Objectives With remarkable progress in the field of RSV prophylaxis, it is critical to understand population immunity against RSV. We aim to describe the RSV pre-F immunoglobin G (IgG) antibodies across all age groups in southern China and evaluate the risk factors associated with lower antibody levels. Methods We conducted a community-based cross-sectional sero-epidemiological study in Anhua County, Hunan Province, southern China, from July to November 2021. Serum samples were tested for IgG antibodies against the RSV prefusion F (pre-F) protein using an enzyme-linked immunosorbent assay. We estimated the geometric mean titres (GMTs) and seropositivity rates across all age groups. Generalized linear models (GLMs) were built to identify factors associated with antibody levels. Results A total of 890 participants aged 4 months to >89 years were enrolled. The lowest RSV pre-F IgG GMTs were observed in infants and toddlers aged 4 months to <2 years (3.0, 95% confidence interval [CI]: 2.6-3.5). With increasing age, RSV pre-F IgG GMT increased to 4.3 (95% CI: 4.1-4.4) between the ages of 2 and <5 years and then stabilized at high levels throughout life. All the children had serological evidence of RSV infection by the age of 5 years. Age was associated with RSV pre-F antibody levels in children, with an estimated 1.8-fold (95% CI: 1.1-2.9) increase in titre per year before 5 years of age, while it was not significantly associated with antibody levels in adults aged >60 years. Conclusions Our findings could provide a comprehensive understanding of the gaps in RSV immunity at the population level and inform the prioritization of immunization platforms.

What is already known about this topic? China has repeatedly contained multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreaks through a comprehensive set of targeted non-pharmaceutical interventions (NPIs). However, the effectiveness of such NPIs has not been systematically assessed. What is added by this report? A multilayer deployment of case isolation, contact tracing, targeted community lockdowns, and mobility restrictions could potentially contain outbreaks caused by the SARS-CoV-2 ancestral strain, without the requirement of city-wide lockdowns. Mass testing could further aid in the efficacy and speed of containment. What are the implications for public health practice? Pursuing containment in a timely fashion at the beginning of the pandemic, before the virus had the opportunity to spread and undergo extensive adaptive evolution, could help in averting an overall pandemic disease burden and be socioeconomically cost-effective.

Abstract Background Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infectious disease in children globally. Transplacental-acquired antibodies are essential in protecting infants during the initial months of their life. This study assessed the efficacy of transferring maternal RSV prefusion protein (pre-F) IgG antibodies via the placenta and reported the dynamics of maternal and natural infection-induced antibodies in children. Methods A longitudinal mother-neonate pairs cohort was started enrolled in southern China in the autumn of 2013. 660 mother-neonate pairs were included in this study. Both cord blood from neonates and venous blood from mothers at delivery were obtained. The children were followed up and blood samples were collected at ages 2, 4, 6, 12, 24, and 36 months, as well as at 6-8 years (Figure 1). RSV-specific pre-F IgG antibodies were identified by the enzyme-linked immunosorbent assay method. The maternal antibody transfer efficacy, decay of maternal antibodies, age-specific antibody level, and seroprevalence were estimated. Results All neonates acquired RSV pre-F IgG antibodies from their mothers. We found a significant correlation between maternal and neonatal antibody titers (ρ=0.86, P< 0.001). The average RSV pre-F IgG antibody titers were higher in cord blood than in maternal blood, with a mean transfer ratio of maternal antibodies of 1.48 (95%CI: 1.44-1.52) (Figure 2). Maternal antibody levels in neonates declined rapidly, with a half-life of 1.4 months. The lowest point of antibodies occurred at 11 months of age, followed by titer increases due to natural RSV infection, and approximately 50% of the children seroconverted at the age of 41.5 months.Figure 2(A) Correlation between neonatal and maternal antibody titer. (B) Transfer ratio with maternal antibody titers. The top orange density plots maternal antibody titers, and the right plots neonatal antibody titers. Conclusion Efficient transfer of RSV maternal antibodies to neonates was observed. As maternal antibodies wane, the seropositive infants gradually reduce to the lowest in the first year of life. After that, the infant’s immune system develops and naturally acquired immunity due to infection. Our findings will optimize future strategies for both vaccine and long-term prophylactic monoclonal antibodies to target RSV pre-F protein. Disclosures Hongjie Yu, PhD, GlaxoSmithKline: Grant/Research Support|Roche: Grant/Research Support|Sanofi: Grant/Research Support|SINOVAC: Grant/Research Support

