Herpes Simplex Virus Type 2 Immediate Early Protein ICP27 Inhibits IFN-β Production in Mucosal Epithelial Cells by Antagonizing IRF3 Activation.

Herpes simplex virus type 2 (HSV-2) is the main cause of genital herpes and infections are common in the lower genital tract. Although neuronal and immune cells can be infected, epithelial cells, and keratinocytes are the primary HSV-2 target cells. HSV-2 establishes latency by evading the host immune system and its infection can also increase the risk of HIV-1 sexual transmission. Our pervious study found that HSV-2 immediate early protein ICP22, inhibited IFN-β production by interfering with the IRF3 pathway. However, ICP22-null HSV-2 did not completely lose the capability of suppressing IFN-β induction, suggesting the involvement of other viral components in the process. In this study, by using an ex vivo cervical explant model, we first demonstrated that HSV-2 can indeed inhibit IFN-β induction in human mucosal tissues. We further identified HSV-2 immediate early protein ICP27 as a potent IFN-β antagonist. ICP27 significantly suppresses the Sendai virus or polyinosinic-polycytidylic acid-induced IFN-β production in human mucosal epithelial cells, showing that ICP27 inhibits the IFN-β promoter activation, and IFN-β production at both mRNA and protein levels. Additional studies revealed that ICP27 directly associates with IRF3 and inhibits its phosphorylation and nuclear translocation, resulting in the inhibition of IFN-β induction. Our findings provide insights into the molecular mechanism underlying HSV-2 mucosal immune evasion, and information for the design of HSV-2 mucosal vaccines

DC-SIGN as an attachment factor mediates Japanese encephalitis virus infection of human dendritic cells via interaction with a single high-mannose residue of viral E glycoprotein

AbstractThe skin-resident dendritic cells (DCs) are thought to be the first defender to encounter incoming viruses and likely play a role in Japanese encephalitis virus (JEV) early infection. In the current study, following the demonstration of JEV productive infection in DCs, we revealed that the interaction between JEV envelope glycoprotein (E glycoprotein) and DC-SIGN was important for such infection as evidenced by antibody neutralization and siRNA knockdown experiments. Moreover, the high-mannose N-linked glycan at N154 of E glycoprotein was shown to be crucial for JEV binding to DC-SIGN and subsequent internalization, while mutation of DC-SIGN internalization motif did not affect JEV uptake and internalization. These data together suggest that DC-SIGN functions as an attachment factor rather than an entry receptor for JEV. Our findings highlight the potential significance of DC-SIGN in JEV early infection, providing a basis for further understanding how JEV exploits DC-SIGN to gain access to dendritic cells

Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment

Introduction: Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of metabolic disorders caused by abnormal protein or lpid glycosylation. DPM2 is one subunit of a heterotrimeric complex for dolichol-phosphatemannose synthase (DPMS), a key enzyme in glycosylation, and only four patients with DPM2-CDG have been reported.Methods: Whole-exome sequencing (WES) was performed in a Chinese family having two siblings with a mild form of DPM2-CDG with developmental delay, mild intellectual disability, hypotonia, and increased serum creatine kinase. Sanger sequencing was used to validate the variants identified in the siblings and their parents. In vitro functional study was performed.Results: A homozygous mutation, c.197G>A (p.Gly66Glu) in exon 4 of DPM2 (NM_003863) was identified by whole exome sequencing (WES). In vitro functional analysis demonstrated that this variant increased the expression level of DPM2 protein and western blot revealed a significant decrease in ICAM1, a universal biomarker for hypoglycosylation in patients with CDG, suggesting abnormal N-linked glycosylation. We also reviewed the 4 previously reported patients carrying homozygous or compound heterozygous variants of DMP2 gene, and found that patients with variants within the region encoding the first domain had more severe clinical symptoms than those with variants within the second domain. However, the actual genotype-phenotype relationship needs more study.Discussion: Overall, our study broadens the variant spectrum of DPM2 gene, attempts to explain the different phenotypes in patients with different DPM2 variants, and emphasizes the need of further functional studies to understand the underlying pathophysiology of the phenotypic heterogeneity

A novel variant in the HX repeat motif of ATN1 in a Chinese patient with CHEDDA syndrome and literature review

