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Abstract Helicobacter pylori (H. pylori) infection is linked to metabolic syndrome and insulin resistance, with the triglyceride-glucose (TyG) index serving as a reliable marker for the latter. This study investigates the association between the TyG index and H. pylori infection. The study utilized cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) conducted between 1999 and 2000. Participants underwent serologic testing for H. pylori, and the TyG index was calculated from fasting laboratory measurements. Multivariate logistic regression and restricted cubic spline methods were used to assess the association and explore the dose–response relationship. The analysis included 2984 participants. Elevated TyG index values were associated with an increased likelihood of H. pylori infection. The risk of infection rose with higher TyG index quartiles, with the highest quartile showing the most significant increase (OR = 1.54, 95% CI: 1.15–2.07, P = 0.004). A linear relationship between the TyG index and H. pylori infection was demonstrated. The study findings indicate a significant positive association between the TyG index and H. pylori infection. This association highlights the importance of metabolic health in the context of H. pylori infection and suggests that further research is needed to explore the potential implications for health promotion strategies.

Abstract Liposarcoma (LPS) is the second most common kind of soft tissue sarcoma, and a heterogeneous malignant tumor derived from adipose tissue. Up to now, the prognostic value of BAG1 or BAG2 in LPS has not been defined yet. Expression profiling data of LPS patients were collected from TCGA and GEO database. Survival curves were plotted to verify the outcome differences of patients based on BAG1 or BAG2 expression. Univariate and multivariate Cox regression models were used to analyze the prognostic ability of BAG1 or BAG2. Chaperone’s regulators BAG1 and BAG2 were identified as prognostic biomarkers for LPS patients, which exhibited distinct expression patterns and survival outcome prediction performances. Patients with high BAG2 expression and/or low BAG1 expression had worse prognosis. Enrichment analysis showed that BAG1 was involved in negative regulation of TGF-β signaling. Low expression of BAG1 was associated with high abundance of regulatory T cells (Tregs). The 2-gene signature model further confirmed the improved risk assessment performance of BAG1 and BAG2: high risk patients displayed poor prognosis. BAG1 and BAG2 are supposed to be potential prognostic biomarkers for LPS and have impacts on liposarcomagenesis and immune infiltration in distinctive manners, which may function as potential therapy targets (BAG1 agonists/BAG2 inhibitors) for LPS.

Objective To explore the spatial and temporal variations in the long-term risk of developing tuberculosis (TB) and the factors influencing it in order to contribute to the goal of eradicating TB.Design Observational longitudinal study.Setting Xinjiang, China, 2005–2019.Primary and secondary outcome measures Comparison of TB incidence across age, period, cohort and space using socioeconomic (including gross domestic product per capita, population density, public budget revenue and total retail sales of consumer goods), public health (including the number of hospital beds, health technicians and basic medical insurance for urban residents) and environmental variables (PM2.5, mean air temperature, mean wind speed, mean relative humidity and precipitation). The relative importance of these variables to pulmonary TB (PTB) is revealed by the Q-value (0, 1), with larger values indicating that the spatial heterogeneity of the explanatory variables to PTB is more pronounced.Participants All clinically diagnosed and confirmed cases in Xinjiang, China, were collected. The descriptive analysis included confirmed cases from 2005 to 2019, while cases from various districts and counties between 2011 and 2019 were subjected to further analysis.Results From 2005 to 2019, a total of 642 332 cases of PTB were reported in Xinjiang, with an average annual incidence rate of 172/100 000. The age risk of PTB presented a bimodal distribution, namely 20–24 years and the elderly (>60 years). The high prevalence of PTB was distributed in the southern part of Xinjiang. Among the influencing factors that had a greater effect on the incidence of PTB, the lower GDP per capita (Q-value=0.65) had a largest effect on PTB in Xinjiang compared with others factors (higher PM2.5: Q-value=0.56, lower health personnel: Q-value=0.49, higher average temperature: Q-value=0.47 and higher urban residents’ health insurance: Q-value=0.46). The main influencing factors were heterogeneous in different regions. Furthermore, the interactions among these factors enhanced the explanatory power regarding the incidence of the disease.Conclusions Identifying the high-risk groups, regions, influencing factors and interactions of PTB in Xinjiang, China, will expand the epidemiological knowledge of PTB in high-risk areas and potentially aid in designing targeted interventions.

