This study aims to clarify host factors of IFN treatment in the treatment of chronic hepatitis B (CHB) patients by screening the differentially expressed genes of IFN pathway CHB patients with different response to interferon (IFN) therapy. Three cases were randomly selected in IFN-responding CHB patients (Rs), non-responding CHB patients (NRs) and healthy participants, respectively. The human type I IFN response RT ² profiler PCR array was used to detect the expression levels of IFN-related genes in peripheral blood monocytes (PBMCs) from healthy participants and CHB patients before and after Peg-IFN-α 2a treatment. The results showed that more differentially expressed genes appeared in Rs group than NRs group after IFN treatment. Comparing with healthy participants, IFNG, IL7R, IRF1, and IRF8 were downregulated in both Rs and NRs group before IFN treatment; CXCL10, IFIT1, and IFITM1 were upregulated in the Rs; IL13RA1 and IFI35 were upregulated in the NRs, while IFRD2, IL11RA, IL4R, IRF3, IRF4, PYHIN1, and ADAR were downregulated. The expression of IL15, IFI35 and IFI44 was downregulated by 4.09 ( t = 10.58, P < 0.001), 5.59 ( t = 3.37, P = 0.028) and 10.83 ( t = 2.8, P = 0.049) fold in the Rs group compared with the NRs group, respectively. In conclusion, IFN-response-related gene array is able to evaluate IFN treatment response by detecting IFN-related genes levels in PBMC. High expression of CXCL10, IFIT1 and IFITM1 before treatment may suggest satisfied IFN efficacy, while high expression of IL13RA1, IL15, IFI35 and IFI44 molecules and low expression of IFRD2, IL11RA, IL4R, IRF3, IRF4, PYHIN1 and ADAR molecules may be associated with poor IFN efficacy.
Humans ; Healthy Volunteers ; Hepatitis B, Chronic/genetics* ; Immunotherapy ; Interleukin-15 ; Leukocytes, Mononuclear ; Nuclear Proteins ; Oligonucleotide Array Sequence Analysis/methods* ; Interferons/therapeutic use* ; Treatment Outcome

Objective: To report the clinical features and genetic variations of monogenic lupus caused by DNASE1L3 deficiency and to introduce preliminary experience on diagnosis and treatment for this disease. Methods: Clinical data of 3 children from the same pedigree were collected who were diagnosed with DNASE1L3 defect-associated monogenic lupus in August 2020 by Department of Pediatrics, Peking Union Medical College Hospital referred from Department of Pediatrics, Boai Hospital of Zhongshan. DNA was extracted from the peripheral blood of the patients and their parients to perform genetic analysis and confirmation. Six interferon-stimulated genes were relatively quantified to examine the activation of the type I interferon signaling. "DNASE1L3" "systemic lupus erythematosus" and "SLE" were searched in PubMed, Wangfang Data, CNKI databases for related reports from database established date to June 2022. Spectrum of genetic variations and clinical phenotypes were analyzed in combination with this pedigree. Results: Case 1, a 14-year-old girl with edema, hematuria, and heavy proteinuria, presented with membranous nephropathy. Case 2, the 12-year-old younger brother of case 1 with hematologic, cardiac, pulmonary, renal involvement, positive antinuclear antibody, positive anti-double-stranded DNA antibody and low complement C3, manifested with systemic lupus erythematosus. Case 3, the 8-year-old younger sister of case 1 with hematologic, cardiac, pulmonary and renal involvement, positive antinuclear antibody, positive anti-double-stranded DNA antibody, and low complement C3 and C4, manifested with systemic lupus erythematosus. Genetic testing revealed that all 3 patients carried homozygous deletions in exons 3 and 4 on DNASE1L3 gene. Interferon scores were elevated in case 1, 2 and their parents but normal in case 3. All 3 patients were diagnosed with monogenic lupus caused by DNASE1L3 defects. Literature searching identified 10 relevant publications in English and 0 publication in Chinese, involving 42 patients from 18 pedigrees (including the 3 cases from this pedigree). Nine variants were found: c.289_290delAC (p.T97Ifs*2), c.643delT (p.W215Gfs*2), c.320+4delAGTA, c.321-1G>A, Ex5 del, c.433G>A, c.581G>A (p.C194Y), c.537G>A (p.W179X), and Ex3-4 del. The hotspot variants were c.643delT (43% (36/84)) and c.289_290delAC (36% (30/84)). Kidney was affected in 31 cases (74%) of the 42 cases. Among the 25 patients, joints were affected in 16 cases (64%), fever were reported in 13 cases (52%) hematologic system was involved 13 cases (52%), rash was present in 10 cases (40%), intestinal tract was involved in 8 cases (32%), lungs were involved in 6 cases (24%), eyes were involved in 4 cases (16%), and the heart was involved in 4 cases (16%). The 2 cardiopulmonary affected patients from literature showed poor prognosis, with 1 died, and 1 right heart failure. Conclusions: The clinical manifestations of monogenic lupus caused by DNASE1L3 defect are highly heterogenous, primarily with renal, blood, joint, intestinal, and cardiopulmonary involvement. There is no correlation between the genotype and the phenotype. DNASE1L3 defects were predominantly mediated by null varations including nonsense, splicing, frameshift and exon deletions. The hotspot variants are c.643delT and c.289_290delAC. DNASE1L3 defects should be cautioned in early-onset lupus-like patients with renal, joint and hematologic involvement. Cardiopulmonary involved patients require close monitoring for poor prognosis. Copy number variations should be carefully analyzed after negative whole exome sequencing.
Male ; Child ; Humans ; Homozygote ; Complement C3 ; Antibodies, Antinuclear ; DNA Copy Number Variations ; Sequence Deletion ; Interferons ; Lupus Erythematosus, Systemic/genetics* ; Antiviral Agents ; Endodeoxyribonucleases

