Control of lupus activity during pregnancy via the engagement of IgG sialylation: novel crosstalk between IgG sialylation and pDC functions / 医学前沿

Immunoglobulin (IgG) glycosylation affects the effector functions of IgG in a myriad of biological processes and has been closely associated with numerous autoimmune diseases, including systemic lupus erythematosus (SLE), thus underlining the pathogenic role of glycosylation aberration in autoimmunity. This study aims to explore the relationship between IgG sialylation patterns and lupus pregnancy. Relative to that in serum samples from the control cohort, IgG sialylation level was aberrantly downregulated in serum samples from the SLE cohort at four stages (from preconception to the third trimester of pregnancy) and was significantly associated with lupus activity and fetal loss during lupus pregnancy. The type I interferon signature of pregnant patients with SLE was negatively correlated with the level of IgG sialylation. The lack of sialylation dampened the ability of IgG to suppress the functions of plasmacytoid dendritic cells (pDCs). RNA-seq analysis further revealed that the expression of genes associated with the spleen tyrosine kinase (SYK) signaling pathway significantly differed between IgG- and deSia-IgG-treated pDCs. This finding was confirmed by the attenuation of the ability to phosphorylate SYK and BLNK in deSia-IgG. Finally, the coculture of pDCs isolated from pregnant patients with SLE with IgG/deSia-IgG demonstrated the sialylation-dependent anti-inflammatory function of IgG. Our findings suggested that IgG influences lupus activity through regulating pDCs function via the modulation of the SYK pathway in a sialic acid-dependent manner.

Contribution of human recombinant Interferon-Alpha 2b treatment in symptomatic and asymptomatic patients with SARS-CoV-2 virus infection / Contribución del tratamiento con Interferón-Alpha 2b humano recombinante en pacientes sintomáticos y asintomáticos con infección por el virus SARS-CoV2

Introduction: Subjects with asymptomatic infections are not generally admitted to health care facilities, however, they may benefit from antiviral therapy. Objective: To evaluate the contribution to treatment with combined therapy based on recombinant human interferon alpha 2b + Lopinavir/Ritonavir + Chloroquine versus Lopinavir/Ritonavir + Chloroquine in asymptomatic and symptomatic patients. Material and Methods: An observational study was carried out in patients with a positive diagnosis of COVID-19 from April 1st to July 30th, 2020. From a total of 308 patients treated with interferon + Lopinavir/Ritonavir + Chloroquine, we selected a statistically representative sample of 40 patients using a simple randomization process. As a control group, 27 patients who only received treatment with Lopinavir/Ritonavir + Chloroquine were selected. These patients underwent determinations of anti-SARS-CoV-2 antibodies, determinations of inflammatory markers, and follow-up by RT-PCR to evaluate the time length of negativization. Results: The group treated with interferon had a significantly shorter time to negativization. Patients treated with interferon showed a significant decrease in inflammatory markers at the time of hospital discharge and they had an increase in antibody titers at two and four months after hospital discharge, compared to the group of patients who did not receive interferon. Conclusions: The treatment with exogenous interferon in patients with COVID-19 had a significant contribution to the regulation of the immune response of the patients(AU)

Introducción: Los sujetos con infección asintomática generalmente no son admitidos en centros de asistencia médica, sin embargo, pueden beneficiarse de la terapia antiviral. Objetivo: evaluar la contribución al tratamiento de la terapia combinada basada en interferón alfa 2b recombinante humano + Lopinavir/Ritonavir + Cloroquina contra Lopinavir/Ritonavir + Cloroquina en pacientes asintomáticos y sintomáticos. Material y Métodos: Se realizó un estudio observacional en pacientes con diagnóstico positivo de COVID-19, durante los días del 1 de abril al 30 de julio de 2020. De un total de 308 pacientes tratados con interferón + Lopinavir/Ritonavir + Cloroquina, se seleccionaron mediante un proceso de aleatorización simple, una muestra estadísticamente representativa de 40 pacientes. Como grupo control se seleccionaron 27 pacientes que solo recibieron tratamiento con Lopinavir/Ritonavir + Cloroquina. Estos pacientes se sometieron a determinaciones de anticuerpos anti-SARS-CoV-2, determinaciones de marcadores inflamatorios y seguimiento por RT-PCR para evaluar el tiempo de negativización. Resultados: El grupo tratado con interferón tuvo un tiempo significativamente más corto de negativización. Los pacientes tratados con interferón mostraron una disminución significativa de los marcadores inflamatorios en el momento del alta hospitalaria y tuvieron un incremento de los títulos de anticuerpos a los dos y cuatro meses posteriores al alta hospitalaria, en comparación con el grupo de pacientes que no recibió interferón. Conclusiones: El tratamiento con interferón exógeno en pacientes con COVID-19 tuvo una contribución significativa en la regulación de la respuesta inmune de los pacientes(AU)