Omicron and its sublineages are currently predominant and have triggered epidemiological waves of SARS-CoV-2 around the world due to their high transmissibility and strong immune escape ability. Vaccines are key measures to control the COVID-19 burden. Omicron BA.2 caused a large-scale outbreak in Shanghai since March 2022 and resulted in over 0.6 million laboratory-confirmed infections. The vaccine coverage of primary immunization among residents aged 3 years and older in Shanghai exceeded 90%, and inactivated COVID-19 vaccines were mainly delivered. In the context of high vaccine coverage, we conducted a cohort study to assess vaccine effects on reducing the probability of developing symptoms or severity of disease in infections or nonsevere cases. A total of 48,243 eligible participants were included in this study, the majority of whom had asymptomatic infections (31.0%) and mild-to-moderate illness (67.9%). Domestically developed COVID-19 vaccines provide limited protection to prevent asymptomatic infection from developing into mild-to-moderate illness and durable protection to prevent nonsevere illness from progressing to severe illness caused by Omicron BA.2. Partial vaccination fails to provide effective protection in any situation. The level of vaccine effects on disease progression in the elderly over 80 years old was relatively lower compared with other age groups. Our study results added robust evidence for the vaccine performance against Omicron infection and could improve vaccine confidence.

Myeloid-derived suppressor cells (MDSCs) are a population of myeloid progenitor cells with immunoregulatory functions and their role in myasthenia gravis (MG) was unknown. In this study, we investigated the phenotypic and functional alterations of MDSCs in MG before and after immunotherapy. The frequency of MDSCs significantly increased and negatively correlated to that of Th1 or Th17 cells after immunotherapy. MDSCs from untreated patients with MG showed an impaired suppression of IFN-γ production in T-cells and improved immunosuppressive function was identified after immunotherapy. The MFI of Arg-1 in MDSCs also increased after immunotherapy. These findings suggested the functional difference in MDSCs before and after immunotherapy, and MDSCs might play a role in disease remission.

Paclitaxel is the best natural anticancer drug and artemisinin also has anticancer effect. In this study, the interactions between BSA and these two drugs were determined in PBS (pH 7.40) by multi-spectroscopic method and molecular dynamics (MD) simulations. The results showed that paclitaxel and artemisinin could statically quench the BSA fluorescence when the complexes were formed and the stoichiometric ratio of BSA-drugs was 1:1. Particularly, the BSA-paclitaxel complex was more stable than BSA-artemisinin complex. During the binding, the surroundings around Trp residue site was largely affected than Tyr site, especially Trp 214 to a more hydrophobic environment. In addition, the binding processes were mainly spontaneous through electrostatic force interaction. In summary, we concluded that the free drug of paclitaxel in blood was low and duration time of artemisinin was shorter.

Introduction: The role of plasma exchange in treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) with severe kidney involvement is controversial. It is urgent to find effective treatments to improve prognosis of AAV patients. In this retrospective study, the outcomes of immunoadsorption (IA) onto protein A in AAV patients with severe kidney involvement were evaluated. Methods: Clinical data of 60 patients with AAV and severe kidney involvement were analyzed. Patients received cyclophosphamide or rituximab for remission induction, among which 16 were additionally treated with IA. Remission, end-stage kidney disease (ESKD), death, and relapse were compared. Results: Of 60 patients, 56 patients (93.3%) were positive for myeloperoxidase (MPO)-ANCA. At diagnosis, the estimated glomerular filtration rate and Birmingham Vasculitis Activity Score (BVAS) was 13.0 (7.7, 18.7) mL/min/1.73 m2 and 11.1 ± 3.4, respectively. After 3–17 days (mean 10.4 days) of induction treatment, the disease activity decreased more obviously in the IA group (p = 0.022) than the control group. IA showed superior over standard regimen in clearance of MPO-ANCA within 3–31 days (median 11 days) after treatment (78.4% vs. 9.3%, p = 0.005). After a median follow-up of 20.2 months, remission was achieved more quickly (p = 0.035) and higher (hazard ratio (HR) = 2.3, 95% confidence interval (CI): 1.1∼7.2, p = 0.033) in the IA group than the control group. IA therapy showed an advantage in reducing death (HR = 0.2, 95% CI: 0.1∼0.9, p = 0.032). There was no difference in developing into ESKD in both groups (HR = 0.7, 95% CI: 0.3∼2.0, p = 0.504). Multivariate Cox regression analysis indicated that early-stage remission was an independent predictor for ESKD (HR = 0.03, 95% CI: 0.003∼0.25, p = 0.001) and death (HR = 0.07, 95% CI: 0.01∼0.51, p = 0.009). Conclusion: IA treatment induces quicker and higher remission and lower mortality in AAV patients with severe kidney involvement. The early remission independently predicts the outcomes for these patients.