Hepatitis B virus (HBV) infection is one of the most serious public health problems. HBV infection could lead to hepatitis B, and even further develop into hepatic cirrhosis and hepatocellular carcinoma. Interferon lambda (IFN-λ) is a member of the interferon (IFN) family and an important cytokine for antiviral defense. There are four members in IFN-λ family, including IFN-λ1, IFN-λ2, IFN-λ3, and IFN-λ4. The genetic polymorphisms in the IFN-λ genes are associated with HBV replication and treatment response of HBV patients. In this review, we summarized the roles of genetic polymorphisms of the IFN-λ genes played in HBV infection, disease progression and treatment, with the aim to better understand their function. This review could serve as a reference for the HBV prevention and treatment of HBV patients, as well as for future clinical usage.
Antiviral Agents/pharmacology* ; Hepatitis B/genetics* ; Hepatitis B virus/genetics* ; Humans ; Interferons/pharmacology* ; Liver Neoplasms ; Polymorphism, Genetic ; Virus Replication/genetics*

Porcine epidemic diarrhea virus (PEDV) is a highly infectious pathogen that can cause severe diseases in pigs and result in enormous economic losses in the worldwide swine industry. Previous studies revealed that PEDV exhibits an obvious capacity for modulating interferon (IFN) signaling or expression. The newly discovered type III IFN, which plays a crucial role in antiviral immunity, has strong antiviral activity against PEDV proliferation in IPEC-J2 cells. In this study, we aimed to investigate the effect of PEDV nucleocapsid (N) protein on type III IFN-λ. We found that the N proteins of ten PEDV strains isolated between 2013 and 2017 from different local farms shared high nucleotide identities, while the N protein of the CV777 vaccine strain formed a monophyletic branch in the phylogenetic tree. The N protein of the epidemic strain could antagonize type III IFN, but not type I or type II IFN expression induced by polyinosinic-polycytidylic acid (poly(I:C)) in IPEC-J2 cells. Subsequently, we demonstrated that the inhibition of poly(I:C)-induced IFN-λ3 production by PEDV N protein was dependent on the blocking of nuclear factor-κB (NF-κB) nuclear translocation. These findings might help increase understanding of the pathogenesis of PEDV and its mechanisms for evading the host immune response.
Active Transport, Cell Nucleus ; Animals ; Coronavirus Infections ; immunology ; veterinary ; virology ; Genes, Viral ; Host-Pathogen Interactions ; immunology ; Interferons ; antagonists & inhibitors ; biosynthesis ; genetics ; Interleukins ; antagonists & inhibitors ; biosynthesis ; genetics ; NF-kappa B ; metabolism ; Nucleocapsid Proteins ; genetics ; immunology ; physiology ; Porcine epidemic diarrhea virus ; genetics ; pathogenicity ; physiology ; Promoter Regions, Genetic ; Swine ; Swine Diseases ; immunology ; virology