Progress on the protective effect of heme oxygenase-1 in viral infection / 药学学报

Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that catalyzes the conversion of heme to CO, biliverdin, and iron, which together protect cells from oxidative and inflammatory damage and play an important role in maintaining cell homeostasis. In recent years, HO-1 has also been found to have antiviral biological effects, and the induced expression of HO-1 inhibits the replication of various viruses such as hepatitis C virus, hepatitis B virus, human immunodeficiency virus, dengue virus, ebolavirus, influenza A virus, Zika virus, severe acute respiratory syndrome coronavirus 2, human respiratory syncytial virus, hepatitis A virus and enterovirus 71. The inhibitory effect of HO-1 on these viruses involves three mechanisms, including direct inhibition of virus replication by HO-1 and its downstream products, enhancement of type I interferon responses in host cell, and attenuation of inflammatory damage caused by viral infection. This review focuses on the recent advances in the antiviral effect of HO-1 and its mechanism, which is expected to provide evidence for HO-1 as a potential target for antiviral therapy.

Niveles de Interferón Tipo I en pacientes con Lupus Eritematoso Sistémico / Type I interferon levels in patients with systemic lupus erythematosus

Introducción: El interferón (IFN) tipo I es una citoquina que juega un rol fundamental en la patogenia del Lupus Eritematoso Sistémico (LES). Diferentes niveles de esta citoquina podrían explicar la heterogeneidad de esta patología y ser útil para evaluar la actividad de la misma. Objetivos: Determinar los niveles de IFN tipo I sérico en pacientes con LES y evaluar su utilidad como biomarcador de actividad. Material y Métodos: 16 pacientes con LES (ACR 1997) y 16 controles. Métodos: Actividad de la enfermedad (SLEDAI-2K), daño orgánico (SLICC), IFN tipo I (HEK-Blue-IFNα/β), anticuerpos anti-DNAdc (Inmunofluorescencia Indirecta), anticuerpos anti-ENA (ELISA), C3-C4 (Inmunoturbidimetría). Estadística: InfoStat/Instat/MedCalc. Valores de p<0,05 fueron considerados estadísticamente significativos. Resultados: Se observó un aumento de la concentración de IFN en el grupo LES con respecto al control (p<0,05). Los pacientes con valores de IFN superiores al punto de corte, se asociaron con la presencia de anticuerpos anti-DNAdc (OR:13,33; p<0,05). Pacientes con hipocomplementemia y aquellos con puntaje de SLEDAI-2K mayor a 8 presentaron mayores niveles de IFN comparados con pacientes con complemento normal y menor puntaje de índice, respectivamente (p<0,05). Conclusiones: Estos resultados sugieren la importancia que podría tener la determinación de IFN tipo I para el monitoreo de la actividad del LES.