Abstract Molecular doping plays an important role in controlling the carrier concentration of organic semiconductors. However, the introduction of dopant counterions often results in increased energetic disorder and traps due to the molecular packing disruption and Coulomb potential wells. To date, no general strategy has been proposed to reduce the counterion-induced structural and energetic disorder. Here, we demonstrate the critical role of non-covalent interactions (NCIs) between counterions and polymers. Employing a computer-aided approach, we identified the optimal counterions and discovered that NCIs determine their docking positions, which significantly affect the counterion-induced energetic disorder. With the optimal counterions, we successfully reduced the energetic disorder to levels even lower than that of the undoped polymer. As a result, we achieved a high n-doped electrical conductivity of over 200 S cm−1 and an eight-fold increase in the thermoelectric power factor. We found that the NCIs have substantial effects on doping efficiency, polymer backbone planarity, and Coulomb potential landscape. Our work not only provides a general strategy for identifying the most suitable counterions but also deepens our understanding of the counterion effects on doped polymeric semiconductors.

Abstract Ambient air temperature is a key factor affecting human health. Female reproductive disorders are representative health risk events under low temperature. However, the mechanism involving in cold-induced female reproductive disorders remains largely unknown. Female mice were intermittently exposed to cold conditions (4 °C) to address the health risk of low temperature on female reproductive system. Primary granulosa cells (GCs) were prepared and cultured under low temperature (35 °C) or exposed to β3-adrenoreceptor agonist, isoproterenol, to mimic the condition of cold exposure. Western-blot, RT-PCR, co-IP, ELISA, pharmacological inhibition or siRNA-mediated knockdown of target gene were performed to investigate the possible role of hormones, gap conjunction proteins, and ER stress sensor protein in regulating female reproductive disorders under cold exposure. Cold exposure induced estrous cycle disorder and follicular dysplasia in female mice, accompanying with abnormal upregulation of progesterone and its synthetic rate-limiting enzyme, StAR, in the ovarian granulosa cells. Under the same conditions, an increase in connexin 43 (CX43) expressions in the GCs was also observed, which contributed to elevated progesterone levels in the ovary. Moreover, ER stress sensor protein, PERK, was activated in the ovarian GCs after cold exposure, leading to the upregulation of downstream NRF2-dependent CX43 transcription and aberrant increase in progesterone synthesis. Most importantly, blocking PERK expression in vivo significantly inhibited NRF2/CX43/StAR/progesterone pathway activation in the ovary and efficiently rescued the prolongation of estrous cycle and the increase in follicular atresia of the female mice induced by cold stress. We have elucidated the mechanism of ovarian PERK/NRF2/CX43/StAR/progesterone pathway activation in mediating female reproductive disorder under cold exposure. Targeting PERK might be helpful for maintaining female reproductive health under cold conditions.

Abstract Exosomes are small membrane vesicles that are released by cells into the extracellular environment. Tumor‐associated exosomes (TAEs) are extracellular vesicles that play a significant role in cancer progression by mediating intercellular communication and contributing to various hallmarks of cancer. These vesicles carry a cargo of proteins, lipids, nucleic acids, and other biomolecules that can be transferred to recipient cells, modifying their behavior and promoting tumor growth, angiogenesis, immune modulation, and drug resistance. Several potential therapeutic targets within the TAEs cargo have been identified, including oncogenic proteins, miRNAs, tumor‐associated antigens, immune checkpoint proteins, drug resistance proteins, and tissue factor. In this review, we will systematically summarize the biogenesis, composition, and function of TAEs in cancer progression and highlight potential therapeutic targets. Considering the complexity of exosome‐mediated signaling and the pleiotropic effects of exosome cargoes has challenge in developing effective therapeutic strategies. Further research is needed to fully understand the role of TAEs in cancer and to develop effective therapies that target them. In particular, the development of strategies to block TAEs release, target TAEs cargo, inhibit TAEs uptake, and modulate TAEs content could provide novel approaches to cancer treatment.