Abstract Background CHEDDA syndrome is a rare neurodevelopmental syndrome caused by heterozygous missense or indel variants in the HX repeat motif of ATN1 gene. To date, CHEDDA has been identified in a few ethnic groups, and only 17 patients have been reported in literature, and no case has been reported in any country or region in Asia. Methods Trio‐exome sequencing (Trio‐ES) examination was conducted in a Chinese girl with global developmental delay and in her parents. Sanger sequencing was performed to confirm the candidate variant. Results This patient presented with mental and motor developmental delay, speech delay, and mild dysmorphic facial features, and had no epilepsy and visual impairment. Brain MRI did not show obvious structural abnormality. Through ES we identified a novel and de novo variant, c.3176_c.3177insGCACCT (p.Ser1059_His1060insHisLeu), within the HX motif of ATN1. No other pathogenic variant in another gene was found to support an alternative clinical and molecular diagnosis. Conclusions This is the first described case of CHEDDA from China. Together with the available literature data, we found that either disruption of HX motif or alteration of the HX repeat number would lead to ATN1‐associated CHEDDA. We also noted that CHEDDA is a clinical heterogenous syndrome, and patients carrying the same or similar variant might have different clinical manifestations and prognosis

Three <i>de novo</i> variants in <i>KMT2A</i> (<i>MLL</i>) identified by whole exome sequencing in patients with Wiedemann–Steiner syndrome

BACKGROUND: Wiedemann–Steiner syndrome (WSS) is an autosomal dominant disorder characterized by short stature, hypertrichosis, intellectual disability, developmental delay, along with facial dysmorphism. WSS patients exhibit great phenotypic heterogeneities. Some variants in KMT2A (MLL) gene have been identified as the cause of WSS. METHODS: Whole exome sequencing on the probands followed by Sanger sequencing validations in the family were applied to determine genetic variants. In silico analyses were used for predicting potential effects of the variants. RESULTS: We identified three novel de novo heterozygous variants: c.883A>T (p.Lys295*), c.4171C>T (p.Gln1391*), and c.3499T>C (p.Cys1167Arg), in KMT2A gene from three unrelated Chinese WSS patients. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, these three variants were classified as pathogenic, pathogenic and likely pathogenic variant, respectively. By reviewing all the available cases with same mutated KMT2A regions as the three patients had, we found that in addition to the representative symptoms, our patients exhibited some sporadically observed symptoms, such as severe ophthalmological symptoms, endocardial fibroelastosis, cytomegalovirus infection, and feet eversion. We also revealed that variants in different KMT2A regions contribute to the phenotypic heterogeneity of WSS, highlighting challenges in the diagnosis of syndromic disorders spanning a broad phenotypic spectrum. CONCLUSION: Our study would aid in further broadening our knowledge about the genotype–phenotype correlation of WSS

A 9‐month‐old Chinese patient with Gabriele‐de Vries syndrome due to novel germline mutation in the YY1

Abstract Background Gabriele‐de Vries syndrome (GADEVS), also known as YY1 haploinsufficiency syndrome, is a very rare autosomal dominant neurodevelopmental disorder (NDD) due to YY1 mutation characterized by mild‐to‐profound developmental delay (DD)/intellectual disability (ID), a wide spectrum of functional and morphologic abnormalities, and intrauterine growth restriction or low birth weight and feeding difficulties are common in the patients. However, NDDs, such as language development disorder and ID, could hardly be assessed in patients younger than 2 years old. Methods We describe a 9‐month‐old female with DD, failure to thrive, and facial dysmorphism. Genetic analysis was conducted by whole exome sequencing (WES) and confirmed by Sanger sequencing. Results In addition to DD and dysmorphic facial features, this patient had urinary tract infection, acute pyelonephritis, bilateral vesicoureteral reflux (grade III), gastroesophageal reflux, and malnutrition. She was found to have foramen ovale or atrial septal defect, and enlarged left lateral ventricle in the brain. After performing WES, a novel heterozygous mutation NM_003403.5:c.1124G>A, p.Arg375Gln in the YY1 gene was identified. Conclusion Our findings suggest that genetic tests are critical technique for diagnosis of GADEVS, especially in patients with early‐childhood, unexplained developmental or growth disorders, thus, the prevalence of GADEVS may be underestimated. The clinical features and identified YY1 mutation in our patient expand the spectra of phenotypes and genotypes of GADEVS, respectively

Tetherin restricts HSV-2 release and is counteracted by multiple viral glycoproteins

AbstractTetherin has been defined as a restriction factor of HIV-1 and several other enveloped viruses. However, the significance of tetherin in viral infection remains to be further addressed. Here, we investigated whether tetherin plays a role in HSV-2 infection. Our study revealed that overexpression of tetherin restricted the release of HSV-2 into the extracellular medium, while knockdown of tetherin by siRNA enhanced its release. We further demonstrated that HSV-2 infection and viral glycoproteins gB, gD, gH and gL but not gM significantly downregulated the endogenous expression of tetherin. Additional study indicated that tetherin likely physically interacted with gB, gD, gH and gL. This is the first time that tetherin has been shown to be counteracted by multiple viral components of a virus. Our findings inform the complexity of HSV-2-host interactions, providing basis for understanding the role of tetherin as a viral restriction factor and the mechanisms underlying viral countermeasures