Association of vaccine-specific regulatory T cells with reduced antibody response to repeated influenza vaccination.

Repeated annual influenza vaccinations have been associated with reduced vaccine-induced antibody responses. This prospective study aimed to explore the role of vaccine antigen-specific regulatory T (Treg) cells in antibody response to repeated annual influenza vaccination. We analyzed pre- and postvaccination hemagglutination inhibition (HI) titers, seroconversion rates, seroprotection rates, vaccine antigen hemagglutinin (HA)-specific Treg cells, and conventional T (Tconv) cells. We compared these parameters between vaccinees with or without vaccine-induced seroconversion. Our multivariate logistic regression revealed that prior vaccination was significantly associated with a decreased likelihood of achieving seroconversion for both H1N1(adjusted OR, 0.03; 95% CI, 0.01-0.13) and H3N2 (adjusted OR, 0.09; 95% CI, 0.03-0.30). Furthermore, individuals who received repeated vaccinations had significantly higher levels of pre-existing HA-specific Treg cells than those who did not. We also found that vaccine-induced fold-increases in HI titers and seroconversion were negatively correlated with pre-existing HA-specific Treg cells and positively correlated with the ratio of Tconv to Treg cells. Overall, our findings suggest that repeated annual influenza vaccination is associated with a lower vaccine-induced antibody response and a higher frequency of vaccine-specific Treg cells. However, a lower frequency of pre-existing Treg cells correlates with a higher postvaccination antibody response.

The Effect of Polyepoxyphenylsilsesquioxane and Diethyl Bis(2-hydroxyethyl)aminomethylphosphonate on the Thermal Stability of Epoxy Resin.

Polyepoxyphenylsilsesquioxane (PEPSQ) and diethyl bis(2-hydroxyethyl) aminomethylphosphonate (DBAMP) can improve the flame retardancy of epoxy resin (EP). In this paper, the results of the limiting oxygen index (LOI) and UL94 tests exhibited that PEPSQ and DBAMP had good synergistic flame retardancy. The non-isothermal degradation kinetics of EP containing PEPSQ and DBAMP was investigated by the Kissinger and Flynn-Wall-Ozawa methods. The results of the Kissinger method displayed that the addition of two flame retardants, PEPSQ and DBAMP, can slightly enhance the activation energy of EP, indicating that the additives delayed the thermal degradation of EP. The Flynn-Wall-Ozawa method further confirmed that the activation energy of EP during the whole thermal degradation process can be significantly increased by addition of the two flame retardants PEPSQ and DBAMP. When the degree of conversion exceeded 80%, the increase was more significant. This illustrated that the flame retardants finally achieved the purpose of improving the flame retardancy of EP by stabilizing the char layer.

An ankylosing spondylitis risk variant alters osteoclast differentiation.

OBJECTIVE: To explore whether the variants in non MHC proteasome gene are associated with AS and explain the role of the variant in the disease. MATERIAL AND METHODS: Case-control analysis to identify AS predisposition genes; dual-luciferase reporter assay, immunoblot analysis and osteoclastogenesis assays to detect the function of the positive variant. Affected individuals were diagnosed according to the modified New York Criteria by at least two experienced rheumatologists, and rechecked by another rheumatologist. RESULTS: The study included 1037 AS patients and 1014 no rheumatic and arthritis disease controls. The main age of AS onset is between 16 and 35 years old. HLA-B27-positive subjects comprised 90.0% of patients. A nonsynonymous SNP rs12717 in proteasome gene PSMB1 significantly associated with AS. Individuals with CC genotype had a higher onset risk compared with those with GG/GC genotypes (OR = 1.89, P = 0.0047). We also discovered that PSMB1 regulates the receptor activator of nuclear factor-κB (RANK)/RANK ligand (RANKL) signalling pathway and the disease-associated variant PSMB1-Pro11 significantly inhibits RANKL-induced NF-κB pathway in osteoclast differentiation via the degradation of IKK-ß compared with PSMB1-Ala11. RANKL induced osteoclast differentiation was significantly lower in primary monocyte osteoclast precursor from individuals with genotype PSMB131C/31C compared with individuals with genotype PSMB131G/31G. CONCLUSIONS: These results reveal a novel understanding of the bone formation and reabsorbing imbalance in AS. The new bone formation phenotype can be attributed to the inhibition of osteoclast differentiation by a more functional PSMB1 gene.

