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IntroductionRespiratory Syncytial Virus (RSV) is a significant cause of respiratory illnesses worldwide, particularly in infants and elderly individuals. Despite the burden RSV imposes, effective preventive measures are limited. The research application of adeno-associated virus (AAV) in vaccine platforms has been expanding, and its potential in prevention and treatment has garnered much attention.MethodsIn this study, we explored the potential application of a recombinant adeno-associated virus 5 (rAAV5) vector-based RSV vaccine, focusing on the expression of the pre-fusion (Pre-F) protein structure. Through intramuscular immunization in mice. The immunogenicity of the vaccine was evaluated in Balb/c mice immunized intramuscularly and intranasal, respectively.ResultsThe rAAV5-RSV-Fm vaccine demonstrated positive humoral and induced antibody titers against RSV strains A and B for up to 120 days post-immunization. Notably, intranasal administration also elicited protective antibodies. Characterization studies confirmed the ability of the vac-cine to express the Pre-F protein and its superior immunogenicity compared to that of full-length F protein.ConclusionThese findings underscore the potential application of rAAV5 vector platforms in RSV vaccine development and further investigation into their protective efficacy is warranted.

Systemic lupus erythematosus (SLE) is a debilitating autoimmune disorder characterized by unknown pathogenesis and heterogeneous clinical manifestations. The current existing serum biomarkers for SLE have limited sensitivity or specificity, making early and precise diagnosis difficult. Here, we identified two N-glycans on serum immunoglobulin G (IgG) as excellent diagnostic biomarkers for SLE based on in-depth glycomic analyses of 389 SLE patients and 304 healthy controls. These two N-glycan biomarkers are specific for diagnosing SLE, as no significant changes in these biomarkers were observed in other systemic autoimmune diseases that are easily confused with SLE, such as rheumatoid arthritis, primary Sjögren’s syndrome, or systemic sclerosis. Notably, the two N-glycan biomarkers proved to be autoantibody-independent and all-stage patient suitable. The two N-glycan biomarkers are demonstrated to be located on the Fc region based on fragment-specific glycan analysis and glycopeptide analysis, suggesting their close correlation with disease activity. Enzyme analyses revealed dysregulation of a series of glycotransferases in SLE, which might be responsible for the observed glycan alteration. Our findings provide insights into efficient population screening based on serum IgG glycosylation and potential new pathogenic factors of SLE.

Abstracts The COVID-19 pandemic, caused by the SARS-CoV-2 virus and its variants, has posed unprecedented challenges worldwide. Existing vaccines have limited effectiveness against SARS-CoV-2 variants. Therefore, novel vaccines to match mutated viral lineages by providing long-term protective immunity are urgently needed. We designed a recombinant adeno-associated virus 5 (rAAV5)-based vaccine (rAAV-COVID-19) by using the SARS-CoV-2 spike protein receptor binding domain (RBD-plus) sequence with both single-stranded (ssAAV5) and self-complementary (scAAV5) delivery vectors and found that it provides excellent protection from SARS-CoV-2 infection. A single-dose vaccination in mice induced a robust immune response; induced neutralizing antibody (NA) titers were maintained at a peak level of over 1:1024 more than a year post-injection and were accompanied by functional T-cell responses. Importantly, both ssAAV- and scAAV-based RBD-plus vaccines produced high levels of serum NAs against the circulating SARS-CoV-2 variants, including Alpha, Beta, Gamma and Delta. A SARS-CoV-2 virus challenge showed that the ssAAV5-RBD-plus vaccine protected both young and old mice from SARS-CoV-2 infection in the upper and lower respiratory tracts. Whole genome sequencing demonstrated that AAV vector DNA sequences were not found in the genomes of vaccinated mice one year after vaccination, demonstrating vaccine safety. These results suggest that the rAAV5-based vaccine is safe and effective against SARS-CoV-2 and several variants as it provides long-term protective immunity. This novel vaccine has a significant potential for development into a human prophylactic vaccination to help end the global pandemic.