Introduction: Type I interferon (IFN) is a cytokine that plays a fundamental role in the pathogenesis of Systemic Lupus Erythematosus (SLE). Different levels of this cytokine could explain the heterogeneity of this pathology and be useful to evaluate its activity. Objectives: To determine the serum type I IFN levels in patients with SLE and evaluate its usefulness as a biomarker of activity. Material and Method: 16 patients with SLE (ACR 1997) and 16 controls. Methods: Disease activity (SLEDAI-2K), organ damage (SLICC), type I IFN (HEK-Blue-IFNα/β), anti-dsDNA antibodies (Indirect Immunofluorescence), anti-ENA antibodies (ELISA), C3-C4 (Immunoturbidimetry). Statistics: InfoStat/Instat/MedCalc. P values <0.05 were statistically significant. Results: An increase in IFN concentration was observed in the SLE group respect to the control (p <0.05). Patients with IFN values above the cut-off point were associated with the presence of anti-dsDNA antibodies (OR: 13.33; p<0.05). Hypocomplementemic patients and those with a SLEDAI-2K score greater than 8 had higher IFN levels compared to patients with normal complement and a lower index score, respectively (p<0.05). Conclusions: These results suggest the importance that the determination of IFN type I could have for the monitoring of SLE activity.

Exploration on mechanism of anti-coronavirus of Sophora flavescens through multi-pathway / 中草药

The coronavirus disease 2019 (COVID-19), originated in Wuhan city, Hubei Province, China in December 2019, and then quickly spread to most provinces and regions in China and even spread to many countries abroad. COVID-19 is characterized by wide epidemic, strong infectivity, rapid onset and critical condition. In the face of this epidemic, all parts of the country quickly set off a peak in the fight against COVID-19, but no effective drug for COVID-19 has been developed in the short term. Recently, many hospitals have combined traditional Chinese medicine with western medicine in treatment, and the clinical effect is remarkable, which proves the antiviral effect of traditional Chinese medicine. A large number of pharmacological and clinical studies have proved that the Chinese materia medica S. flavescens has significant antiviral effect. In this paper, the mechanism of anti-coronavirus effect of S. flavescens is expounded from multiple pathways, such as type I interferon, NF-κB signal pathway, ERK signal pathway, PI3K/Akt signal pathway and matrine alkaloids, etc. It is intended to provide reference for clinical treatment of coronavirus infection pneumonia and research and development of related drugs of S. flavescens.

The Role of Plasmacytoid Dendritic Cells in Gut Health

Plasmacytoid dendritic cells (pDCs) are a unique subset of cells with different functional characteristics compared to classical dendritic cells. The pDCs are critical for the production of type I IFN in response to microbial and self-nucleic acids. They have an important role for host defense against viral pathogen infections. In addition, pDCs have been well studied as a critical player for breaking tolerance to self-nucleic acids that induce autoimmune disorders such as systemic lupus erythematosus. However, pDCs have an immunoregulatory role in inducing the immune tolerance by generating Tregs and various regulatory mechanisms in mucosal tissues. Here, we summarize the recent studies of pDCs that focused on the functional characteristics of gut pDCs, including interactions with other immune cells in the gut. Furthermore, the dynamic role of gut pDCs will be investigated with respect to disease status including gut infection, inflammatory bowel disease, and cancers.

Effect of porcine kidney epithelial cells type I interferon receptor 1 knockdown on Pseudorabies virus replication / 解剖学报

Objective: To investigate the effect of type I interferon receptor 1 (IFNAR1) on Pseudorabies virus (PRV) replication. Methods: A stable cell line in which porcine kidney epithelial cells (PK 15) knocked out the IFNAR1 gene was constructed using a lentiviral-mediated CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats, CRISPR) gene editing technique. The function of IFNAR1 was verified by cell viability assay, fluorescence observation, flow cytometry detection, titer determination, and Real-time PCR. Results: With the prolongation of PRV infection, knocking out the IFNAR1 gene can significantly promote transcription of PRV-TK mRNA, translation of PRV-gE protein, and virulence of progeny virus. Conclusion: IFNAR1 plays an important role in inhibiting the proliferation of PRV.