Risks of posterior segment ocular ischaemic events in patients with systemic lupus erythematosus: a population-based cohort study in Taiwan.

BACKGROUD/AIM: Ocular involvement in systemic lupus erythematosus (SLE) is often primarily recognised by ophthalmologists rather than internists. This study aims to investigate the incidence and risk factors for the occurrence of posterior ocular ischaemic events (OIE), including retinal vein occlusion (RVO), retinal artery occlusion (RAO) and ischaemic optic neuropathy (ION), in patients with SLE. METHODS: A national database in Taiwan was used to identify 24 472 patients newly diagnosed with SLE and 244 720 age-matched and sex-matched controls between 1997 and 2012. New occurrences of OIE and confounding factors were recorded. The Kaplan-Meier method was used to compare the risk of OIE between the two groups. Fixed effect models were applied to evaluate the risk factors for OIE. RESULTS: The mean age was 36.24±15.82 years and women accounted for 88.4%. Patients with SLE had significantly increased risk of overall OIE (HR 3.89, 95% CI 3.36 to 4.50, p<0.001) as well as each OIE subtype. End-stage renal disease (ESRD; HR 2.91, 95% CI 2.05 to 4.14, p<0.001), hypertension (HR 1.77, 95% CI 1.21 to 2.58, p=0.003) and congestive heart failure (HR 1.67, 95% CI 1.12 to 2.48, p=0.01) were associated with RVO development. Hypertension (HR 2.89, 95% CI 1.10 to 3.96, p=0.02) and ischaemic stroke (HR 3.58, 95% CI 1.97 to 6.48, p<0.001) had increased risk of RAO. ESRD was associated with ION (HR 3.03, 95% CI 1.41 to 6.51, p=0.004). Intravenous steroid was associated with RVO development (HR 2.54, 95% CI 1.67 to 3.84, p<0.001). CONCLUSIONS: SLE increases the risk of developing OIE. Systemic comorbidities and higher dosage of steroid in patients with SLE are associated with severe ocular ischaemic complications.

Synthesis, Self-Assembly, and Cell Responses of Aromatic IKVAV Peptide Amphiphiles.

Synthetic bioactive aromatic peptide amphiphiles have been recognized as key elements of emerging biomedical strategies due to their biocompatibility, design flexibility, and functionality. Inspired by natural proteins, we synthesized two supramolecular materials of phenyl-capped Ile-Lys-Val-Ala-Val (Ben-IKVAV) and perfluorophenyl-capped Ile-Lys-Val-Ala-Val (PFB-IKVAV). We employed UV-vis absorption, fluorescence, circular dichroism, and Fourier-transform infrared spectroscopy to examine the driving force in the self-assembly of the newly discovered materials. It was found that both compounds exhibited ordered π-π interactions and secondary structures, especially PFB-IKVAV. The cytotoxicity of human mesenchymal stem cells (hMSCs) and cell differentiation studies was also performed. In addition, the immunofluorescent staining for neuronal-specific markers of MAP2 was 4.6 times (neural induction medium in the presence of PFB-IKVAV) that of the neural induction medium (control) on day 7. From analyzing the expression of neuronal-specific markers in hMSCs, it can be concluded that PFB-IKVAV may be a potential supramolecular biomaterial for biomedical applications.

Aging Promotes Chronic Stress-Induced Depressive-Like Behavior by Activating NLRP1 Inflammasome-Driven Inflammatory Signaling in Mice.

