV-2) genital infections. In this study, we provide evidence that the Nemo-related protein, optineurin (OPTN), plays a key role in restricting HSV-2 infection both in vitro and in vivo. Contrary to previous reports regarding the proviral role of OPTN during Sendai virus infection, we demonstrate that lack of OPTN in cells causes enhanced virus production. OPTN deficiency negatively affects the host autophagy response and results in a marked reduction of CCL5 induction. OPTN knockout (OPTN-/-) mice display exacerbated genital disease and dysregulated T cell frequencies in infected tissues and lymph nodes. A human transcriptomic profile dataset provides further credence that a strong positive correlation exists between CCL5 upregulation and OPTN expression during HSV-2 genital infection. Our findings underscore a previously unknown OPTN/CCL5 nexus that restricts hyperproliferative spread of primary HSV-2 infection, which may constitute an intrinsic host defense mechanism against herpesviruses in general.

INFLAMMATORY DISEASES OF THE PELVIC ORGANS AS ONE OF THE CAUSES OF FEMALE INFERTILITY

Abstract: The problem of inflammatory diseases of the small organs is very urgent, since pathology is registered in 60-65% of women of reproductive age, this indicator has no tendency to decrease. Inflammatory diseases of the pelvic organs have an extremely adverse effect on reproductive potential, occupying a leading place in the structure of the causes of female infertility, forming a negative dynamics of demographic indicators in the state, which allows us to consider this problem not only as a medical, but also as a social one. This article highlights the main etiological factors of inflammatory diseases of the pelvic organs, among which the leading role belongs to the bacterial – viral – mycotic association (Chlamydia trachomatis, Neisseria gonorrhoeae, opportunistic microorganisms (Esherichia coli, Mycoplasma hominis, Ureaplasma urealiticum, Gardnerella vaginalis), HSV type 1 and HSV type 2, CMVI, virus Epstein – Barr, HPV, HIV). Various pathogenetic mechanisms of the impact of microorganisms on the organs of the reproductive system are also highlighted: stimulation of pathoimmunological and pathomorphological changes in the endometrium that prevent the adhesion and implantation of blastocysts and the development of trophoblasts, changes in the receptor field of the endometrium, increased secretion of antisperm antibodies that activate sperm agglutination, which prevents their advancement through the female genital tract, capacitation and fertilization. Some infectious agents are able to adsorb on the surface of spermatozoa, reduce their mobility and prevent penetration. The complex of these influences determines the formation of structural and functional prerequisites for the development of infertility. Inflammatory diseases of the pelvic organs are characterized by latent or abortive variants of the course, which significantly complicates their diagnosis at early stages and the appointment of timely and optimal therapy. It is important to note that inflammatory diseases of the reproductive organs can lead to infertility, but also significantly reduce the successful outcome of the use of assisted reproductive technologies.

IFI16 Isoforms with Cytoplasmic and Nuclear Locations Play Differential Roles in Recognizing Invaded DNA Viruses.

IFN-γ-inducible protein 16 (IFI16) recognizes viral DNAs from both nucleus-replicating viruses and cytoplasm-replicating viruses. Isoform 2 of IFI16 (IFI16-iso2) with nuclear localization sequence (NLS) has been studied extensively as a well-known DNA sensor. However, the characteristics and functions of other IFI16 isoforms are almost unknown. Here, we find that IFI16-iso1, with exactly the same length as IFI16-iso2, lacks the NLS and locates in the cytoplasm. To distinguish the functions of IFI16-iso1 and IFI16-iso2, we have developed novel nuclear viral DNA mimics that can be recognized by the nuclear DNA sensors, including IFI16-iso2 and hnRNPA2B1. The hexanucleotide motif 5'-AGTGTT-3' DNA form of the nuclear localization sequence (DNLS) effectively drives cytoplasmic viral DNA nuclear translocation. These nuclear viral DNA mimics potently induce IFN-β and antiviral IFN-stimulated genes in human A549 cells, HEK293T cells, and mouse macrophages. The subcellular location difference of IFI16 isoforms determines their differential functions in recognizing viral DNA and activating type I IFN-dependent antiviral immunity. IFI16-iso1 preferentially colocalizes with cytoplasmic HSV60mer and cytoplasm-replicating vaccinia virus (VACV), whereas IFI16-iso2 mainly colocalizes with nuclear HSV60-DNLS and nucleus-replicating HSV-1. Compared with IFI16-iso2, IFI16-iso1 induces more transcription of IFN-β and IFN-stimulated genes, as well as stronger antiviral immunity upon HSV60mer transfection or VACV infection. IFI16-iso2, with the ability of nuclear-cytoplasmic shuttling, clears both invaded HSV type 1 and VACV significantly. However, IFI16-iso2 induces more type I IFN-dependent antiviral immunity than IFI16-iso1 upon HSV60-DNLS transfection or HSV type 1 infection. Our study has developed potent agonists for nuclear DNA sensors and also has demonstrated that IFI16 isoforms with cytoplasmic and nuclear locations play differential roles in innate immunity against DNA viruses.

Tupaia GBP1 Interacts with STING to Initiate Autophagy and Restrict Herpes Simplex Virus Type 1 Infection.

Stimulator of IFN genes (STING) is a key molecule that binds to cyclic dinucleotides produced by the cyclic GMP-AMP synthase to activate IFN expression and autophagy in the fight against microbial infection. The regulation of STING in the activation of IFN expression has been extensively reported, whereas the regulation of STING in the initiation of autophagy is still insufficiently determined. IFN-inducible guanylate-binding proteins (GBPs) are central to the cell-autonomous immunity in defending a host against viral, bacterial, and protozoan infections. In this study using the Chinese tree shrew (Tupaia belangeri chinensis), which is genetically close to primates, we found that Tupaia GBP1 (tGBP1) combines with Tupaia STING (tSTING), promotes autophagy, and moderately inhibits HSV type 1 (HSV-1) infection. The antiviral effects of tGBP1 are IFN independent. Mechanistically, tGBP1 interacted with tSTING, Tupaia sequestosome 1, and Tupaia microtubule associated protein 1 L chain 3, forming a complex which promotes autophagy in response to HSV-1 infection. This function of tGBP1 against HSV-1 infection was lost in tSTING knockout cells. Overexpression of either tSTING or its mutant tSTING-ΔCTT that can only activate autophagy rescued the anti-HSV-1 activity of tGBP1 in tSTING knockout cells. Our study not only elucidated the underlying mechanism of tGBP1 antiviral activity against HSV-1 infection, but also uncovered the regulation of tSTING in the initiation of autophagy in response to HSV-1 infection.