Using ATAC-seq to identify the chromatin accessibility activated by type I interferon in human monocytes / 上海交通大学学报（医学版）

Objective • To detect the genome-wide profiling of chromatin accessibility in human monocytes after stimulated with interferon α (IFNα). Methods • Blood samples were collected from a healthy donor. Assay for transposase-accessible chromatin using sequencing (ATAC-seq) technique was performed to detect the chromatin accessibility. Bioinformatic tools were used for enrichment analysis and visual analysis. Results • With the treatment of IFNα, there were 430 significant up-regulated regions, and 442 significant down-regulated regions. Most of the accessible regions were located at promoters and the adjacent areas of the genes, followed by the intergenic areas and introns. The enrichment analysis showed that the genes related with up-regulated regions were enriched to interferon relevant pathways or anti-virus reactions. To visualize the corresponding chromatin regions, it showed that the intensity of ATAC-seq signal was significantly enhanced at the promoters and transcriptional start sites of effect or interferon-stimulated genes (ISGs) after IFNα stimulation; while for the regulatory ISGs, there was a certain degree of accessibility before stimulation, and the signal intensity was mildly improved. The motif analysis showed significant enrichment of interferon-stimulated response element and interferon regulatory factor in up-regulated regions. Conclusion • Chromatin accessibility of human monocytes has characteristic changes after typeinterferon stimulation and makes preparation for downstream gene expression.

The latent infection of HSV-1 and stress-induced reactivation / 中国药理学通报

Herpes simplex virus type Ⅰ(HSV-1) is a common pathogen, and human is the only natural host of it.Following a period of lytic replication in epithelial cells, HSV-1 enters axon terminals of sensory neurons and then travels via retrograde transport to the sensory ganglia where latency can be established.Upon the stimulation of some stressors, the latent virus can reactivate, leading to recurrent diseases.Therefore, to clarify the mechanism of HSV-1 latent infection and stress-induced reactivation will offer new insights into the prevention, treatment and control of HSV-1 infection.In this review, we describes the mechanisms underlying HSV-1 latent infection and stress-induced reactivation.

Effect of porcine epidemic diarrhea virus nsp1 on type Ⅰ interferon response / 生物工程学报

Porcine epidemic diarrhea virus (PEDV) inhibits the host typeⅠinterferon and cellular antiviral response, but its inhibition mechanism is unclear, and the roles of PEDV nonstructural proteins in regulating typeⅠinterferon responses have been seldom studied. To study the effect of nsp1 on typeⅠinterferon response, nsp1 gene was cloned into a eukaryotic expression vector pCAGGS. The expression of nsp1 in transfected cells was determined by Western blot and indirect immunofluorescence assay. The effects of nsp1 on the induction of typeⅠinterferon were evaluated by dual luciferase reporter gene assay, ELISA and VSV bioassay. Western blot and indirect immunofluorescence assay showed that nsp1 was highly expressed in transfected cells and PEDV-infected cells. Dual luciferase reporter gene assay results indicated that nsp1 strongly inhibited the IFN-β promoter activity, and the inhibitory effect was nsp1 dose-dependent. ELISA results showed that nsp1 significantly inhibited the expression of IFN-β in protein level. And VSV replication-inhibition bioassay revealed that nsp1 significantly inhibited typeⅠIFN antiviral activities induced by poly(I:C). Our results implied that nsp1 was a highly conserved protein of PEDV and exhibited antagonistic function on interferon promoter activity. The results have laid a foundation for further understanding the immune evasion mechanism of PEDV and for developing new effective vaccine against PEDV.

Primary dengue haemorrhagic fever in patients from northeast of Brazil is associated with high levels of interferon-β during acute phase

Dengue is an acute febrile disease caused by the mosquito-borne dengue virus (DENV) that according to clinical manifestations can be classified as asymptomatic, mild or severe dengue. Severe dengue cases have been associated with an unbalanced immune response characterised by an over secretion of inflammatory cytokines. In the present study we measured type I interferon (IFN-I) transcript and circulating levels in primary and secondary DENV infected patients. We observed that dengue fever (DF) and dengue haemorrhagic fever (DHF) patients express IFN-I differently. While DF and DHF patients express interferon-α similarly (52,71 ± 7,40 and 49,05 ± 7,70, respectively), IFN- β were associated with primary DHF patients. On the other hand, secondary DHF patients were not able to secrete large amounts of IFN- β which in turn may have influenced the high-level of viraemia. Our results suggest that, in patients from our cohort, infection by DENV serotype 3 elicits an innate response characterised by higher levels of IFN- β in the DHF patients with primary infection, which could contribute to control infection evidenced by the low-level of viraemia in these patients. The present findings may contribute to shed light in the role of innate immune response in dengue pathogenesis.

