Myxovirus Resistance A Research Articles

Interleukin-8 in HepG2 cells: Enhancing antiviral proteins in uninfected cells but promoting HBV replication in infected cells

In vitro studies have revealed that hepatitis B virus (HBV) infection upregulates interleukin-8 (IL-8), which enhances HBV replication. Clinically, elevated IL-8 levels in chronic HBV patients are associated with diminished therapeutic efficacy of interferon-α (IFN-α). Our study advances these findings by demonstrating that IL-8 promotes the expression of myxovirus resistance A (MxA) and protein kinase R (PKR) in HepG2 cells via the PI3K-AKT pathway. However, HBV-infected cells fail to exhibit IL-8-induced upregulation of MxA and PKR, likely due to HBV's upregulation of PP2A that inhibits the PI3K-AKT pathway. Notably, IL-8 targets the C/EBPα transcription factor, increasing HBV promoter activity and viral replication, which in turn partially suppresses the expression of MxA and PKR induced by IFN-α. Our findings uncover a mechanism by which HBV may evade immune responses, suggesting potential new strategies for immunotherapy against chronic HBV infection.

Diagnosis of anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis led by sarcoplasmic myxovirus resistance protein A expression on muscle pathology

A 44-year-old woman with autism spectrum disorder developed bulbar symptoms and generalized muscle weakness 7 months before referral. Six months before, she was administered glucocorticoid for liver involvement. During the course, while she presented alopecia, skin ulcers, and poikiloderma, hyperCKemia was observed only twice. Due to complications including cardiac involvement and hearing loss as well, we suspected mitochondrial disease and performed a muscle biopsy. The muscle pathology showed sarcoplasmic myxovirus resistance A (MxA) expression with scattered pattern. Since anti-melanoma differentiation-associated gene 5 (MDA5) antibody was detected, we diagnosed the patient with anti-MDA5 antibody-positive dermatomyositis (DM). We reinforced immunosuppressive therapy, and her clinical symptoms and liver involvement were improved. When we diagnose a case of anti-MDA5 antibody-positive DM who is difficult to make clinical diagnosis, it may be valuable to evaluate sarcoplasmic MxA expression on muscle pathology.

Premortem Skin Biopsy Assessing Microthrombi, Interferon Type I Antiviral and Regulatory Proteins, and Complement Deposition Correlates with Coronavirus Disease 2019 Clinical Stage

Apart from autopsy, tissue correlates of coronavirus disease 2019 (COVID-19) clinical stage are lacking. In the current study, cutaneous punch biopsy specimens of 15 individuals with severe/critical COVID-19 and six with mild/moderate COVID-19 were examined. Evidence for arterial and venous microthrombi, deposition of C5b-9 and MASP2 (representative of alternative and lectin complement pathways, respectively), and differential expression of interferon type I–driven antiviral protein MxA (myxovirus resistance A) versus SIN3A, a promoter of interferon type I–based proinflammatory signaling, were assessed. Control subjects included nine patients with sepsis-related acute respiratory distress syndrome (ARDS) and/or acute kidney injury (AKI) pre–COVID-19. Microthrombi were detected in 13 (87%) of 15 patients with severe/critical COVID-19 versus zero of six patients with mild/moderate COVID-19 (P < 0.001) and none of the nine patients with pre–COVID-19 ARDS/AKI (P < 0.001). Cells lining the microvasculature staining for spike protein of severe acute respiratory syndrome coronavirus 2, the etiologic agent of COVID-19, also expressed tissue factor. C5b-9 deposition occurred in 13 (87%) of 15 patients with severe/critical COVID-19 versus zero of six patients with mild/moderate COVID-19 (P < 0.001) and none of the nine patients with pre–COVID-19 ARDS/AKI (P < 0.001). MASP2 deposition was also restricted to severe/critical COVID-19 cases. MxA expression occurred in all six mild/moderate versus two (15%) of 13 severe/critical cases (P < 0.001) of COVID-19. In contrast, SIN3A was restricted to severe/critical COVID-19 cases co-localizing with severe acute respiratory syndrome coronavirus 2 spike protein. SIN3A was also elevated in plasma of patients with severe/critical COVID-19 versus control subjects (P ≤ 0.02). In conclusion, the study identified premortem tissue correlates of COVID-19 clinical stage using skin. If validated in a longitudinal cohort, this approach could identify individuals at risk for disease progression and enable targeted interventions.