Interferon-induced Transmembrane Proteins (IFITMs) were identified through small interference RNA (siRNA) screening method in 1980s. The antiviral properties of the IFITMs were firstly discovered in 1996. Recently, its antiviral effect and mechanism have become a research hotspot. Many studies have shown that IFITM can inhibit the replication of multiple pathogenic viruses, including influenza A virus (IAV), Human Immunodeficiency Virus (HIV-1), hepatitis C virus (HCV), Ebola virus (EBOV), West Nile virus and so on. IFITMs inhibit the replication of virus in the early stage of the viral life cycle, which occurred before the release of viral genomes into the cytosol. Recent studies indicate that IFITM proteins could block viral replication by mediate viral membrane fusion. However, the mechanism is still under investigation. Here we review the discovery and characterization of the IFITM proteins, elucidate their antiviral activities and the potential mechanisms.
Animals ; Humans ; Interferons ; genetics ; immunology ; Membrane Proteins ; genetics ; immunology ; Virus Diseases ; genetics ; immunology ; virology ; Viruses ; genetics ; immunology

OBJECTIVE: To explore the effects of novaferon on dextran sulfate sodium (DSS)-induced colitis and expression of TNF-α in mice and to evaluate the efficacy of novaferon on ulcerative colitis and the possible mechanisms. METHODS: A total of 70 BALB/C mice [weight (20.0±2.0) g, 8-week years old, female, pathogen free] were randomly divided into 7 groups: a normal group, a model group, a mesalazine treatment group, a prednisone treatment group, a low-dose novaferon group, a middle-dose novaferon group and a high-dose novaferon group (10 mice per group). The normal group-mice were given distilled water. The ulcerative colitis model was established by treated the mice with 4% DSS for 7 continuous days. At the 8th day, the mice in the all of drug treatment groups were injected corresponding drugs (i.p.). During the experiment, the general situation, daily weight, stool trait and occult blood were recorded, and the mice were killed on the 14th day. The disease activity index (DAI), colon length, histological scores were assessed. Immunohistochemistry was used to measure the expression of TNF-α in colonic mucosa. RESULTS: 1) The mice treated with DSS solution showed diarrhea, mucous stool and bloody stool, and the DAI score increased gradually. The mesalazine, predinison and nofaferon could ameliorate the general situation of the mice, reduce the DAI and histological scores, and reverse the decrease in the colon length. 2) Compared with the model group, the DAI scores were significantly decreased in the novaferon groups (at low, middle or high dose), the mesalazine group or the prednisone group (all P<0.01), but there was no difference among the mesalazine group, the prednisone group and the low-dose novaferon group (all P>0.05). The efficacy of novaferon in the middle-dose group and the high-dose group are better than that in the mesalazine group, the prednisone group and the low-dose novaferon group (all P<0.01). The efficacy of novaferon showed a dose-dependent manner. 3) The injury of colonic mucosa was relatively mild in the novaferon groups (at low-dose, middle-dose or high-dose), the mesalazine group and the prednisone group, and there were partial glands and less inflammatory cells. Compared with the model group, there was statistics difference (all P<0.05). The tissue injury was significantly alleviated, and the DAI score was decreased in the high-dose novaferon group compared the middle-dose novaferon group (P<0.05), but there was no significant difference between the low-dose novaferon group and the middle-dose novaferon group or between the mesalazine group and the prednisone group (both P>0.05). 4) The TNF-α expression was significantly down-regulated in the novaferon groups (at low-dose, middle-dose or high-dose), the mesalazine group and the prednisone group compared with model group (all P<0.01); but there was no significant difference between the mesalazine group and the prednisone group (P>0.05); the decrease of TNF-α expression by novaferon displayed a dose-dependent manner. Compared with the mesalazine group or the prednisone group, the TNF-α expression in novaferon groups at all dosages was dramatically reduced (all P<0.01). CONCLUSION Novaferon can improve the DAI scores and colonic tissue injury in ulcerative colitis induced by DSS in mice, and down-regulate the TNF-α expression in dose-dependent manner.
Animals ; Colitis, Ulcerative ; chemically induced ; drug therapy ; Dextran Sulfate ; adverse effects ; Female ; Interferons ; therapeutic use ; Intestinal Mucosa ; drug effects ; Mesalamine ; therapeutic use ; Mice ; Mice, Inbred BALB C ; Prednisone ; therapeutic use ; Recombinant Proteins ; therapeutic use ; Tumor Necrosis Factor-alpha ; genetics ; metabolism