Accidents occur frequently in underground chambers owing to the high-stress environment, poor stability of rocks, and unreasonable mining and construction layout. Significant damage to the deep surrounding rock mass by confined water can result in water inrush and flooding accidents. This study numerically investigated the mechanical properties and acoustic emission (AE) signal evolution mechanism of water-bearing sandstone in deep high-stress mining environments. The results showed that, the lower the confining pressure, the lower is the compressive strength of the specimen, resulting in evident failure. The confining pressure inhibited the radial strain and enhanced the strength of the specimen. Furthermore, under the same confining pressure and different water pressure, the higher the water pressure value, the more evident was the failure phenomenon, and the lower was the peak stress. The water pressure decreased the strength of the specimen and its ability to resist damage. Moreover, for the same water pressure, the smaller the confining pressure, the larger was the maximum AE number and the total cumulative amount of acoustic emissions. When the specimen reached the peak stress and produced macroscopic failure, the AE number reached the maximum value. Finally, the AE activity decreased as the water pressure increased, and the higher the water pressure, the smaller was the cumulative AE number. Owing to the existence of water pressure, the internal structure of the model specimen was affected by the softening effect, which decreased the model strength, thereby suppressing the AE activity of the specimen. Our findings can provide a basis for numerical simulation research on mechanical properties and AE evolution mechanism of water-bearing sandstone under three-way stress state.

Semiconducting polymers with high-spin at their neutral ground state are rarely reported. Here the authors synthesize three semiconducting polymers with different spin ground states and high hole/electron mobility, by appropriate choice of the building blocks’ singlet-triplet energy gap, spin distributions and solid-state interchain interactions.

ABSTRACT Plastic wastes have been recognized as the most common and durable marine contaminants, which are not only found in the shallow water, but also on the sea floor. However, whether deep-sea microorganisms have evolved the capability of degrading plastic remains elusive. In this study, a deep-sea bacterium Bacillus velezensis GUIA was found to be capable of degrading waterborne polyurethane. Transcriptomic analysis showed that the supplement of waterborne polyurethane upregulated the expression of many genes related to spore germination, indicating that the presence of plastic had effects on the growth of strain GUIA. In addition, the supplement of waterborne polyurethane also evidently upregulated the expressions of many genes encoding lipase, protease, and oxidoreductase. Liquid chromatography-mass spectrometry (LC-MS) results showed that potential enzymes responsible for plastic degradation in strain GUIA were identified as oxidoreductase, protease, and lipase, which was consistent with the transcriptomic analysis. In combination of in vitro expression and degradation assays as well as Fourier transform infrared (FTIR) analysis, we demonstrated that the oxidoreductase Oxr-1 of strain GUIA was the key degradation enzyme toward waterborne polyurethane. Moreover, the oxidoreductase Oxr-1 was also shown to degrade the biodegradable polybutylene adipate terephthalate (PBAT) film indicating its wide application potential. IMPORTANCE The widespread and indiscriminate disposal of plastics inevitably leads to environmental pollution. The secondary pollution by current landfill and incineration methods causes serious damage to the atmosphere, land, and rivers. Therefore, microbial degradation is an ideal way to solve plastic pollution. Recently, the marine environment is becoming a hot spot to screen microorganisms possessing potential plastic degradation capabilities. In this study, a deep-sea Bacillus strain was shown to degrade both waterborne polyurethane and biodegradable PBAT film. The FAD-binding oxidoreductase Oxr-1 was demonstrated to be the key enzyme mediating plastic degradation. Our study not only provided a good candidate for developing bio-products toward plastic degradation but also paved a way to investigate the carbon cycle mediated by plastic degradation in deep-sea microorganisms.