Anna A Artaryan: paediatric neurosurgeon who created the first chair in the specialty

<h3>Background</h3> Multiple Sclerosis (MS) is the most common demyelinating disorder. Still today its pathogenesis is not well known, but there are several drugs to slow down disease progression. Interferon-B (IFN-B)...

MicroRNA-21-3p modulates FGF2 to facilitate influenza A virus H5N1 replication by refraining type I interferon response.

Background: Influenza A virus (IAV) has greatly affected public health in recent decades. Accumulating data indicated that host microRNAs (miRNAs) were related to IAV replication. The present study mainly focused on the effects of microRNA-21-3p (miR-21-3p) on H5N1 replication.Methods: The levels of miR-21-3p, virus structural factors (matrix 1 (M1), nucleoprotein (NP)), type I interferon (IFN) response markers (IFN-β, IFN-α), IFN-stimulated genes (protein kinase R (PKR), myxovirus resistance A (MxA), 2′-5′-oligoadenylate synthetase 2 (OAS)), and fibroblast growth factor 2 (FGF2) were measured by quantitative real-time polymerase chain reaction (qRT-PCR). The protein levels of M1, NP, and FGF2 were tested by Western blot assay. The virus titer was assessed by tissue culture infective dose 50% (TCID50) assay. The dual-luciferase reporter assay and ribonucleic acid (RNA) immunoprecipitation (RIP) assay were used to verify the interaction between miR-21-3p and FGF2.Results: MiR-21-3p was reduced in H5N1-infected patients and A549 cells. MiR-21-3p overexpression facilitated the levels of M1, NP, TCID50 value, and reduced the levels of IFN-β, IFN-α, PKR, MxA, and OAS in H5N1-infected A549 cells. FGF2 was verified as a direct target of miR-21-3p. The introduction of FGF2 counteracted miR-21-3p-mediated decrease in the levels of M1, NP, and TCID50 value, as well as reduction in the levels of IFN-β, IFN-α, PKR, MxA, and OAS in H5N1-infected A549 cells.Conclusion: MiR-21-3p down-regulated FGF2 expression to accelerate H5N1 replication and confine IFN response.

Human Cervical Epithelial Cells Release Antiviral Factors and Inhibit HIV Replication in Macrophages

The female reproductive tract is a major site of HIV sexual transmission. We here examined whether human cervical epithelial cells (HCEs) can be immunologically activated and produce antiviral factors against HIV. We demonstrated that HCEs (End1/E6E7 cells) possess the functional toll-like receptor (TLR)3 signaling system, which could be activated by Poly I:C and induce multiple cellular HIV restriction factors. The treatment of primary human macrophages with supernatant (SN) from TLR3-activated End1/E6E7 cell cultures resulted in HIV inhibition. This SN-mediated HIV inhibition was mainly through the induction of interferons (IFN)-β and IFN-λs, as the antibodies to IFN-β or IFN-λs receptor could effectively block the SN-mediated anti-HIV effect. Further studies showed that the incubation of macrophages with SN from the activated cervical epithelial cell cultures induced the expression of a number of IFN-stimulated genes (ISGs), including IFN-stimulated gene (ISG15), ISG56, 2′, 5′-oligoadenylate synthetase 1 (OAS 1), OAS 2, Myxovirus Resistance A (MxA), MxB, and Guanylate-binding protein 5 (GBP5). In addition, TLR3-activated cells produced the CC chemokines [regulated on activation, normal T cell expressed and secreted (RANTES), Human macrophage inflammatory protein 1 alpha (MIP-1α), MIP-1β] the ligands of HIV entry co-receptor CCR5. These observations support further studies on HCEs as potentially crucial and alternative targets for immunological intervention to control and prevent HIV sexual transmission.