Coronavirus disease (COVID-19) is highly contagious and is now a tragic pandemic. Maintenance hemodialysis (MHD) patients are susceptible to COVID-19 and more prone to develop into severe cases because of the older age, heavy comorbidities, and impaired immunity. Patients who receive in-center dialysis have to travel to and from dialysis centers; patients have to share the dialysis hall with others during dialysis, making the prevention and control of COVID-19 in dialysis centers different from that in community and more difficult. This article provides key points in coping with COVID-19 in dialysis centers during this pandemic based on experience: (1) enforcing infection control management of dialysis centers, (2) training of hemodialysis patients and medical staffs, (3) screening for COVID-19 among patients and medical staffs, and (4) providing graded isolated dialysis to close contacts, suspected cases, and confirmed cases of COVID-19. We hope our single-center experience can be referenced by other dialysis centers around the world in coping with the COVID-19 pandemic.

Objectives: The aim of this study wasto investigate the efficacy of tacrolimus treatment in patients with refractory generalized myasthenia gravis (MG) and explore its impact on lymphocytic phenotypes and related cytokines mRNA expression. Methods: A total of 24 refractory generalized MG patients were enrolled. Before treatment and at 2, 6, and 12 months after tacrolimus treatment, the therapeutic effect was evaluated by the quantitative MG score of the Myasthenia Gravis Foundation of America (QMG), Manual Muscle Test (MMT), MG-specific Activities of Daily Living (MG-ADL), 15-item Myasthenia Gravis Quality-of-Life Scale (MG-QOL15), and changes of prednisone dosage. Also, we used the flow cytometer for the lymphocytic immunophenotyping and real-time PCR for the qualification of cytokine mRNA in peripheral blood mononuclear cells (PBMCs) at different time points during the treatment. Results: Significantly decreased QMG, MMT, MG-ADL, and MG-QOL15 were observed at all time points during the tacrolimus treatment. The dosage of prednisone also reduced at the end of the observation period with only 6 adverse events reported. The immunological impact of tacrolimus was revealed by reduced percentages of Tfh, Breg, CD19(+)BAFF-R+ B cells, and increased percentages of Treg cells as well as down-regulated expression of IL-2, IL-4, IL-10, and IL-13 mRNA levels in PBMCs during the treatment. Conclusion: Our study indicated the clinical efficacy of tacrolimus in patients with refractory generalized MG. The underlying immunoregulatory mechanism of tacrolimus may involve alterations in the phenotypes of peripheral blood lymphocytes and Th1/Th2-related cytokine expression of PBMCs.

Background Highly pathogenic avian influenza A(H5N1) virus poses a global public health threat given severe and fatal zoonotic infections since 1997 and ongoing A(H5N1) virus circulation among poultry in several countries. A comprehensive assessment of the seroprevalence of A(H5N1) virus antibodies remains a gap and limits understanding of the true risk of A(H5N1) virus infection. Methods We conducted a systematic review and meta-analysis of published serosurveys to assess the risk of subclinical and clinically mild A(H5N1) virus infections. We assessed A(H5N1) virus antibody titers and changes in titers among populations with variable exposures to different A(H5N1) viruses. Results Across studies using the World Health Organization-recommended seropositive definition, the point estimates of the seroprevalence of A(H5N1) virus-specific antibodies were higher in poultry-exposed populations (range 0–0.6%) and persons exposed to both human A(H5N1) cases and infected birds (range 0.4–1.8%) than in close contacts of A(H5N1) cases or the general population (none to very low frequencies). Seroprevalence was higher in persons exposed to A(H5N1) clade 0 virus (1.9%, range 0.7–3.2%) than in participants exposed to other clades of A(H5N1) virus (range 0–0.5%) ( p < 0.05). Seroprevalence was higher in poultry-exposed populations (range 0–1.9%) if such studies utilized antigenically similar A(H5N1) virus antigens in assays to A(H5N1) viruses circulating among poultry. Conclusions These low seroprevalences suggest that subclinical and clinically mild human A(H5N1) virus infections are uncommon. Standardized serological survey and laboratory methods are needed to fully understand the extent and risk of human A(H5N1) virus infections.