Ras plays an essential role in the development of acinar-to-ductal metaplasia (ADM) and pancreatic ductal adenocarcinoma (PDAC). However, mutant Kras is an inefficient driver for PDAC development. The mechanisms of the switching from low Ras activity to high Ras activity that are required for development and progression of pancreatic intraepithelial neoplasias (PanINs) are unclear. In this study, we found that hematopoietic progenitor kinase 1 (HPK1) was upregulated during pancreatic injury and ADM. HPK1 interacted with the SH3 domain and phosphorylated Ras GTPase-activating protein (RasGAP) and upregulated RasGAP activity. Using transgenic mouse models of HPK1 or M46, a kinase-dead mutant of HPK1, we showed that HPK1 inhibited Ras activity and its downstream signaling and regulated acinar cell plasticity. M46 promoted the development of ADM and PanINs. Expression of M46 in KrasG12D Bac mice promoted the infiltration of myeloid-derived suppressor cells and macrophages, inhibited the infiltration of T cells, and accelerated the progression of PanINs to invasive and metastatic PDAC, while HPK1 attenuated mutant Kras–driven PanIN progression. Our results showed that HPK1 plays an important role in ADM and the progression of PanINs by regulating Ras signaling. Loss of HPK1 kinase activity promotes an immunosuppressive tumor microenvironment and accelerates the progression of PanINs to PDAC.

The booming mudflat aquaculture poses an accumulation of organic matter and a certain environmental threat. Protease-producing bacteria are key players in regulating the nitrogen content in ecosystems. However, knowledge of the diversity of protease-producing bacteria in coastal mudflats is limited. This study investigated the bacterial diversity in the coastal mudflat, especially protease-producing bacteria and their extracellular proteases, by using culture-independent methods and culture-dependent methods. The clam aquaculture area exhibited a higher concentration of carbon, nitrogen, and phosphorus when compared with the non-clam area, and a lower richness and diversity of bacterial community when compared with the clam naturally growing area. The major classes in the coastal mud samples were Bacteroidia, Gammaproteobacteria, and Alphaproteobacteria. The Bacillus-like bacterial community was the dominant cultivated protease-producing group, accounting for 52.94% in the non-clam area, 30.77% in the clam naturally growing area, and 50% in the clam aquaculture area, respectively. Additionally, serine protease and metalloprotease were the principal extracellular protease of the isolated coastal bacteria. These findings shed light on the understanding of the microbes involved in organic nitrogen degradation in coastal mudflats and lays a foundation for the development of novel protease-producing bacterial agents for coastal mudflat purification.

High altitudes or exposure to hypoxia leads to female reproductive disorders. Circadian clocks are intrinsic time-tracking systems that enable organisms to adapt to the Earth’s 24-h light/dark cycle, which can be entrained by other environmental stimuli to regulate physiological and pathological responses. In this study, we focused on whether ovarian circadian clock proteins were involved in regulating female reproductive dysfunction under hypoxic conditions. Hypobaric hypoxia was found to induce a significantly prolonged estrous cycle in female mice, accompanied by follicular atresia, pituitary/ovarian hormone synthesis disorder, and decreased LHCGR expression in the ovaries. Under the same conditions, the levels of the ovarian circadian clock proteins, CLOCK and BMAL1, were suppressed, whereas E4BP4 levels were upregulated. Results from granulosa cells (GCs) further demonstrated that CLOCK: BMAL1 and E4BP4 function as transcriptional activators and repressors of LHCGR in ovarian GCs, respectively, whose responses were mediated by HIF1ɑ-dependent (E4BP4 upregulation) and ɑ-independent (CLOCK and BMAL1 downregulation) manners. The LHCGR agonist was shown to efficiently recover the impairment of ovulation-related gene (EREG and PGR) expression in GCs induced by hypoxia. We conclude that hypoxia exposure causes dysregulation of ovarian circadian clock protein (CLOCK, BMAL1, and E4BP4) expression, which mediates female reproductive dysfunction by impairing LHCGR-dependent signaling events. Adjusting the timing system or recovering the LHCGR level in the ovaries may be helpful in overcoming female reproductive disorders occurring in the highlands.