Influence of IL28B and MxA gene polymorphisms on HCV clearance in Han Chinese population.

The high rate of chronic hepatitis C (CHC) was one of the key issues of global public health concern. Interferon (IFN)-λ relevant genes were in the antiviral treatment pathway, not only influenced hepatitis C virus (HCV) spontaneous clearance, but also affected the IFN-mediated viral clearance. The aim of this study was to identify the association of interleukin 28B (IL28B), myxovirus resistance A (MxA) gene polymorphisms with HCV spontaneous clearance and therapeutic response in Chinese CHC patients. IL28B and MxA gene genotypes were detected among 231 CHC carriers, 428 subjects with HCV spontaneous clearance and 662 CHC patients with pegylated IFN-α and ribavirin (pegIFN-α/RBV) treatment. Patients with MxA rs2071430 TT genotype were more likely to develop HCV infection chronicity (additive model: odds ratio (OR) 1.22, 95% confidence interval (CI) 1.01-1.48, P = 0.042). IL28B rs1298075 variant genotypes (additive model: OR 0.58, 95% CI 0.34-0.98, P = 0.040) and MxA rs17000900 variant genotypes (additive model: OR 0.54, 95% CI 0.30-0.99, P = 0.048) were less likely to achieve a sustained virological response. The life table indicated that patients with IL28B rs1298075 AG genotype were slower to achieve a viral load 106 copies/ml (all P < 0.05). This study illustrated that the carriage of IL28B rs12980275 AA had a positive effect on treatment response to pegIFN-α/RBV among Chinese CHC patients.

Type 1 interferon signature as a diagnostic marker of dermatomyositis

Background: Type 1 interferon is regarded as having an important role in the pathogenesis of dermatomyositis (DM). A recent report has shown that sarcoplasmic expression of myxovirus resistance A (MxA), one of the type 1 interferon-inducible proteins, can be used as a diagnostic marker of DM. However, the correlation between MxA expression and subtypes of DM remains unclear.

Author update: Sarcoplasmic MxA expression: A valuable marker of dermatomyositis.

Soon after our article published,1 we learned the sale of the myxovirus resistance A (MxA) polyclonal antibodies used in the study (Mx1/2/3 [H-285], sc-50509, Santa Cruz Biotechnology, Dallas, TX) had been discontinued. Furthermore, we received inquiries from several physicians concerning alternate MxA antibodies. We tested the company's monoclonal antibody alternate (Mx1/2/3 [C-1], sc-166412) on frozen muscle sections at various dilutions in 2% bovine serum albumin in PBS using the Ventana immunohistochemistry detection system (Ventana Medical Systems, Tucson, AZ) with or without the enhancement mode. Muscle samples tested included MxA-positive dermatomyositis (n = 3, including 1 juvenile participant), MxA-negative dermatomyositis (n = 3), anti-Jo-1 myopathy (n = 3, MxA-negative), and immune-mediated necrotizing myopathy (n = 3, comprising 1 with anti-signal recognition particle antibodies [MxA-negative], 1 with anti-3-hydroxy-3-methylglutaryl-CoA reductase antibodies [MxA-negative], and 1 without those antibodies [MxA-positive]). We observed essentially the same staining pattern at comparable signal intensity as the original polyclonal antibodies at 1:10 dilution with the enhancement mode although the signal was barely detected at the manufacturer's recommended dilution (starting dilution: 1:50), indicating that the monoclonal antibody alternate can be similarly used to detect sarcoplasmic MxA expression on frozen muscle sections for the diagnosis of dermatomyositis (although higher concentration is necessary).