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which can be activated by cytokines, growth factor receptors, and nonreceptor-like tyrosine kinase. An activated STAT3 translocates into the nucleus and combines with DNA to regulate the expression of target genes involved in cell proliferation, differentiation, apoptosis and metastasis. Recent studies have shown that STAT3 plays important roles in viral infection and pathogenesis. STAT3 exhibits a proviral function in several viral infections, including those of HBV, HCV, HSV-1, varicella zoster virus, human CMV and measles virus. However, in some circumstances, STAT3 has an antiviral function in other viral infections, such as enterovirus 71, severe acute respiratory syndrome coronavirus and human metapneumovirus. This review summarizes the roles of STAT3 in viral infection and pathogenesis, and briefly discusses the molecular mechanisms involved in these processes.

Enterovirus 71 (EV71) has caused major outbreaks of hand, foot and mouth disease. EV71 infections increase the production of many host cytokines and pro-inflammatory factors, including interleukin (IL)-6, IL-10 and COX-2. Some of these molecules could stimulate the signal transducer and activator of transcription 3 (STAT3), which plays a key role in regulating host immune responses and several viral diseases. However, the role of STAT3 in EV71 infection remains unknown. This study found that the phosphorylation levels of STAT3 (pY705-STAT3) are closely related to EV71 infection. Further experiments revealed that STAT3 exerts an anti-EV71 activity. However, the antiviral activity of STAT3 is partially antagonized by EV71-induced miR-124, which directly targets STAT3 mRNA. Similarly, IL-6R, the α-subunit of the IL-6 receptor complex, exhibits anti-EV71 activity and is directly targeted by the virus-induced miR-124. These results indicate that EV71 can evade host IL-6R- and STAT3-mediated antiviral activities by EV71-induced miR-124. This suggests that controlling miR-124 and the downstream targets, IL-6R and STAT3, might benefit the antiviral treatment of EV71 infection.

Enterovirus 71 (EV71) causes major outbreaks of hand, foot, and mouth disease. Host factors and signaling pathways exhibit important functions in the EV71 life cycle. We conducted algorithm analysis based on miRNA profiles and their target genes to identify the miRNAs and downstream signaling pathways involved in EV71 infection. The miRNA profiles of human rhabdomyosarcoma cells treated with interferon (IFN-)-α or IFN-γ were compared with those of cells infected with EV71. Genes targeted by differentially expressed miRNAs were identified and assigned to different signaling pathways according to public databases. The results showed that host miRNAs specifically responded to the viral infection and IFN treatment. Some miRNAs, including miR-124 and miR-491-3p, were regulated in opposite manners by the IFNs and EV71. Some signaling pathways regulated by both EV71 infection and IFN treatment were also predicted. These pathways included axon guidance, Wingless/Int1 (Wnt) signaling cascade, platelet-derived growth factor receptor (PDGFR)/PDGF, phosphatidylinositol 3-kinase (PI3K), Jun N-terminal kinase (JNK)/mitogen-activated protein kinase (MAPK), transforming growth factor-beta receptor (TGF-βR)/TGF-β, SMAD2/3, insulin/insulin-like growth factor (IGF), bone morphogenetic protein (BMP), CDC42, ERB1, hepatocyte growth factor receptor (c-Met), eukaryotic translation initiation factor 4E (eIF4E), protein kinase A (PKA), and IFN-γ pathways. The identified miRNA and downstream signaling pathways would help to elucidate the interaction between the virus and the host. The genomics method using algorithm analysis also provided a new way to investigate the host factors and signaling pathways critical for viral replication.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells and have a tremendous potential to suppress immune responses. MDSCs accumulate during tumor progression, autoimmunity, chronic infection, transplantation, and other pathological conditions and can potently suppress T-cell function. Here, we discuss recent findings that describe the molecular mechanisms of MDSCs suppressing T-cell immune responses as well as recent observations that MDSCs may have roles in transplant tolerance.