NLRP1 inflammasome has been reported to participate in many neurological disorders. Our previous study has demonstrated that NLRP1 inflammasome is implicated in chronic stress-induced depressive-like behaviors in mice. Age has been reported to be related to depression. Here we examine whether NLRP1 inflammasome is involved in the effect of age on depressive disorder. Two chronic stress stimuli, chronic social defeat stress (CSDS) and repeat social defeat stress (RSDS), were used to establish a depression model in mice of different ages. We found that aged mice exhibited worse depressive-like behaviors and locomotor activity compared to young mice. Interestingly, the expression of hippocampal NLRP1 inflammasome complexes and the levels of the inflammatory cytokines were increased in an age-dependent manner. Also, chronic stress-induced increase in the expression of the hippocampal chemokine C-X-C motif ligand 1 (CXCL1), and its cognate receptor, CXC-motif receptor 2 (CXCR2), was more remarkable in aged mice than that in young mice. Moreover, aged mice exhibited lower hippocampal BDNF levels compared to young mice. Hippocampal Nlrp1a knockdown reduced the levels of pro-inflammatory cytokines and the expression of CXCL1/CXCR2, restored BDNF levels, and alleviated chronic stress-induced depressive-like behaviors in aged mice. Our results suggest that NLRP1 inflammasome-CXCL1/CXCR2-BDNF signaling contributes to the effect of age on chronic stress-induced depressive-like behavior in mice.

Global, Regional, and National Levels and Trends in the Burden of Pressure Ulcer from 1990 to 2019: A Systematic Analysis for the Global Burden of Disease 2019.

Pressure ulcer (PU) is a type of chronic ulcer, placing a high burden not only on patients' families but also on national healthcare systems globally. To determine the level, trends, and burden of PU worldwide and to provide an essential foundation for building targeted public policies on PUs at the national, regional, and global levels, data on PU were obtained from the Global Burden of Disease (GBD) 2019 Study. The incidence, disability-adjusted life years (DALYs), and deaths of PUs in 204 countries and regions from 1990 to 2019 were calculated and stratified by sex, age, geographical location, and sociodemographic index (SDI). The estimated annual percentage change (EAPC) of incidence, DALYs, and deaths was calculated to evaluate the temporal trends. A total of 3,170,796 new cases (95% uncertainty interval (UI), 3,499,729-2,875,433 cases) of PU were identified globally in 2019, more than 55% of which were among male individuals, and most of the new cases were concentrated in those 75-90 years of age. The burden of PU measured in DALYs was 481 423 (95% UI, 583 429-374 334) in 2019, 73% and 27% of which could be attributed to years of life lost (YLLs) and years lived with disability (YLDs), respectively. The burden increased gradually from 1990 to 2019 (from 267 846 [360 562-211 024] to 481 423 [95% UI, 583 429-374 334]). A total of 24 389 deaths were attributed to PU (95% UI, 31 260.82-17 299). The EAPC of incidence, DALYs, and deaths were negative in most regions, the age-standardized rate (ASR) of incidence, DALYs, and deaths were considered to be decreasing in most of the regions, and the EAPCs were negatively correlated with the SDI levels, universal health coverage (UHC), and gross domestic product (GDP), which shows that the ASRs of PU decreased as the economy developed and countries' healthcare system performances improved.

Flame Retardancy and Thermal Degradation Behaviors of Thiol-Ene Composites Containing a Novel Phosphorus and Silicon-Containing Flame Retardant.

In this article, a novel phosphorus and silicon-containing flame retardant (DOPO-V-PA) was synthesized via condensation reaction and then added into thiol-ene (TE) to prepare a flame-retardant composite. The results of cone calorimeter measurement demonstrated that, compared with pure TE, 22.7% and 53.2% reduction of TE/DOPO-V-PA (thiol-ene/9,10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxide-vinyltrimethoxysilane-phenyltrimethoxysilane-(3-aminopropyl)trimethoxysilane copolymer) was found for the peak heat release rate (PHRR) and total heat release (THR), respectively. The thermal degradation of TE composites was investigated by the TGA measurement under non-isothermal conditions, and kinetic parameters were both calculated by the Kissinger and Flynn-Wall-Ozawa methods. It was indicated that the activation energies of TE at conversions exceeding 50% were enhanced by the incorporation of DOPO-V-PA for the whole conversion range.