Editors' Note

Editors' Note: In response to the article “Hand postures in primary and secondary generalized tonic-clonic seizures,” Dr. Mintzer explains why the statistical methodology employed by the authors, Fisher exact test with Bonferroni correction for multiple comparisons, was not ideal and that the version for multiple groups would have been preferable. He also reinforces a point brought up in a previous comment by Dr. Lanska: multiple events from the same patient should not be considered independent for the purpose of statistical analysis. Authors Siegel and Tatum describe how they addressed the problem statistically. Authors Uruha et al. report that the myxovirus resistance A (MxA) polyclonal antibodies used in their study, “Sarcoplasmic MxA expression: A valuable marker of dermatomyositis,” have been discontinued by the company that produced them. The authors describe the results of their tests into the company's monoclonal antibody alternative, concluding that the alternative can be used comparably to the original, but may require higher concentrations. —Megan Alcauskas, MD, and Robert C. Griggs, MD Editors' Note: In response to the article “Hand postures in primary and secondary generalized tonic-clonic seizures,” Dr. Mintzer explains why the statistical methodology employed by the authors, Fisher exact test with Bonferroni correction for multiple comparisons, was not ideal and that the version for multiple groups would have been preferable.

Sarcoplasmic MxA expression: A valuable marker of dermatomyositis.

To evaluate the diagnostic value of myxovirus resistance A (MxA) expression in the cytoplasm of myofibers in the diagnosis of dermatomyositis (DM). We assessed the sensitivity and specificity of the sarcoplasmic expression of MxA in muscles with DM by immunohistochemistry in consecutive cases of DM (n = 34) and other idiopathic inflammatory myopathies (n = 120: 8 with polymyositis, 16 with anti-tRNA-synthetase antibody-associated myositis, 46 with immune-mediated necrotizing myopathy, and 50 with inclusion body myositis) and compared them with conventional pathologic hallmarks of DM, including perifascicular atrophy (PFA) and membrane attack complex (MAC) deposition on endomysial capillaries. The sensitivity and specificity of sarcoplasmic MxA expression were 71% and 98%, respectively. While the specificity was almost comparable to that of PFA and capillary MAC deposition, the sensitivity was higher, with PFA showing 47% sensitivity and 98% specificity and capillary MAC deposition showing 35% sensitivity and 93% specificity. Of note, in patients with DM with typical skin rash but no PFA, 44% of the samples showed sarcoplasmic MxA expression, which was higher than the 17% sensitivity of capillary MAC deposition in the population. Sarcoplasmic MxA expression detected by immunohistochemistry is a more sensitive marker of DM than the conventional hallmarks, indicating its practical utility in the diagnosis of DM. It may well be included in the routine immunohistochemistry panel for myositis. This study provides Class II evidence that immunohistochemistry-detected sarcoplasmic MxA expression accurately identifies patients with dermatomyositis.

Expression of Myxovirus Resistance A (MxA) Is Associated with Tumor-Infiltrating Lymphocytes in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancers.

PurposeThe prognostic significance of tumor-infiltrating lymphocytes (TILs) has been determined in breast cancers. Interferons can affect T-cell activity through direct and indirect mechanisms. Myxovirus resistance A (MxA) is an excellent marker of interferon activity. Here,we evaluated TILs and MxA expression in human epidermal growth factor receptor 2 (HER2)–positive breast cancers.Materials and MethodsNinety cases of hormone receptor (HR)+/HER2+ tumors and 78 cases of HR–/HER2+ tumors were included. The TILs level was assessed using hematoxylin and eosin–stained full face sections, and MxA expressionwas evaluated by immunohistochemistrywith a tissue microarray.ResultsMxA protein expression was significantly higher in tumors with high histologic grade (p=0.023) and high levels of TILs (p=0.002). High levels of TILs were correlated with high histological grade (p=0.001), negative lymphovascular invasion (p=0.007), negative lymph node metastasis (p=0.007), absence of HR expression (p < 0.001), abundant tertiary lymphoid structures (TLSs) around ductal carcinoma in situ (p=0.018), and abundant TLSs around the invasive component (p < 0.001). High levels of TILs were also associated with improved disease-free survival, particularly in HR–/HER2+ breast cancers. However, MxA was not a prognostic factor.ConclusionHigh expression of MxA in tumor cells was associated with high levels of TILs in HER2-positive breast cancers. Additionally, a high level of TILs was a prognostic factor for breast cancer, whereas the level of MxA expression had no prognostic value.