Introduction: Microcomputed tomography (micro-CT) is powerful for assessment of the progression of lung fibrosis in animal model, but current whole lung analysis (WLA) methods are time-consuming. Here, a longitudinal and regional analysis (LRA) method was developed to assess fibrosis easily and quickly by micro-CT. Method: Firstly, we investigated the distribution pattern of lesions in BLM-induced pulmonary fibrosis mice. Then, the VOIs for LRA were selected based on the anatomical locations and we compared the robustness, accuracy, repeatability, analysis time of LRA to WLA. Additionally, LRA was applied to assess different stages of pulmonary fibrosis, and was validated with conventional endpoint measurements (such as lung hydroxyproline and histopathology). Results: The lesions of fibrosis in 66 bleomycin (BLM)-induced pulmonary fibrosis mice were mostly in the middle and upper parts of lungs. By applying LRA, the percentages of high-density voxels in selected volumes of interest (VOIs) were well correlated with that in WLA both at Day 7 and Day 21 after bleomycin induction (R2 = 0.8784 and 0.8464, respectively). The relative standard deviation (RSD) of the percentage of high-density voxels in the VOIs was lower than that of WLA (P

IntrodcutionAcute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are major causes of COVID-19 mortality. However, drug delivery to lung tissues is impeded by endothelial cell barriers, limiting the efficacy of existing treatments. A prompt and aggressive treatment strategy is therefore necessary.MethodsWe assessed the ability of anti-CD31-ORI-NPs to penetrate endothelial cell barriers and specifically accumulate in lung tissues using an animal model. We also compared the efficacy of anti-CD31-ORI-NPs to that of free oridonin in ameliorating acute lung injury and evaluated the cytotoxicity of both treatments on endothelial cells.ResultsCompared to free ORI, the amount of anti-CD31-ORI-NPs accumulated in lung tissues increase at least three times. Accordingly, anti-CD31-ORI-NPs improve the efficacy three times on suppressing IL-6 and TNF-a secretion, ROS production, eventually ameliorating acute lung injury in animal model. Importantly, anti-CD31-ORI-NPs significantly decrease the cytotoxicity at least two times than free oridonin on endothelial cells.DiscussionOur results from this study will not only offer a novel therapeutic strategy with high efficacy and low toxicity, but also provide the rational design of nanomaterials of a potential drug for acute lung injury therapy.

Abstract Background The worldwide pandemic of COVID-19 remains a serious public health menace as the lack of efficacious treatments. Cytokine storm syndrome (CSS) characterized with elevated inflammation and multi-organs failure is closely correlated with the bad outcome of COVID-19. Hence, inhibit the process of CSS by controlling excessive inflammation is considered one of the most promising ways for COVID-19 treatment. Results Here, we developed a biomimetic nanocarrier based drug delivery system against COVID-19 via anti-inflammation and antiviral treatment simultaneously. Firstly, lopinavir (LPV) as model antiviral drug was loaded in the polymeric nanoparticles (PLGA-LPV NPs). Afterwards, macrophage membranes were coated on the PLGA-LPV NPs to constitute drugs loaded macrophage biomimetic nanocarriers (PLGA-LPV@M). In the study, PLGA-LPV@M could neutralize multiple proinflammatory cytokines and effectively suppress the activation of macrophages and neutrophils. Furthermore, the formation of NETs induced by COVID-19 patients serum could be reduced by PLGA-LPV@M as well. In a mouse model of coronavirus infection, PLGA-LPV@M exhibited significant targeted ability to inflammation sites, and superior therapeutic efficacy in inflammation alleviation and tissues viral loads reduction. Conclusion Collectively, such macrophage biomimetic nanocarriers based drug delivery system showed favorable anti-inflammation and targeted antiviral effects, which may possess a comprehensive therapeutic value in COVID-19 treatment.