One-Step Reduction of Graphene Oxide with Phosphorus/Silicon-Containing Compound and Its Flame Retardancy in Epoxy Resin.

A novel graphene-based phosphorus/silicon-containing flame retardant (GO-DOPO-V) was obtained via one-step reduction of graphene oxide (GO) with phosphorus/silicon-containing compound (DOPO-V). The Fourier transform infrared (FTIR) spectroscopy, X-ray photoelectron spectrometer (XPS), Atomic force microscope (AFM) and Thermogravimetric analysis (TGA) measurements were used to confirm the structure and morphology. After incorporation of 2 wt% GO-DOPO-V, the maximum decreases of 28.8% in peak heat release rate and 15.6% in total heat release are achieved compared to that of pure epoxy resin (EP). Furthermore, TGA and Scanning electron microscopy (SEM) measurement showed that GO-DOPO-V significantly enhanced the thermal stability and residual char strength of EP. Thus, attributed to the barrier effect of GO and phosphorus/silicon layer formation by DOPO-V, GO-DOPO-V was a high-efficient flame retardant to improve the combustion behavior of EP nanocomposite.

Thermal Degradation Behavior of Epoxy Resin Containing Modified Carbon Nanotubes.

Via the surface-grafting of carbon nanotubes (CNTs) with a silicon-containing flame retardant (PMDA), a novel flame retardant CNTs-PMDA was synthesized. The flame retardancy was tested by cone calorimeter. Compared with pure epoxy resin, the total heat release (THR) and peak heat release rate (PHRR) of epoxy resin containing CNTs-PMDA were significantly reduced, by 44.6% and 24.6%, respectively. Furthermore, thermal degradation behavior of epoxy resin based composite was studied by the thermogravimetric analysis with differences in heating rates. The kinetic parameters of the thermal degradation for epoxy resin composites were evaluated by the Kissinger method and Flynn-Wall-Ozawa method. The results suggested that activation energy values of epoxy resin containing CNTs-PMDA in thermal degradation process were higher than those of pure epoxy resin in the final stage of the thermal degradation process, which was closely related to the final formation of char layer residues. Finally, the results from Dynamic mechanical thermal analysis (DMTA) and Scanning electron microscopy (SEM) measurements exhibited that the functionalization of CNTs with PMDA obviously improved the dispersion of CNTs in the epoxy resin matrix.

Whole genome deep sequencing analysis of viral quasispecies diversity and evolution in HBeAg seroconverters.

BACKGROUND & AIMS: We aimed to investigate how viral quasispecies of the HBV whole genome evolves and diversifies in response to HBeAg seroconversion and viral control utilising next-generation sequencing (NGS). METHODS: Fifty HBeAg-positive chronic hepatitis B patients, including 18 treatment-naïve and 32 interferon (IFN)-treated individuals, were recruited. Serial HBV whole genomes in serum were analysed by NGS to determine sequence characteristics and viral quasispecies. RESULTS: HBV quasispecies diversity, measured by nucleotide diversity, was negatively correlated with viral load and hepatitis activity. Spontaneous HBeAg seroconverters exhibited significantly greater viral quasispecies diversity than treatment-naïve non-seroconverters from >1 year before seroconversion (0.0112 vs. 0.0060, p <0.01) to >1 year after seroconversion (0.0103 vs. 0.0068, p <0.01). IFN-induced HBeAg seroconverters tended to have higher viral genetic diversity than non-seroconverters along with treatment. Particularly, the IFN responders, defined as IFN-induced HBeAg seroconversion with low viraemia, exhibited significantly greater genetic diversity of whole HBV genome at 6 months post-IFN treatment than IFN non-responders (0.0148 vs. 0.0106, p = 0.048). Moreover, spontaneous HBeAg seroconverters and IFN responders exhibited significantly higher evolutionary rates and more intra-host single-nucleotide variants. Interestingly, in spontaneous HBeAg seroconverters and IFN responders, there were distinct evolutionary patterns in the HBV genome. CONCLUSIONS: Higher HBV quasispecies diversity is associated with spontaneous HBeAg seroconversion and IFN-induced HBeAg seroconversion with low viraemia, conferring a favourable clinical outcome. LAY SUMMARY: HBeAg seroconversion is a landmark in the natural history of chronic HBV infection. Using next-generation sequencing, we found that the nucleotide diversity of HBV was negatively correlated with viral load and hepatitis activity. Patients undergoing HBeAg seroconversion had more diverse HBV genomes and a faster viral evolution rate. Our findings suggest HBeAg seroconversion is driven by host selection pressure, likely immune selection pressure.