MxA expression is associated with tumor-infiltrating lymphocytes and is a prognostic factor in triple-negative breast cancer.

Interferons (IFNs) play an important role in tumor-immune system interactions. As one of the main mediators of IFNs, myxovirus resistance A (MxA) is upregulated in various cancers. However, the exact role of MxA in breast cancer is not fully understood. As part of the immune response to tumors, tumor-infiltrating lymphocytes (TILs) have prognostic significance in breast cancer. The aim of our present study was to examine the relationship between MxA and immune system components, including the amount of TILs and human leukocyte antigen (HLA) expression, in breast cancer. TILs, MxA expression, HLA intensity, and clinicopathological factors were retrospectively analyzed in 688 patients with primary breast cancer between 1993 and 1998 and in 705 patients with triple-negative breast cancer (TNBC) between 2004 and 2011. MxA expression was higher in TNBC tumors than in other subtypes. High MxA levels were associated with a higher histologic grade, abundant TILs, and stronger HLA-ABC expression in both the TNBC subtype within the consecutive breast cancer cohort and the validation TNBC cohort. MxA expression showed a significant positive correlation with TILs, the number of CD8(+) cells, and the number of CD69(+) cells in the validation TNBC cohort. High MxA levels and abundant TILs were found to be independent prognostic factors for disease-free survival in patients with TNBC. These results indicate that MxA expression is closely related to TILs in TNBC and, along with TILs, provides prognostic information after chemotherapy in patients with TNBC.

Induction of interferon-λ contributes to TLR3 and RIG-I activation-mediated inhibition of herpes simplex virus type 2 replication in human cervical epithelial cells.