ObjectiveThe study aimed to investigate the serum antigenomic profiling in rheumatoid arthritis (RA) and determine potential diagnostic biomarkers using label-free proteomic technology implemented with machine-learning algorithm.MethodSerum antigens were captured from a cohort consisting of 60 RA patients (45 ACPA-positive RA patients and 15 ACPA-negative RA patients), together with sex- and age-matched 30 osteoarthritis (OA) patients and 30 healthy controls. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was then performed. The significantly upregulated and downregulated proteins with fold change > 1.5 (p < 0.05) were selected. Based on these differentially expressed proteins (DEPs), a machine learning model was trained and validated to classify RA, ACPA-positive RA, and ACPA-negative RA.ResultsWe identified 62, 71, and 49 DEPs in RA, ACPA-positive RA, and ACPA-negative RA, respectively, as compared to OA and healthy controls. Typical pathway enrichment and protein–protein interaction networks were shown among these DEPs. Three panels were constructed to classify RA, ACPA-positive RA, and ACPA-negative RA using random forest models algorithm based on the molecular signature of DEPs, whose area under curve (AUC) were calculated as 0.9949 (95% CI = 0.9792–1), 0.9913 (95% CI = 0.9653–1), and 1.0 (95% CI = 1–1).ConclusionThis study illustrated the serum auto-antigen profiling of RA. Among them, three panels of antigens were identified as diagnostic biomarkers to classify RA, ACPA-positive, and ACPA-negative RA patients.

Scavenger receptor-A (SR-A) is mostly expressed by myeloid cells and has been attributed a variety of biological functions. Here the authors assess SR-A as a biomarker for diagnosis of rheumatoid arthritis (RA) using large-scale training and validation cohorts and show that modulating SR-A levels can alter progression of collagen-induced arthritis in mice.

Background: Coronavirus disease 2019 (COVID-2019), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a worldwide epidemic and claimed millions of lives. Accumulating evidence suggests that cytokines storms are closely associated to COVID-19 severity and death. Here, we aimed to explore the key factors related to COVID-19 severity and death, especially in terms of the male patients and those in western countries.Methods: To clarify whether inflammatory cytokines have role in COVID-19 severity and death, we systematically searched PubMed, Embase, Cochrane library and Web of Science to identify related studies with the keywords “COVID-19″ and “cytokines”. The data were measured as the mean with 95% confidence interval (CI) by Review Manager 5.3 software. The risk of bias was assessed for each study using appropriate checklists.Results: We preliminarily screened 13,468 studies from the databases. A total of 77 articles with 13,468 patients were ultimately included in our study. The serum levels of cytokines such as interleukin-6 (IL-6), IL-10, interleukin-2 receptor (IL-2R), tumor necrosis factor (TNF)-α, IL-1β, IL-4, IL-8 and IL-17 were higher in the severity or death group. Notably, we also found that the circulating levels of IL-6, IL-10, IL-2R and TNF-α were significantly different between males and females. The serum levels of IL-6, IL-10, IL-2R and TNF-α were much higher in males than in females, which implies that the increased mortality and severity in males was partly due to the higher level of these cytokines. Moreover, we found that in the severe and non-survivor groups, European patients had elevated levels of IL-6 compared with Asian patients.Conclusion: These large-scale data demonstrated that the circulating levels of IL-6, IL-10, IL-2R, IL-1β, IL-4, IL-8 and IL-17 are potential risk factors for severity and high mortality in COVID-19. Simultaneously, the upregulation of these cytokines may be driving factors for the sex and region predisposition.

Abstract Background Early treatment is key for optimizing the therapeutic success of drugs, and the current initiating treatment that blocks the progression of bone destruction during the pre-arthritic stages remains unsatisfactory. The microbial disorder in rheumatoid arthritis (RA) patients is significantly reversed with effective treatment. Modulating aberrant gut microbiomes into a healthy state is a potential therapeutic approach for preventing bone damage. Results By using metagenomic shotgun sequencing and a metagenome-wide association study, we assessed the effect of Lactobacillus casei (L. casei) on the induction of arthritis as well as on the associated gut microbiota and immune disorders in adjuvant-induced arthritis (AIA) rats. Treatment of AIA rats with L. casei inhibited joint swelling, lowered arthritis scores, and prevented bone destruction. Along with the relief of arthritis symptoms, dysbiosis in the microbiome of arthritic rats was significantly reduced after L. casei intervention. The relative abundance of AIA-decreased Lactobacillus strains, including Lactobacillus hominis, Lactobacillus reuteri, and Lactobacillus vaginalis, were restored to normal and Lactobacillus acidophilus was upregulated by the administration of L. casei to the AIA rats. Moreover, L. casei downregulated the expression of pro-inflammatory cytokines, which are closely linked to the effect of the L. casei treatment-associated microbes. Functionally, the maintenance of the redox balance of oxidative stress was involved in the improvement in the L. casei-treated AIA rats. Conclusion A single bacterium, L. casei (ATCC334), was able to significantly suppress the induction of AIA and protect bones from destruction in AIA rats by restoring the microbiome dysbiosis in the gut, indicating that using probiotics may be a promising strategy for treating RA, especially in the early stage of the disease.