The heated tobacco product (HTP) heats rather than burns tobacco to release an aerosol with significantly fewer toxicants than conventional cigarette smoke and has received global attention in recent years. To investigate whether changes in biomarkers of exposure could be detected after switching from conventional cigarettes (CCs) to HTPs, 224 subjects from four cities in China participated in this study. Nine biomarkers containing tobacco-specific nitrosamines (TSNAs), volatile organic compounds (VOCs), and the biomarkers for acrolein and crotonaldehyde were determined by UPLC-MS/MS. The levels of the sum of nine biomarkers in CCs were 5.4 and 5.2 times higher than in an Original-HTP and Menthol-HTP, respectively. Among the nine biomarkers, 3HPMA and 3HMPMA accounted for the highest proportions. Switching from CCs to HTPs is good for both men and women because the changes in each biomarker in urine samples were the same in men and women. Among all the subjects, subjects aged 20–39 years had the greatest reduction in biomarker residues in urine. The findings of the present study provided useful information for the health risk research of HTPs in China.

Soil proteinase and proteinase-producing microbial community are closely associated with soil fertility and soil health. Sea rice has been planted in the coastal beach of Jiaozhou Bay, China, in an effort to transform saline-alkali soil into arable land. However, the knowledge regarding the bacterial degradation of organic nitrogen in sea rice soils is limited. This study aims to investigate the physicochemical characteristics and enzymatic activities of the sea rice soils, as well as the microbial communities by both the Illumina sequencing-based culture-independent technology and culture-dependent methods. Sea rice soils exhibited a lower salinity and higher organic matter content and proteinase activity, as well as an increase in both the richness and diversity of the proteinase-producing bacterial community, compared to the adjacent non-rice soils. The Proteobacteria phylum and the Gammaproteobacteria class were dominant in sea rice soils, showing higher abundance than in the reference soils. The Planococcus genus and Bacillus-like bacterial communities were abundant in the cultivable proteinase-producing bacteria isolated from sea rice soils. Furthermore, a significant proportion of the extracellular proteinase produced by the isolated soil bacteria consisted of serine proteinases and metalloproteinases. These findings provided new insights into the degradation of soil organic nitrogen in coastal agricultural regions.

The soluble form of aluminum (Al) is a major constraint to crop production in acidic soils. The Al exclusion correlated with the Al-induced organic acid is considered as an important mechanism of Al resistance. The regulation of organic acid exudation in response to Al stress mediated by the root organic acid transporters has been extensively studied. However, how plants respond to Al stress through the regulation of organic acid homeostasis is not well understood. In this study, we identified the functionally unknown Transition zone1 (TZ1) as an Al-inducible gene in the root transition zone, the most sensitive region to Al stress, in Arabidopsis. tz1 mutants showed enhanced Al resistance and displayed greatly reduced root growth inhibition. Furthermore, TZ1 was found to interact with the aconitases (ACOs) which can catalyze the conversion from citrate, one of the most important organic acids, into isocitrate. Consistently, in tz1 mutants, the citric acid content was highly increased. Collectively, this study provides evidence to show that TZ1 negatively regulates root growth response to Al stress through interacting with ACOs and regulating citric acid homeostasis.

Background/Aims: Bile duct cancer, although not among the most common tumors, still accounts for more and more worldwide deaths each year. By attempting to verify an overexpression of ALDOA in cholangiocarcinoma tissues and cells and explore the underlying molecular mechanism regulated by miR-122-5p, this study was designed to provide a potential molecular target in bile duct cancer treatment. Methods: Western blot and immunohistochemistry were performed to detect the ALDOA protein level in duct carcinoma tissues. The transfection efficiency was confirmed by western blot and/or RT-qPCR assay. The proliferation of bile duct carcinoma cells was determined by MTT and colony formation assay. The invasion ability of bile duct carcinoma cells was evaluated with Transwell invasion assay. Flow cytometry detected cell apoptosis of bile duct carcinoma cells. The miRNAs which modulate ALDOA were filtrated from bioinformatics software and clinical specimens. The target relationship was confirmed by dual luciferase reporter assay. Furthermore, a xenograft model was completed to verify the impact of miRNA on inhibition growth of bile duct carcinoma cells. Results: ALDOA was found up-regulated in bile duct carcinoma tissues and cells. Knockdown of ALDOA promoted the apoptosis of cells and inhibited the proliferation and invasion of bile duct carcinoma cells. Bioinformatics and clinical specimens indicated the negative correlation and targeted regulation between miR-122-5p and ALDOA. By down-regulating ALDOA, overexpression of miR-122-5p appeared to promote cell apoptosis and significantly inhibit cell proliferation, invasion in vitro and suppress the tumor growth in vivo. Conclusion: miR-122-5p inhibited proliferation and invasion of bile duct carcinoma cells and promoted cell apoptosis by targeting ALDOA expression.