Effects of alcohol on HCV replication and its mechanism / 中华微生物学和免疫学杂志

Objective To investigate the effects of alcohol on hepatitis C virus( HCV) replication and type I interferon signaling pathway in human hepatocytes .Methods Primary hepatocytes were treated with different concentrations of alcohol , and then infected with HCV .The infected cells were collected to measure the level of HCV RNA .The alcohol-treated hepatocytes were also collected to detect the expression of HCV Core, IFN-α, IFN-β, IRF-7, suppressor of cytokine signaling SOCS-2 and SOCS-3 at mRNA and protein levels by real-time quantitative PCR and ELISA or Western blot , respectively .Results Alcohol treatment enhanced HCV infection and replication in primary hepatocytes at concentrations higher than 10 mmol/L in a dose-dependent manner (P<0.05).Treatment with 40 mmol/L of alcohol significantly reduced the expression of IFN-α, IFN-βand IRF-7 at mRNA and protein levels , and increased the expression of SOCS-2 and SOCS-3 at mRNA and protein levels .Conclusion Alcohol treatment could damage the host in-nate immunity in human hepatocytes and promote HCV replication by reducing the expression of type Ⅰinter-feron ( IFN-αand IFN-β) and IRF-7 and increasing the expression of negative regulators including SOCS-2 and SOCS-3.These results demonstrated that the impairment of innate immunity in liver of alcohol abusers might contribute to the enhancement of HCV infection and result in poor therapeutic effect of IFN -α.

Expression and Significance of SHP-2 in Human Papillomavirus Infected Cervical Cancer / 华中科技大学学报（医学）（英德文版）

This study investigated the expression and prognostic value of SHP-2 in cervical cancer caused by human papillomavirus (HPV) infection.Forty-five specimens from patients with cervical cancer (stage Ⅰ -Ⅲ),32 specimens from patients with cervical intraepithelial neoplasia (CIN) ( Ⅰ,Ⅱ) and 20 normal cervical samples from patients with hysteromyoma were collected in Department of Pathology for comparison.The expression levels of SHP-2 and IFN-β proteins were detected by using immunohistochemistry.The mRNA expression level of SHP-2 was detected by using quantitative real-time polymerase chain reaction (PCR).HPVs were detected by HPV GenoArray Test.The Spearman correlation was used to compare the expression level of SHP-2 in HPV infected cervical cancer vs non-HPV infected normal cervix.The level of SHP-2 protein expression in the cancer tissues (88.8％) was significantly higher than in CIN tissues (62.5％) and normal cervixes (45％) (P＜0.05 and P＜0.05,respectively).The SHP-2 mRNA levels in the cancer tissues were upregulated as compared with those in the normal cervixes (P＜0.05).Twenty-one (46.7％) cervical cancers,25 (78.1％) CINs and 17 (85％) normal cervixes showed IFN-β positive staining in cytoplasm.There was statistically significant difference in the expression rate of IFN-β between cervical cancer and normal cervix (x2=8.378,P＜0.05) as well as between cervical cancer and CIN (x2=7.695,P＜0.05).HPV16/18 infections could be found in normal cervixs (15％),CINs (68.7％) and cervical cancers (84.4％).There was a correlation between HPV infection and SHP-2 expression in cervical cancer (rs=0.653,P＜0.05).SHP-2 may be a useful prognostic and diagnostic indicator for HPV infected cervical cancer.In cervical canccrs,SHP-2 mRNA and protein overexpression was associated with IFN-β lower-expression.