Comorbidity in Older Patients Hospitalized with Cancer in Northeast China based on Hospital Discharge Data.

Patients with cancer often carry the dual burden of the cancer itself and other co-existing medical conditions. The problems associated with comorbidities among elderly cancer patients are more prominent compared with younger patients. This study aimed to identify common cancer-related comorbidities in elderly patients through routinely collected hospital discharge data and to use association rules to analyze the prevalence and patterns of these comorbidities in elderly cancer patients at different cancer sites. We collected the discharge data of 80,574 patients who were diagnosed with cancers of the esophagus, stomach, colorectum, liver, lung, female breast, cervix, and thyroid between 2016 and 2018. The same number of non-cancer patients were randomly selected as the control group and matched with the case group by age and gender. The results showed that cardiovascular diseases, metabolic diseases, digestive diseases, and anemia were the most common comorbidities in elderly patients with cancer. The comorbidity patterns differed based on the cancer site. Elderly patients with liver cancer had the highest risk of comorbidities, followed by lung cancer, gastrointestinal cancer, thyroid cancer, and reproductive cancer. For example, elderly patients with liver cancer had the higher risk of the comorbid infectious and digestive diseases, whereas patients with lung cancer had the higher risk of the comorbid respiratory system diseases. The findings can assist clinicians in diagnosing comorbidities and contribute to the allocation of medical resources.

Permanent Inactivation of HBV Genomes by CRISPR/Cas9-Mediated Non-cleavage Base Editing.

Current antiviral therapy fails to cure chronic hepatitis B virus (HBV) infection because of persistent covalently closed circular DNA (cccDNA). CRISPR/Cas9-mediated specific cleavage of cccDNA is a potentially curative strategy for chronic hepatitis B (CHB). However, the CRISPR/Cas system inevitably targets integrated HBV DNA and induces double-strand breaks (DSBs) of host genome, bearing the risk of genomic rearrangement and damage. Herein, we examined the utility of recently developed CRISPR/Cas-mediated "base editors" (BEs) in inactivating HBV gene expression without cleavage of DNA. Candidate target sites of the SpCas9-derived BE and its variants in HBV genomes were screened for generating nonsense mutations of viral genes with individual guide RNAs (gRNAs). SpCas9-BE with certain gRNAs effectively base-edited polymerase and surface genes and reduced HBV gene expression in cells harboring integrated HBV genomes, but induced very few insertions or deletions (indels). Interestingly, some point mutations introduced by base editing resulted in simultaneous suppression of both polymerase and surface genes. Finally, the episomal cccDNA was successfully edited by SpCas9-BE for suppression of viral gene expression in an in vitro HBV infection system. In conclusion, Cas9-mediated base editing is a potential strategy to cure CHB by permanent inactivation of integrated HBV DNA and cccDNA without DSBs of the host genome.

Endogenous Retrovirus-Derived Long Noncoding RNA Enhances Innate Immune Responses via Derepressing RELA Expression.