In this paper, BT ((E)-2-(4-(4-(bis(pyridin-2-ylmethyl)amino)styryl)-3-cyano-5,5-dimethylfuran-2(5H)-ylidene)malononitrile) with strong donor–π-acceptor structure was synthesized, which showed both colorimetric and fluorescent sensing ability toward Cu2+ with high selectivity and sensitivity. Job plot and mass spectra measurement revealed a 1 : 1 coordination mode between Cu2+ and probe BT in ethanol/HEPES (1 : 4 v/v) buffer (pH 7.2) solution, and the binding constant was calculated to be 3.6 × 104 M–1. The colour of BT solution (10 µM) immediately turned from purple red to yellow and the red fluorescence was quenched obviously when a certain amount of Cu2+ was added, which enabled a dual-channel detection of Cu2+. A paper strip pre-stained with BT solution was further fabricated and it also showed excellent sensing ability toward Cu2+ with a detection limit as low as 10−6 M with the naked eye, which represents better portability and operation simplicity that is favourable for on-site analysis of Cu2+ in water.

Auxin is necessary for the inhibition of root growth induced by aluminium (Al) stress, however the molecular mechanism controlling this is largely unknown. Here, we report that YUCCA (YUC), which encodes flavin monooxygenase-like proteins, regulates local auxin biosynthesis in the root apex transition zone (TZ) in response to Al stress. Al stress up-regulates YUC3/5/7/8/9 in the root-apex TZ, which we show results in the accumulation of auxin in the root-apex TZ and root-growth inhibition during the Al stress response. These Al-dependent changes in the regulation of YUCs in the root-apex TZ and YUC-regulated root growth inhibition are dependent on ethylene signalling. Increasing or disruption of ethylene signalling caused either enhanced or reduced up-regulation, respectively, of YUCs in root-apex TZ in response to Al stress. In addition, ethylene enhanced root growth inhibition under Al stress was strongly alleviated in yuc mutants or by co-treatment with yucasin, an inhibitor of YUC activity, suggesting a downstream role of YUCs in this process. Moreover, ethylene-insensitive 3 (EIN3) is involved into the direct regulation of YUC9 transcription in this process. Furthermore, we demonstrated that PHYTOCHROME INTERACTING FACTOR4 (PIF4) functions as a transcriptional activator for YUC5/8/9. PIF4 promotes Al-inhibited primary root growth by regulating the local expression of YUCs and auxin signal in the root-apex TZ. The Al-induced expression of PIF4 in root TZ acts downstream of ethylene signalling. Taken together, our results highlight a regulatory cascade for YUCs-regulated local auxin biosynthesis in the root-apex TZ mediating root growth inhibition in response to Al stress.

OCILRP2 is a typical Type-II transmembrane protein that is selectively expressed in activated T lymphocytes, dendritic cells, and B cells and functions as a novel co-stimulator of T cell activation. However, the signaling pathways underlying OCILRP2 in T cell activation are still not completely understood. In this study, we found that the knockdown of OCILRP2 expression with shRNA or the blockage of its activity by an anti-OCILRP2 antagonist antibody reduced CD3/CD28-costimulated EL4 T cell viability and IL-2 production, inhibit Raf1, MAPK3, and MAPK8 activation, and impair NFAT and NF-κB transcriptional activities. Furthermore, immunoprecipitation results indicated that OCILRP2 could interact with the DAP12 protein, an adaptor containing an intracellular ITAM motif that can transduce signals to induce MAP kinase activation for T cell activation. Our data reveal that after binding with DAP12, OCILRP2 activates the Raf-MAP kinase pathways, resulting in T cell activation.