Is it possible to immunologically activate human cervical epithelial cells to produce antiviral factors that inhibit herpes simplex virus type 2 (HSV-2) replication? Our results indicate that human cervical epithelial cells possess a functional TLR3/RIG-I signaling system, the activation of which can mount an Interferon-λ (IFN-λ)-mediated anti-HSV-2 response. There is limited information about the role of cervical epithelial cells in genital innate immunity against HSV-2 infection. We examined the expression of toll-like receptors (TLRs) and retinoic acid-inducible I (RIG-I) in End1/E6E7 cells by real-time PCR. The IFN-λ induced by TLR3 and RIG-I activation of End1/E6E7 cells was also examined by real-time PCR and ELISA. HSV-2 infection of End1/E6E7 cells was evaluated by the real-time PCR detection of HSV-2 gD expression. The antibody to IL-10Rβ was used to determine whether IFN-λ contributes to TLR3/RIG-I mediated HSV-2 inhibition. Expression of interferon regulatory factor 3 (IRF3), IRF7, IFN-stimulated gene 56 (ISG56), 2'-5'-oligoadenylate synthetase I (OAS-1) and myxovirus resistance A (MxA) were determined by the real-time PCR and western blot. End1/E6E7 cells were transfected with shRNA to knockdown the IRF3, IRF7 or RIG-I expression. Student's t-test and post Newman-Keuls test were used to analyze stabilized differences in the immunological parameters above between TLR3/RIG-I-activated cells and control cells. Human cervical epithelial cells expressed functional TLR3 and RIG-I, which could be activated by poly I:C and 5'ppp double-strand RNAs (5'ppp dsRNA), resulting in the induction of endogenous interferon lambda (IFN-λ). The induced IFN-λ contributed to TLR3/RIG-I-mediated inhibition of HSV-2 replication in human cervical epithelial cells, as an antibody to IL-10Rβ, an IFN-λ receptor subunit, could compromise TLR3/RIG-I-mediated inhibition of HSV-2. Further studies showed that TLR3/RIG-I signaling in the cervical epithelial cells by dsRNA induced the expression of the IFN-stimulated genes (ISGs), ISG56, 2'-5'-oligoadenylate synthetase I (OAS-1) and myxovirus resistance A (MxA), the key antiviral elements in the IFN signaling pathway. In addition, we observed that the topical treatment of genital mucosa with poly I:C could protect mice from genital HSV-2 infection. Future prospective studies with primary cells and suitable animal models are needed in order to confirm these outcomes. The findings provide direct and compelling evidence that there is intracellular expression and regulation of IFN-λ in human cervical epithelial cells, which may have a key role in the innate genital protection against viral infections. Not applicable. This work was supported by the National Natural Science Foundation of China (81301428 to L.Z. and 81271334 to W.-Z.H.), the Fundamental Research Funds for the Central Universities (2042015kf0188 to L.Z.), the China Postdoctoral Science Foundation (2013M531745 to L.Z.), the Development Program of China ('973', 2012CB518900 to W.-Z.H.) from the Ministry of Science and Technology of the People's Republic of China, grants (DA12815 and DA022177 to W.-Z.H.) from the National Institute on Drug Abuse (NIDA) and the open project of Hubei Key Laboratory of Wudang Local Chinese Medicine Research (WDCM005 to M.S.). The authors declare no competing financial interests.

Human endogenous retrovirus expression is inversely related with the up-regulation of interferon-inducible genes in the skin of patients with lichen planus.

Lichen planus (LP) is a common inflammatory skin disease of unknown etiology. Reports of a common transactivation of quiescent human endogenous retroviruses (HERVs) support the connection of viruses to the disease. HERVs are ancient retroviral sequences in the human genome and their transcription is often deregulated in cancer and autoimmune diseases. We explored the transcriptional activity of HERV sequences as well as the antiviral restriction factor and interferon-inducible genes in the skin from LP patients and healthy control (HC) donors. The study included 13 skin biopsies from patients with LP and 12 controls. Real-time PCR assay identified significant decrease in the HERV-K gag and env mRNA expression levels in LP subjects, when compared to control group. The expressions of HERV-K18 and HERV-W env were also inhibited in the skin of LP patients. We observed a strong correlation between HERV-K gag with other HERV sequences, regardless the down-modulation of transcripts levels in LP group. In contrast, a significant up-regulation of the cytidine deaminase APOBEC 3G (apolipoprotein B mRNA-editing), and the GTPase MxA (Myxovirus resistance A) mRNA expression level was identified in the LP skin specimens. Other transcript expressions, such as the master regulator of type I interferon-dependent immune responses, STING (stimulator of interferon genes) and IRF-7 (interferon regulatory factor 7), IFN-β and the inflammassome NALP3, had increased levels in LP, when compared to HC group. Our study suggests that interferon-inducible factors, in addition to their role in innate immunity against exogenous pathogens, contribute to the immune control of HERVs. Evaluation of the balance between HERV and interferon-inducible factor expression could possibly contribute to surveillance of inflammatory/malignant status of skin diseases.