Disease-modifying antirheumatic drugs (DMARDs) are the first line medications to treat rheumatoid arthritis (RA), a chronic and systemic autoimmune disease affecting multiple joints. Sinomenine (SIN) is thought a natural DMARD (nDMARD) and effectively utilized to treat RA in clinic for several decades in China. Here we reported that it is not methotrexate (MTX), a representative drug of DMARDs, but SIN protected joints from destruction to alleviate the symptoms of the mice with arthritis, indicating that the underlying mechanism of SIN is different from MTX to treat arthritis. Due to the dominate role of synovium fibroblasts in the joint destruction of arthritis, we applied synovium fibroblasts derived from RA patients (RASFs) to investigate the anti-arthritic effect and explore the underlying mechanism of SIN. We found that SIN significantly inhibited the secretion of IL-6 and IL-33 and ROS production in RASFs to mediate protective effect on bone destruction to mediate anti-arthritis effect. Underlying mechanistic study showed that SIN induced phosphorylation of p62 at Ser349 and Thr269/Ser272 to activate Keap1-Nrf2 signaling in RASFs. In line with the results, we then observed that the anti-arthritic effect of SIN was significantly attenuated in Nrf2 deficient (Nrf2−/−) mice. Notably, we found that p62 expression and phosphorylation at Thr269/Ser272 remarkably reduced, while p62 phosphorylation at Ser351 was up-regulated in Nrf2 deficient mice compared to its wild littermates, indicating that Nrf2 probably negative regulates p62 phosphorylation at Ser351. Collectively, our findings demonstrate that SIN phosphorylated p62 at Ser351 (corresponding to human Ser349) to degrade Keap1 expression and accumulate Nrf2 expression, increased p62 expression and phosphorylation at Thr269/Ser272 to activate p62-Keap1-Nrf2 axis, and finally exerted anti-arthritic effect. The current study not only clarified the anti-arthritic characteristics of SIN but also provided the clue to elucidate the correlation of p62 phosphorylation sites and Nrf2 signaling activation.

Gut and oral microflora are important factors in the pathogenesis and development of rheumatoid arthritis (RA). Recent studies have shown that probiotic supplements have beneficial consequences on experimental arthritis in rats. However, results from randomized clinical trials on the effects of probiotics have not been consistent. The aim of this study was to systematically review the existing evidence for the effects of probiotic intervention in RA. We included randomized controlled trials (RCTs) of RA patients receiving stable treatment with disease-modifying anti-rheumatic drugs (DMARDs) that: ① were combined with additional probiotic supplements or ② were combined with either no additional supplements or only a placebo treatment. Statistical analysis was performed using Review Manager 5.3.3. Six randomized clinical trials were eligible for inclusion in the meta-analysis, with 249 participants in total. The results showed that the probiotic intervention treatment has not yet achieved significant improvement in the American College of Rheumatology 20% improvement criteria (ACR20) score and the disease activity score in 28 joints (DAS28). The laboratory index C-reactive protein (CRP) (mg·L−1) was significantly reduced in the intervention group. The expression of inflammatory cytokines tumor necrosis factor (TNF)-α and interleukine (IL)−1β was also significantly reduced, while IL-10 expression increased in the probiotic intervention groups. This article is the first systematic review and meta-analysis providing a comprehensive assessment of the benefits of treating RA with probiotics. We found that probiotic supplementation may show a limited improvement in RA therapy in existing reports because of a lack of sufficiently high-quality work on the part of clinicians. More multi-centered, large-sample RCTs are needed in order to evaluate the benefits of probiotics in RA treatment.