Guanylate-binding protein 1 (GBP1) is an interferon induced protein, that belongs to the guany late-binding protein family. GBP1 is widely involved in anti-infection immune responses, anti-tumor activity and various biological reactions. Recent studies have proved that IFN-alpha, IFN-beta, IFN-gamma, IL1alpha, IL1beta, TNF-alpha and LPS can induce GBP1 expression; hence, the diverse biological functions of GBP1 have been gradually deduced and exploited. Many studies have been performed over recent years to understand the exact mechanisms that underlie the anti-infection and anti-tumor properties of GBP1. This review describes the molecular structure, biological activity, anti-infective properties and other functions of GBP1, in order to provide insights into the divergent roles of GBP1 in the regulation of various biological processes.
Animals ; Antineoplastic Agents ; metabolism ; Antiviral Agents ; metabolism ; GTP-Binding Proteins ; chemistry ; genetics ; metabolism ; Humans ; Interferons ; genetics ; metabolism

Since the discovery of HBsAg in the early 1960s, presence of HBsAg in serum has only served to diagnose hepatitis B. Recent development in the quantitative measurement of serum HBsAg has enabled us to improve our understanding on the management of chronic hepatitis B. The surface antigen (sAg) level is at its highest in immune tolerance phase and decreases to the lowest level in immune control/inactive phase when HBeAg is cleared from the serum. Combination of serum sAg titer less than 1,000 IU/mL and serum HBV DNA less than 2,000 IU/mL can identify true inactive carrier from e antigen (eAg) negative hepatitis with diagnostic accuracy of 95%. During the natural course of chronic hepatitis B, changes or absolute level of sAg less than certain level can predict spontaneous sero-clearance of HBsAg. Although the decline of sAg is very slow in interferon (IFN)/pegylated interferon (PEG-IFN) or oral nucleos(-t)ide treated patients, interferon based therapy results in a greater decrease of sAg level and sAg loss. Lack of any decline in sAg titer during PEG-IFN therapy could identify the group of patients who do not response to IFN/PEG-IFN therapy. With the aid of serum HBV DNA, quantitative measurement of serum HBsAg level can be used to optimize the management of chronic hepatitis B in our daily practice.
Antiviral Agents/therapeutic use ; DNA, Viral/blood ; Hepatitis B Surface Antigens/*blood ; Hepatitis B e Antigens/blood ; Hepatitis B, Chronic/*diagnosis/drug therapy/genetics ; Humans ; Interferons/therapeutic use ; Liver Neoplasms/diagnosis ; Prognosis