Interleukin-32 isoforms: expression, interaction with interferon-regulated genes and clinical significance in chronically HIV-1-infected patients

Given the growing evidence for a role of interleukin-32 (IL-32) in the immune response to HIV-1 infection and its interplay with type I and III interferons (IFNs), we studied the gene expression of IL-32 isoforms (α and nonα) in untreated chronically HIV-1-infected patients and in gender- and age-matched healthy individuals. To further characterize both the anti-HIV properties of IL-32 and the cytokine's relationship with host antiviral innate immune responses, we evaluated whether IL-32 can induce ex vivo the expression of antiviral IFN-induced genes (ISGs), namely myxovirus resistance A (MxA), and apolipoprotein B mRNA-editing enzyme catalytic (APOBEC)3G and APOBEC3F. We also investigated whether in vivo IL-32 (α and nonα) mRNA levels were correlated with those of MxA and APOBEC3G/3F. Results indicated that IL-32 (α and nonα) mRNA levels were significantly higher in HIV-1-infected patients than in healthy individuals. Furthermore, IL-32 (α and nonα) mRNA levels correlated negatively with HIV RNA levels, but not with the CD4(+) T-cell count. Our ex vivo studies disclosed that ISGs mRNA levels were increased after IL-32γ treatment of peripheral blood mononuclear cells. Interestingly, significant positive correlations were found between transcript levels of both IL-32α and IL-32nonα and those of MxA and APOBEC3G/3F in untreated chronically HIV-1-infected patients. Overall, our results demonstrated that IL-32 isoforms are highly expressed during chronic HIV-1 infection and that IL-32 could have a central role in the antiviral immune response against HIV-1.

Endogenous IFNγ in chronic HCV genotype 4 patients treated with PEG-IFNα and ribavirin

Hepatitis C virus (HCV) infections remain an increasingly prevalent and emergent health problem worldwide, causing a wide spectrum of liver diseases. Combination therapy with pegylated interferon (PEG-IFN) of peginterferon alfa-2a and oral ribavirin is currently recognized as the standard treatment of chronic HCV infection. Several complex immunological mechanisms are involved during the course of HCV treatment using interferons. The role of endogenous interferon gamma (IFNγ) in Egyptian patients infected with chronic HCV and treated with PEG-IFN/ribavirin is uncertain. The goal of this study was to evaluate the association of IFNγ and chronic HCV infection among patients treated with combination therapy of PEG-IFN/ribavirin. Samples from 20 patients infected with HCV genotype-4 (HCV-4) and 20 non-infected individuals as healthy controls were used in this retrospective study. IFNγ levels in peripheral blood monocytes were analyzed, along with liver enzyme alanine aminotransferase (ALT) levels, and single nucleotide polymorphism (SNP) of the myxovirus resistance-A (MxA) gene. The results showed that an increase of IFNγ and a decrease of ALT levels in chronic HCV-infected patients after 12 weeks of treatment with combination therapy. Enhanced IFNγ secretion and decreased liver enzyme ALT production are indicative of HCV clearance and improvement of liver function. In addition, the SNP of the MxA gene is an important host genetic factor that independently influenced the response to IFNα in patients with chronic HCV infection, especially in those with a low viral load.

Association of functional polymorphisms in the MxA gene with susceptibility to enterovirus 71 infection

Myxovirus resistance A (MxA) is an antiviral protein induced by type I interferons α and β (IFN-α and IFN-β) that can inhibit virus replication. We examined whether the MxA polymorphisms were related to the risk and severity of enterovirus 71 (EV71) infection in Chinese populations. The MxA C-123A and G-88T polymorphisms were genotyped in two independent case–control populations in China by polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) analysis. Multivariate logistic regression analysis was used to calculate adjusted odds ratios (ORs) and 95 % confidence intervals (95 % CIs). MxA messenger RNA was quantified by real-time quantitative PCR in peripheral blood mononuclear cells (PBMCs) from 45 healthy children and 19 patients with EV71 infection. Significantly decreased susceptibility to EV71 infection was observed for the -123A allele and -88T allele carriers, with ORs (95 % CIs) estimated as 0.56 (0.39–0.81) and 0.64 (0.47–0.88), respectively, in the northern population. This association was confirmed in the southern population, with ORs (95 % CIs) estimated as 0.58 (0.38–0.89) and 0.67(0.47–0.95), respectively. The A- 123T- 88 haplotype was also significantly associated with lower risk of EV71 infection in both the northern (OR = 0.62; 95 % CI = 0.44–0.85) and the southern population (OR = 0.63; 95 % CI = 0.43–0.92). Furthermore, we observed higher MxA messenger RNA levels in IFNβ1a-stimulated PBMCs from the -123A or -88T allele carriers compared with that from nocarriers. Our findings suggest that polymorphisms in the MxA promoter may play a role in mediating the susceptibility to EV71 infection in Chinese population.