Endogenous retroviruses (ERVs) are transposable elements that cause host genome instability and usually play deleterious roles in disease such as tumorigenesis. Recent advances also suggest that this "enemy within" may encode a viral mimic to induce antiviral immune responses through viral sensors. Here, through whole-genome transcriptome analysis with RNA sequencing (RNA-Seq), we discovered that a full-length ERV-derived long noncoding RNA (lncRNA), designated lnc-EPAV (ERV-derived lncRNA positively regulates antiviral responses), was a positive regulator of NF-κB signaling. lnc-EPAV expression was rapidly upregulated by viral RNA mimics or RNA viruses to facilitate the expression of RELA, an NF-κB subunit that plays a crucial role in antiviral responses. Transcriptome analysis of lnc-EPAV-silenced macrophages showed that lnc-EPAV was critical for RELA target gene expression and innate immune responses. Consistently, lnc-EPAV-deficient mice exhibited reduced expression of type I interferons (IFNs) and, consequently, increased viral loads and mortality following lethal RNA virus infection. Mechanistically, lnc-EPAV promoted expression of RELA by competitively binding to and displacing SFPQ, a transcriptional repressor of Rela Altogether, our work demonstrates an alternative mechanism by which ERVs regulate antiviral immune responses.IMPORTANCE Endogenous retroviruses are transposable genetic elements comprising 8% to 10% of the human and mouse genomes. Although most ERVs have been inactivated due to deleterious mutations, some are still transcribed. However, the biological functions of transcribed ERVs are largely unknown. Here, we identified a full-length ERV-derived lncRNA, designated lnc-EPAV, as a positive regulator of host innate immune responses. We found that silencing lnc-EPAV impaired virus-induced cytokine production, resulting in increased viral replication in cells. The lnc-EPAV-deficient mice exhibited enhanced susceptibility to viral challenge. We also found that lnc-EPAV regulated expression of RELA, an NF-κB subunit that plays a critical role in antiviral responses. ERV-derived lncRNA coordinated with a transcription repressor, SFPQ, to control Rela transcription. Our report provides new insights into the previously unrecognized immune gene regulatory mechanism of ERV-derived lncRNAs.

PSMB1 Negatively Regulates the Innate Antiviral Immunity by Facilitating Degradation of IKK-ε.

Proteasome is a large protein complex, which degrades most intracellular proteins. It regulates numerous cellular processes, including the removal of misfolded or unfolded proteins, cell cycle control, and regulation of apoptosis. However, the function of proteasome subunits in viral immunity has not been well characterized. In this study, we identified PSMB1, a member of the proteasome ß subunits (PSMB) family, as a negative regulator of innate immune responses during viral infection. Knockdown of PSMB1 enhanced the RNA virus-induced cytokine and chemokine production. Overexpression of PSMB1 abolished virus-induced activation of the interferon-stimulated response element (ISRE) and interferon beta (IFNß) promoters. Mechanistically, PSMB1 inhibited the activation of RIG-I-like receptor (RLR) and Toll-like receptor 3 (TLR3) signaling pathways. PSMB1 was induced after viral infection and its interaction with IKK-ε promoted degradation of IKK-ε through the ubiquitin-proteasome system. Collectively, our study demonstrates PSMB1 is an important regulator of innate immune signaling.

Exploitation of nuclear protein SFPQ by the encephalomyocarditis virus to facilitate its replication.

The encephalomyocarditis virus (EMCV) is a single-stranded RNA virus that induces sudden death, diabetes, myocarditis and nervous disorders in non-human primates. The rapid development of xenografts such as heart transplantation from pig to human raises the issue of EMCV safety in human cells. SFPQ, a proline and glutamine rich splicing factor that participates in diverse molecular functions including paraspeckle formation, microRNA synthesis and transcription regulation, is known to regulate host innate immune response to viruses. However, the role of SFPQ in EMCV infection remains unclear. Here we reported that the SFPQ was essential for EMCV replication. Depletion of SFPQ impaired EMCV production, while forced expression of SFPQ promoted viral replication. Mechanistically, loss of SFPQ affected the transcription profile of host mitochondria pathway related genes. In addition, cellular SFPQ was exploited by EMCV and accumulated in cytoplasm and it interacted with eukaryotic initiation factors and ribosomal proteins to facilitate internal ribosome entry site (IRES)-dependent translation of EMCV protein. Altogether, our work discovered host SFPQ as a new target to inhibit EMCV replication and infection.

Asthma medication increases dental caries among children in Taiwan: An analysis using the National Health Insurance Research Database.