Since the discovery of HBsAg in the early 1960s, presence of HBsAg in serum has only served to diagnose hepatitis B. Recent development in the quantitative measurement of serum HBsAg has enabled us to improve our understanding on the management of chronic hepatitis B. The surface antigen (sAg) level is at its highest in immune tolerance phase and decreases to the lowest level in immune control/inactive phase when HBeAg is cleared from the serum. Combination of serum sAg titer less than 1,000 IU/mL and serum HBV DNA less than 2,000 IU/mL can identify true inactive carrier from e antigen (eAg) negative hepatitis with diagnostic accuracy of 95%. During the natural course of chronic hepatitis B, changes or absolute level of sAg less than certain level can predict spontaneous sero-clearance of HBsAg. Although the decline of sAg is very slow in interferon (IFN)/pegylated interferon (PEG-IFN) or oral nucleos(-t)ide treated patients, interferon based therapy results in a greater decrease of sAg level and sAg loss. Lack of any decline in sAg titer during PEG-IFN therapy could identify the group of patients who do not response to IFN/PEG-IFN therapy. With the aid of serum HBV DNA, quantitative measurement of serum HBsAg level can be used to optimize the management of chronic hepatitis B in our daily practice.
Antiviral Agents/therapeutic use ; DNA, Viral/blood ; Hepatitis B Surface Antigens/*blood ; Hepatitis B e Antigens/blood ; Hepatitis B, Chronic/*diagnosis/drug therapy/genetics ; Humans ; Interferons/therapeutic use ; Liver Neoplasms/diagnosis ; Prognosis

OBJECTIVETo determine the role of hepatitis C virus (HCV) genotype 1 b genetic variation in the open reading frame for treatment outcomes of the pegylated-interferon/ribavirin (peg-IFN/RBV) combination therapy by examining patients from Henan Province with chronic hepatitis C (CHC).

METHODSThirty-seven treatment naive patients infected with HCV genotype 1b were included in the study. Prior to initiation of a 48-week course of peg-IFN/RBV therapy, peripheral blood was drawn for sequencing of the viral ORF 5'-half. Patients were assessed at the end of the 48 weeks of treatment and at a 6-month follow-up appointment. The patient data was stratified according to the status of sustained viral response (SVR) group and non-response (NR) and statistical analysis was performed to determine the correlation between detected genetic variations and treatment response status.

RESULTSGenetic variability in the ORF 5'-half was significantly higher among the individuals in the SVR group than among those of the NR group. Significant differences were found in the gene regions encoding p7, NS2 and NS3. For p7, the NR group had actual and expected frequencies of special mutation of 9.0 and 17.4 and total mutation of 77.0 and 68.6, while the SVR group had actual and expected frequencies of special mutation of 42.0 and 33.6 and total mutation of 124.0 and 132.4 (x2 =7.725, P =0.05). For NS2, the NR group had actual and expected frequencies of special mutation of 36.0 and 54.3 and total mutation of 270.0 and 251.7, while the SVR group had actual and expected frequencies of special mutation of 106.0 and 87.7 and total mutation of 388.0 and 406.3 (x2 = 12.16, P less than 0.01). For NS3, the NR group had actual and expected frequencies of special mutation of 49.0 and 53.4 and total mutation of 241.0 and 236.6, while the SVR group had actual and expected frequencies of special mutation of 81.0 and 76.6 and total mutation of 335.0 and 339.4 (x2 =6.745, P =0.043). The inter-patient genetic variations in the NS3 gene were concentrated in the protease domain. Furthermore, there was a strong correlation between HCV diversity in p7 and treatment outcome.

CONCLUSIONThe genetic data reported here provides strong support for the role of NS2, NS3 and p7 in antagonizing the peg-IFN/RBV response during the treatment of HCV infections. We conclude that higher inter-patient viral genetic diversity correlates with successful treatment and may modulate the efficacy of antiviral therapy in CHC patients of Henan.

Adult ; Drug Therapy, Combination ; Female ; Genotype ; Hepacivirus ; genetics ; Hepatitis C, Chronic ; drug therapy ; virology ; Humans ; Interferons ; administration & dosage ; therapeutic use ; Male ; Middle Aged ; Open Reading Frames ; Ribavirin ; administration & dosage ; therapeutic use ; Treatment Outcome