Background OTUB1 is a member of OTUs (Ovarian-tumor-domain-containing proteases), a deubiquitinating enzymes family (DUBs), which was shown as a proteasome-associated DUB to be involved in the proteins Ub-dependent degradation. It has been reported that OTUB1 was expressed in kidney tissue. But its concrete cellular location and function in the kidney remain unclear. Decorin (DCN) in mesangial cells (MC) is considered to be a potentially important factor for antagonizing glomerulonephritides, and its degradation is mediated by ubiquitination. The aim of this study is to investigate the role of OTUB1 expression in MC and its relationship with DCN during glomerulonephritis. Methodology/Principal Findings Using quantitative RT-PCR and Western blot, we demonstrated that OTUB1 mRNA and protein were constitutively expressed in cultured rat MC and found to be upregulated by the stimulation of IL-1β or ATS. OTUB1 overexpression was detected in the mesangial area of glomeruli in some immunocomplex mediated nephritides such as IgA nephropathy, acute diffuse proliferative glomerulonephritis and lupus nephritis by immunohistochemistry. The immunoprecipitation assay demonstrated that OTUB1 interacted with DCN. The overexpression of OTUB1 enhanced the ubiquitination and degradation of DCN in MC. Conclusion/Significance These data showed the inflammatory injury could up-regulate OTUB1 expression in MC, which might attribute the promoting effect of OTUB1 on glomerulonephritides to the decrease of DCN level.

Hepatitis C virus (HCV) F protein has been identified for more than ten years, but its functions remain unclear. In order to understand its roles in viral replication and infection, in this study 5 stop codons (nt406T-A, nt433T-A, nt472G-A, nt479/481G-A, G-A, nt613C-A) were introduced in plasmid J6JFH1 to construct J6JFH1/Delta F which interrupt F protein expression, and then monitor the viral RNA replication and viral protein expression. Our data showed that the five mutations did not affect core gene replication and expression. The virus strain J6JFH1/Delta F significantly reduced in the expression of viral proteins in transfected cells compared with wild-type J6JFH1, and viral RNA levels dropped by nearly 95% (J6JFH1/Delta F (7.39x10(6)+/-2.54x10(4)) vs wild type (1.17x10(8)+/-1.46x10(7)), P < 0.001). The infectivity of virus released into the supernatant significantly reduced similarly. Further study found that these five mutations changed secondary structure of HCV core gene. In order to further explore the underlying reasons for the weakening of J6JFH1/Delta F virus replication and infection, we constructed five separate mutant viruses based on J6JFH1, respectively, and form J6JFH1m1 nt406T-A, J6JFH1m2 nt433T-A, J6JFH1m3 nt472G-A, J6JFH1m4 nt479/481G-A, G-A, J6JFH1m5 nt613C-A. These 5 virus mutants do not influence the secondary structure of the core region, while J6JFH1m1, J6JFH1m2, J6JFH1m3, J6JFH1m4, J6JFH1m5 respectively stopped F protein expression shifting from nt374-383, nt417-419, nt436-445, nt474-477, nt597-605, in which J6JFH1m5 stopped all reported forms of F protein. By in vitro transcription and transfection into Huh7.5.1 cells, 48 hours post-transfection, the detection of intracellular viral protein NS5A expression levels, viral RNA in transfected cells, and virus titers in supernatant were carried out. The results showed that no significant differences were found among groups five separate mutants and wild type. These results indicated that the lack of F protein itself did not affect HCV viral replication and virion assembly and infectivity. All the results were seemed to result from the secondary structure of the core gene, but the mechanism was yet to be further studied. We concluded that HCV F protein deficiency did not affect translation of viral replication and packaging and release of virus particles, the core gene secondary structure changes had a great impact on viral replication and protein expression.