Progranulin Decreases Susceptibility to Streptococcus pneumoniae in Influenza and Protects against Lethal Coinfection.

Streptococcus pneumoniae coinfection is a major cause of mortality in influenza pandemics. Growing evidence shows that uncontrolled immune response results in severe tissue damage and thereby promotes death in coinfection. Progranulin (PGRN) is widely expressed in immune and epithelial cells and exerts anti-inflammatory role in many diseases. We found that PGRN levels were significantly elevated in clinical influenza/S. pneumoniae-coinfected patients. C57BL/6 wild-type (WT) and PGRN-deficient (PGRN-/-) mice were infected with influenza virus PR8 and then superchallenged with S. pneumoniae serotype 19F. Coinfected PGRN-/- mice showed increased mortality and weight loss compared with WT mice. PGRN deficiency led to increased bacterial loads in lungs without altering influenza virus replication, suggesting a role of PGRN in decreasing postinfluenza susceptibility to S. pneumoniae coinfection. Administration of recombinant PGRN improved survival of WT and PGRN-/- mice in lethal coinfection. Additionally, loss of PGRN resulted in aggravated lung damage along with massive proinflammatory cytokine production and immune cell infiltration during coinfection. Endoplasmic reticulum stress (ERS) during influenza, and coinfection was strongly induced in PGRN-/- mice that subsequently activated apoptosis signaling pathways. Treatment of recombinant PGRN or inhibition of ERS by 4-phenylbutyrate decreased apoptosis and bacterial loads in lungs of coinfected mice. These results suggest that PGRN decreases postinfluenza susceptibility to S. pneumoniae coinfection via suppressing ERS-mediated apoptosis. Impaired bacterial clearance and increased lung inflammation are associated with the lethal outcome of coinfected PGRN-/- mice. Our study provides therapeutic implication of PGRN to reduce morbidity and mortality in influenza/S. pneumoniae coinfection.

Fertility quality of life (FertiQoL) among Chinese women undergoing frozen embryo transfer.

BACKGROUND: Women undergoing infertility treatment have poor quality of life. This may cause them to withdraw from or refuse treatment. Women undergoing frozen embryo transfer have a treatment interval. The aim of this study was to investigate the status quo of the fertility quality of life in women undergoing frozen embryo transfer and analyse its predictors. METHODS: A cross-sectional survey was conducted from August 2019 to August 2020 among women undergoing frozen embryo transfer in a tertiary hospital reproductive centre in Beijing, China. The survey collected demographic characteristics and treatment data and included the fertility problem inventory, the fertility quality of life scale (FertiQoL) and the state-trait anxiety scale. Multiple linear stepwise regression was used to explore the predictors of fertility quality of life. RESULTS: In total, 1062 women completed the survey. Participants reported that they had high levels of fertility-related stress and anxiety during treatment. They also had lower fertility-related quality of life, and the Treatment FertiQoL scored the lowest. The regression results showed that social concern, trait anxiety, duration of treatment and age were risk factors for diminished fertility quality of life. CONCLUSION: Chinese women undergoing frozen embryo transfer have relatively poor quality of life. The potential predictors of fertility quality of life include social concern, trait anxiety, duration of treatment and age.

IL-6 Prevents Lung Macrophage Death and Lung Inflammation Injury by Inhibiting GSDME- and GSDMD-Mediated Pyroptosis during Pneumococcal Pneumosepsis.

Streptococcus pneumoniae is a leading bacterial cause of a wide range of infections, and pneumococcal pneumosepsis causes high mortality in hosts infected with antibiotic-resistant strains and those who cannot resolve ongoing inflammation. The factors which influence the development and outcome of pneumosepsis are currently unclear. IL-6 is critical for maintaining immune homeostasis, and we determined that this cytokine is also essential for resisting pneumosepsis, as it inhibits macrophage pyroptosis and pyroptosis-related inflammation injury in the lung. IL-6 affected infection outcomes in mice and exerted a protective role, primarily via macrophages. We further found that IL-6 deficiency led to increased lung macrophage death and aggravated lung inflammation, and that exogenous administration of IL-6 protein could decrease macrophage death and alleviate lung tissue inflammation. IL-6 also protected Streptococcus pneumoniae-induced lung macrophage death and lung inflammation injury by inhibiting gasdermin E (GSDME)- and gasdermin D (GSDMD)-mediated pyroptosis. Together, these data reveal a novel mechanism for the development of pneumosepsis and the critical protective role of IL-6. These findings may assist in the early identification and treatment of pneumococcal pneumosepsis. IMPORTANCE Pneumococcal pneumonia has been a significant cause of morbidity and mortality throughout human history. Failing to control pneumococcal pneumonia and resolve ongoing inflammation in a host can cause sepsis, namely pneumococcal pneumosepsis, and death ensues. Few theories have suggested an optimally therapeutic option for this infectious disease. The interleukin-6 (IL-6, a cytokine featuring pleiotropic activity) theory, proposed here, implies that IL-6 acts as a protector against pneumococcal pneumosepsis. IL-6 prevents lung macrophage death and lung inflammation injury by inhibiting a caspase-3-GSDME-mediated switch from apoptosis to pyroptosis and inhibiting caspase-1-GSDMD-mediated classic pyroptosis during pneumococcal pneumosepsis. Thus, IL-6 is an important determinant for controlling bacterial invasion and a homeostatic coordinator of pneumococcal pneumosepsis. This study clarifies a novel mechanism of occurrence and development of pneumonia and secondary sepsis following a Streptococcus pneumoniae infection. It is important for the early identification and treatment of pneumococcal pneumosepsis.