BACKGROUND/PURPOSE: Asthma is a common, chronic disease that causes respiratory symptoms in children. Dental caries is also a common chronic disease in the pediatric population. Therefore, the aim of the present study was to investigate the correlation between asthma medications and dental caries among children in Taiwan. MATERIALS AND METHODS: The Taiwan National Health Insurance Research Database was used in this retrospective cohort study to analyze the correlation between asthma and dental caries in children. The prevalence and severity of caries were compared between children with and without asthma. The effects of different asthma medications on dental caries were also compared. RESULTS: A total of 4601 children with asthma and 4589 children without asthma were included in this study. The caries prevalence of children without asthma was 85.2%, and that of children with asthma was 90.0%. The prevalence of caries in children with asthma was significantly higher than that in children without asthma (P < 0.001). The caries status was categorized into mild, moderate and severe dental caries. The rate of mild dental caries was higher in the children without asthma (35.1%) than in the children with asthma (29.8%). The rate of severe caries was significantly higher in children with asthma (34.3%) than in those without asthma (30.7%). Also, children with asthma using bronchodilators had a higher rate of severe dental caries (39%) than in children without asthma (30.7%). CONCLUSION: Children receiving asthma medications had higher dental caries prevalence and higher rate of severe caries than children without asthma.

SIRT6 Acts as a Negative Regulator in Dengue Virus-Induced Inflammatory Response by Targeting the DNA Binding Domain of NF-κB p65.

Dengue virus (DENV) is a mosquito-borne single-stranded RNA virus causing human disease with variable severity. The production of massive inflammatory cytokines in dengue patients has been associated with dengue disease severity. However, the regulation of these inflammatory responses remains unclear. In this study, we report that SIRT6 is a negative regulator of innate immune responses during DENV infection. Silencing of Sirt6 enhances DENV-induced proinflammatory cytokine and chemokine production. Overexpression of SIRT6 inhibits RIG-I-like receptor (RLR) and Toll-like receptor 3 (TLR3) mediated NF-κB activation. The sirtuin core domain of SIRT6 is required for the inhibition of NF-κB p65 function. SIRT6 interacts with the DNA binding domain of p65 and competes with p65 to occupy the Il6 promoter during DENV infection. Collectively, our study demonstrates that SIRT6 negatively regulates DENV-induced inflammatory response via RLR and TLR3 signaling pathways.

Vaccine-induced antigen-specific regulatory T cells attenuate the antiviral immunity against acute influenza virus infection.

Peptide-based T cell vaccines targeting the conserved epitopes of influenza virus can provide cross-protection against distantly related strains, but they are generally not immunogenic. Foreign antigen-specific regulatory T (Treg) cells are induced under subimmunogenic conditions peripherally, although their development and role in vaccine-mediated antiviral immunity is unclear. Here, we demonstrated primary vaccination with peptides alone significantly induced antigen-specific Foxp3+ Treg cells, which were further expanded by repeated vaccination with unadjuvanted peptides. Certain adjuvants, including CpG, suppressed the induction and expansion of antigen-specific Treg cells by peptide vaccination. Interestingly, secondary influenza virus infection significantly increased the frequency of preexisting antigen-specific Treg cells, although primary infection barely induced them. Importantly, specific depletion of vaccine-induced antigen-specific Treg cells promoted influenza viral clearance, indicating their inhibitory role in vivo. Immunization with CpG-adjuvanted peptides by the subcutaneous prime-intranasal-boost strategy restricted the recruitment and accumulation of antigen-specific Treg cells in lung, and stimulated robust T cell immunity. Finally, subcutaneous prime-intranasal-boost immunization with CpG-adjuvanted peptides or whole-inactivated influenza vaccines protected mice from heterosubtypic influenza virus infection. In conclusion, antigen-specific Treg cells induced by peptide vaccines attenuate the antiviral immunity against influenza virus infection. CpG-adjuvanted peptide vaccines provide heterosubtypic influenza protection probably by inhibiting Treg development and enhancing T cell immunity.