Chlamydia trachomatis genital infection is the most common sexually transmitted bacterial disease, causing a significant burden to females due to reproductive dysfunction. Intensive screening and antibiotic treatment are unable to completely prevent female reproductive dysfunction, thus, efforts have become focused on developing a vaccine. A major impediment is identifying a safe and effective adjuvant which induces cluster of differentiation 4 (CD4) cells with attributes capable of halting genital infection and inflammation. Previously, we described a natural nanocapsule called the vault which was engineered to contain major outer membrane protein (MOMP) and was an effective vaccine which significantly reduced early infection and favored development of a cellular immune response in a mouse model. In the current study, we used another chlamydial antigen, a polymorphic membrane protein G-1 (PmpG) peptide, to track antigen-specific cells and evaluate, in depth, the vault vaccine for its protective capacity in the absence of an added adjuvant. We found PmpG-vault immunized mice significantly reduced the genital bacterial burden and histopathologic parameters of inflammation following a C. muridarum challenge. Immunization boosted antigen-specific CD4 cells with a multiple cytokine secretion pattern and reduced the number of inflammatory cells in the genital tract making the vault vaccine platform safe and effective for chlamydial genital infection. We conclude that vaccination with a Chlamydia-vault vaccine boosts antigen-specific immunities that are effective at eradicating infection and preventing reproductive tract inflammation.

BackgroundRegulation of immune responses is critical for controlling inflammation and disruption of this process can lead to tissue damage. We reported that CXCL13 was induced in fallopian tube tissue following C. trachomatis infection. Here, we examined the influence of the CXCL13-CXCR5 axis in chlamydial genital infection.Methodology and principal findingsDisruption of the CXCL13-CXCR5 axis by injecting anti-CXCL13 Ab to BALB/c mice or using Cxcr5-/- mice increased chronic inflammation in the upper genital tract (UGT; uterine horns and oviducts) after Chlamydia muridarum genital infection (GT). Further studies in Cxcr5-/- mice showed an elevation in bacterial burden in the GT and increased numbers of neutrophils, activated DCs and activated NKT cells early after infection. After resolution, we noted increased fibrosis and the accumulation of a variety of T cells subsets (CD4-IFNγ, CD4-IL-17, CD4-IL-10 & CD8-TNFα) in the oviducts. NKT cell depletion in vitro reduced IL-17α and various cytokines and chemokines, suggesting that activated NKT cells modulate neutrophils and DCs through cytokine/chemokine secretion. Further, chlamydial glycolipids directly activated two distinct types of NKT cell hybridomas in a cell-free CD1d presentation assay and genital infection of Cd1d-/- mice showed reduced oviduct inflammation compared to WT mice. CXCR5 involvement in pathology was also noted using single-nucleotide polymorphism analysis in C. trachomatis infected women attending a sub-fertility clinic. Women who developed tubal pathology after a C. trachomatis infection had a decrease in the frequency of CXCR5 SNP +10950 T>C (rs3922).Conclusions/significanceThese experiments indicate that disruption of the CXCL13-CXCR5 axis permits increased activation of NKT cells by type I and type II glycolipids of Chlamydia muridarum and results in UGT pathology potentially through increased numbers of neutrophils and T cell subsets associated with UGT pathology. In addition, CXCR5 appears to contribute to inter-individual differences in human tubal pathology following C. trachomatis infection.

Generation of robust cell-mediated immune responses at mucosal surfaces while reducing overall inflammation is a primary goal for vaccination. Here we report the use of a recombinant nanoparticle as a vaccine delivery platform against mucosal infections requiring T cell-mediated immunity for eradication.We encapsulated an immunogenic protein, the major outer membrane protein (MOMP) of Chlamydia muridarum, within hollow, vault nanocapsules (MOMP-vaults) that were engineered to bind IgG for enhanced immunity. Intranasal immunization (i.n) with MOMP-vaults induced anti-chlamydial immunity plus significantly attenuated bacterial burden following challenge infection. Vault immunization induced anti-chlamydial immune responses and inflammasome formation but did not activate toll-like receptors. Moreover, MOMP-vault immunization enhanced microbial eradication without the inflammation usually associated with adjuvants.Vault nanoparticles containing immunogenic proteins delivered to the respiratory tract by the i.n. route can act as "smart adjuvants" for inducing protective immunity at distant mucosal surfaces while avoiding destructive inflammation.