Molecular antibiotic resistance mechanisms and co-transmission of the mcr-9 and metallo-ß-lactamase genes in carbapenem-resistant Enterobacter cloacae complex.

Carbapenem-resistant Enterobacter cloacae complex (CRECC) has increasingly emerged as a major cause of healthcare-associated infections, with colistin being one of the last-resort antibiotics of treatment. Mobile colistin resistance (mcr)-9 is a member of a growing family of mcr genes and has been reported to be an inducible gene encoding an acquired phosphoethanolamine transferase. Here, we collected 24 ECC strains from Chongqing, China from 2018 to 2021. Subsequently, antibiotic resistance genes and the transmission dynamics of the strains were determined by PCR, whole-genome sequencing, and bioinformatic analysis. The mcr-9 was identified in IncHI2/2A or IncHI2/2A + IncN plasmids from six CRECC strains and was co-located with bla NDM-1 or bla IMP-4 in 2/6 plasmids. The genetic environment of mcr-9.1 was composed of IS903B-mcr-9.1-wbuC-IS26 in the five mcr-9.1-harboring-plasmid, but IS1B was located downstream of mcr-9.2 in the pECL414-1 sequence. We also found that the pNDM-068001 plasmid carrying mcr-9.1 could be a hybrid plasmid, formed by a Tn6360-like bla NDM-1 region inserted into an mcr-9.1-positive IncHI2/2A plasmid. A conjugation assay showed that plasmids mediated the co-dissemination of mcr-9 and metallo-ß-lactamase (MBL) genes. In addition, we performed induction assays with sub-inhibitory concentrations of colistin and found an increase in the relative expression levels of the mcr-9.2, qseC, and qseB genes, as well as an increase in the minimum inhibitory concentration values of colistin in the CRECC414 strain. These findings provide a basis for studying the regulatory mechanisms of mcr-9 expression and highlight the importance of effective monitoring to assess the prevalence of MBL and mcr-9 co-existing plasmids.

IL-6 During Influenza-Streptococcus pneumoniae Co-Infected Pneumonia-A Protector.

Understanding of pathogenesis and protection mechanisms underlying influenza-Streptococcus pneumoniae co-infection may provide potential strategies for decreasing its high morbidity and mortality. Interleukin-6 (IL-6) is an important cytokine that acts to limit infection-related inflammation; however, its role in co-infected pneumonia remains unclear. Here we show that the clinically relevant co-infected mice displayed dramatically elevated IL-6 levels; which was also observed in patients with co-infected pneumonia. IL-6-/- mice presented with increased bacterial burden, early dissemination of bacteria to extrapulmonary sites accompanied by aggravated pulmonary lesions and high mortality when co-infection. This protective function of IL-6 is associated with cellular death and macrophage function. Importantly, therapeutic administration of recombinant IL-6 protein reduced cells death in BALF, and enhanced macrophage phagocytosis through increased MARCO expression. This protective immune mechanism furthers our understanding of the potential impact of immune components during infection and provides potential therapeutic avenues for influenza-Streptococcus pneumoniae co-infected pneumonia.

Bioremediation of petroleum-contaminated soil using aged refuse from landfills.

This study explored the effects and mechanisms of petroleum-contaminated soil bioremediation using aged refuse (AR) from landfills. Three treatments of petroleum-contaminated soil (47.28 mg·g-1) amended with AR, sterilized aged refuse (SAR) and petroleum-contaminated soil only (as a control) were tested. During 98 days of incubation, changes in soil physicochemical properties, residual total petroleum hydrocarbon (TPH), biodegradation kinetics, enzyme activities and the microbial community were investigated. The results demonstrated that AR was an effective soil conditioner and biostimulation agent that could comprehensively improve the quality of petroleum-contaminated soil and promote microbial growth, with an 74.64% TPH removal rate, 22.36 day half-life for SAR treatment, compared with the control (half-life: 138.63 days; TPH removal rate: 22.40%). In addition, the petroleum-degrading bacteria isolation results demonstrated that AR was also a petroleum-degrading microbial agent containing abundant microorganisms. AR addition significantly improved both the biotic and abiotic conditions of petroleum-contaminated soil without other additives. The cooperation of conditioner addition, biostimulation and bioaugmentation in AR treatment led to better bioremediation effects (half-life: 13.86 days; TPH removal rate: 89.83%). In conclusion, AR amendment is a cost-effective, easy-to-use method facilitating in situ large-scale application while simultaneously recycling huge amounts of AR from landfills.