Hepatitis C virus impairs TLR3 signaling and inhibits IFN-λ 1 expression in human hepatoma cell line

Toll-like receptor 3 (TLR3) activation plays an important role in the innate immune responses to viral infections. We show here that the activation of TLR3 signaling pathway by poly I:C, a synthetic mimic of dsRNA, could induce high-level expression of interferon (IFN)-λ1 in a hepatoma cell line. The induced IFN-λ1 contributed to poly I:C-mediated inhibition of hepatitis C virus (HCV) Japanese fulminant hepatitis-1 (JFH-1) replication in Huh7 cells. This inhibitory effect of poly I:C on HCV replication, however, was compromised by HCV infection of Huh7 cells. Investigation of the mechanisms showed that HCV infection suppressed the expression of poly I:C-induced IFN-λ1 and IFN-stimulated genes [IFN-stimulated gene 56 (ISG-56), myxovirus resistance A (MxA) and 2'-5'-oligoadenylate synthetase 1 (OAS-1))], the key antiviral elements in IFN signaling pathway. Among the HCV nonstructural (NS) proteins tested, NS3/4A, NS5A and NS5B had the ability to inhibit poly I:C-induced IFN-λ1 expression in Huh7 cells. These observations provide the experimental evidence that HCV and its proteins impair TLR3 signaling and inhibit intracellular IFN-λ1/ISG expression in a hepatoma cell line, which may account for HCV persistence in the liver.

The myxovirus resistance A (MxA) gene −88G>T single nucleotide polymorphism is associated with prostate cancer

BackgroundMyxovirus (influenza virus) resistance A (MxA) is an interferon stimulated antiviral protein that is required for a complete antiviral response. MxA polymorphism (rs2071430) is located within an Interferon Stimulated Response Element (ISRE) at position −88 in the gene’s promoter region, and it has been associated with increased susceptibility to infections and various diseases. In general, the low promoter activity genotype (GG) promotes susceptibility, whereas the high promoter activity genotype (TT) confers protection to Hepatitis C viral infection. MxA’s role in prostate cancer is not fully understood. Previous literature has shown that MxA may be a mediator of the effect of IFN on normal and tumor cell motility. MxA may act as a tumor suppressor and the level of expression may be a predictor of metastatic potential. Based on this information, in this study we investigated the association of this functional polymorphism (rs2071430) in MxA with prostate cancer. MethodsSample size and power was calculated using the PGA software. Genomic DNA from a controls (n=140) and prostate cancer patients (n=164) were used for genotyping SNP rs2071430 on all samples. Statistical analysis was performed using logistic regression model. ResultsA significant association was observed between rs2071430 genotype GG and prostate cancer. Individuals harboring the GG genotype are at an increased risk of prostate cancer. Data stratification reveals that the mutant GT genotype offers either offers some protection against prostate cancer in Caucasians. ConclusionsMxA SNP rs2071430 GG genotype is significantly associated with prostate cancer irrespective of race. However, data stratification also suggests that the GT genotype is under-represented in Caucasian subjects suggesting its role in protection against prostate cancer in Caucasians. Although MxA is primarily implicated in viral infection, but it may be also be associated with prostate cancer. Recent studies have implicated viral and bacterial infections with increased prostate cancer risk. Expression of the high promoter activity genotype may offer resistance to prostate cancer infection and possibly influence clinical outcomes.