Intrinsic Cellular Defenses against Virus Infection by Antiviral Type I Interferon

Intrinsic cellular defenses are non-specific antiviral activities by recognizing pathogen-associated molecular patterns (PAMPs). Toll-like receptors (TLRs), one of the pathogen recognize receptor (PRR), sense various microbial ligands. Especially, TLR2, TLR3, TLR4, TLR7, TLR8 and TLR9 recognize viral ligands such as glycoprotein, single- or double-stranded RNA and CpG nucleotides. The binding of viral ligands to TLRs transmits its signal to Toll/interleukin-1 receptor (TIR) to activate transcription factors via signal transduction pathway. Through activation of transcription factors, such as interferon regulatory factor-3, 5, and 7 (IRF-3, 5, 7) or nuclear factor-kappaB (NF-kappaB), type I interferons are induced, and antiviral proteins such as myxovirus-resistance protein (Mx) GTPase, RNA-dependent Protein Kinase (PKR), ribonuclease L (RNase L), Oligo-adenylate Synthetase (OAS) and Interferon Stimulated Gene (ISG) are further expressed. These antiviral proteins play an important role of antiviral resistancy against several viral pathogens in infected cells and further activate innate immune responses.

The expression levels of interferon inducible genes in peripheral blood cells and their correlation with clinical features in human systemic lmpus erytbematosus / 中华风湿病学杂志

Objective To correlate the expression levels of interferon inducible genes (IFIGs) with disease activity and clinical features in systemic lupus erythematosus (SLE) patiems,.Methods Peripheral blood cells obtained from 67 SLE patients and 23 healthy donors (HDs) were subjected to real-time PCR to measure the transcriptional levels of five IFIGs (OAS-1,Mx-1,Ly6e,IFIT1 and IFIT4).Interferon scores were calculated and were compared between various groups of SLE patients as well as between patients and controls;ISRE lucife:rase reporter gene activity was measured in 17 of 67 patients and correlated with interferon score.Results Interferon scores were strongly correlated with ISRIE reporter gene aetivity,which represented for the type Ⅰ interferon activity in serum.The expression.levels of IFIGs and jinterferon scores were significantly elevated in SLE patients compared with HDs (P＜0.0001).Interferon scores were correlated positively with SLEDAI-2K(P=0.0006) and negatively with C3 levels(P=0.0162).Interferon scores were also significantly elevated in SLE patients with a positive anti-Sm or anti-RNP autoantibodies.Clonclusion The interferon score may be regarded as a good indicator for serum type I interferon activity in SLE and serves as a new hiomarker for disease activity in SLE patients.

Interferons de tipo I (type-I IFNs) e infecção micobacteriana / Interferon type I and mycobaterial infection

Introdução: após a infecção por Mycobacterium tuberculosis, a grande maioria dos adultos controlam a proliferação micobacteriana intracelular. Diversos fatores (idade, estress, denutrição, alcoolismo, infecções intercorrentes e câncer) têm sido correlacionados com a reativação da tuberculose. Durante as infecções virais, o IFN-α/β é produzido em grande quantidade. Métodos: estudo do efeito da estimulação direta dos macrófagos humanos pelo IFN-α sobre a multiplicação micobacteriana intracelular in vitro. Resultados: o pré-tratamento dos monócitos/macrófagos humanos com o IFN-α, aumentou de modo significativo o crescimento micobacteriano intracelular. Conclusão: nossos resultados são compatíveis com a idéia de que o aumento da produção do IFN-α, poderia contribuir para a realização da tuberculose latente nos pacientes portadores de infecções virais agudas ou crônicas.

Introduction: following infection with Mycobacterium tuberculosis, most adults are able to control mycobacterial proliferation. In a minority of individuals, a variety of factors (aging, stress, malnutrition, alcoholism, intercurrent infections, and cancer), can subsequently blunt this acquired resistance, resulting in the development of overt disease. IFN-α/β are copiously produced during viral infections. Methods: we evaluated the effect of INF-α/β on mycobacterial growth in human macrophages in vitro. Results: after pretreatment of human monocytes with IFN-α striking loss of mycobacteriostatic activity of these cells was observed. Conclusion: these results are compatible with the possibility that the secretion of IFN-/β could directly promote mycobacterial growth in patients harboring these organisms.