Fordharboe2751

Here, we demonstrate that the Hut system is conserved among pathogenic Acinetobacter and regulated by the transcriptional repressor HutC. Additionally, the Hut system is required for energy generation using histidine as a carbon and nitrogen source. Histidine was also detected extracellularly in the murine lung, demonstrating that it is bioavailable during infection. Finally, the ammonia-releasing enzyme HutH is required for acquiring nitrogen from histidine in vitro, and strains inactivated for hutH are severely attenuated in a murine model of pneumonia. These results suggest that bioavailable histidine in the lung promotes Acinetobacter pathogenesis and that histidine serves as a crucial nitrogen source during infection. Copyright © 2020 American Society for Microbiology.Sexually transmitted Chlamydia trachomatis may ascend to infect endometrium, leading to pelvic inflammatory diseases in some women. To identify endometrial innate immune components that interact with Chlamydia, we introduced C. trachomatis into mouse endometrium via a transcervical inoculation and compared the infectious yields in mice with or without immunodeficiency. Live C. trachomatis recovered from vaginal swabs or endometrial tissues peaked on day 3 and then declined in all mice with or without deficiency in adaptive immunity, indicating a critical role of innate immunity in endometrial control of C. trachomatis infection. Additional knockout of IL-2 receptor common gamma chain (IL-2Rγc) from adaptive immunity-deficient mice significantly compromised the endometrial innate immunity, demonstrating an important role of innate lymphoid cells (ILCs). Consistently, deficiency in IL-7 receptor alone, a common gamma chain-containing receptor required for ILC development, significantly reduced endometrial innate immunity. Furthermore, mice deficient in RORγt or T-bet became more susceptible to endometrial infection with C. trachomatis, suggesting a role of group 3-like ILCs in endometrial innate immunity. Furthermore, genetic deletion of IFNγ but not IL-22 or antibody-mediated depletion of IFNγ from adaptive immunity-deficient mice significantly compromised the endometrial innate immunity. Finally, depletion of NK1.1+ cells from adaptive immunity-deficient mice both significantly reduced IFNγ and increased C. trachomatis burden in the endometrial tissue, validating that mouse ILCs contribute significantly to endometrial innate immunity via an IFNγ-dependent effector mechanism. It will be worth investigating whether IFNγ-producing ILCs also improve endometrial resistance to sexually transmitted C. trachomatis infection in women. Copyright © 2020 American Society for Microbiology.Staphylococcus aureus, an important cause of mastitis in mammals, is becoming increasingly problematic due to the development of resistance to conventional antibiotics. The ability of S. aureus to invade host cells is key to its propensity to evade immune defense and antibiotics. This study focused on functions of cathelicidins, small cationic peptides secreted by epithelial cells and leukocytes, in the pathogenesis of S. aureus mastitis in mice. We determined that endogenous murine cathelicidin (CRAMP; Camp) was important in controlling S. aureus infection, as cathelicidin knock-out mice (Camp-/- ) intramammarily challenged with S. aureus had a higher bacterial burden and more severe mastitis than wild-type mice. Exogenous administration of both synthetic human cathelicidin (LL-37) and synthetic murine cathelicidin (CRAMP) (8 μM), reduced invasion of S. aureus into murine mammary epithelium. Additionally, this exogenous LL-37 was internalized into cultured mammary epithelial cells and impaired S. aureus growth in vitro We concluded that cathelicidins may be potential therapeutic agents against mastitis; both endogenous and exogenous cathelicidins conferred protection against S. aureus infection by reducing bacterial internalization and potentially by directly killing this pathogen. Copyright © 2020 American Society for Microbiology.The orchestration of host immune responses to enteric bacterial pathogens is a complex process involving the integration of numerous signals including from the nervous system. Despite the recent progress in understanding the contribution of neuro-immune interactions in the regulation of inflammation, the mechanisms and effects of this communication during enteric bacterial infection are only beginning to be characterized. As part of this neuro-immune communication, neurons specialized to detect painful or otherwise noxious stimuli can respond to bacterial pathogens. Highlighting the complexity of these systems, the immunological consequences of sensory neuron activation can be either host adaptive or maladaptive depending on the pathogen, and organ system. These are but one of many types of neuro-immune circuits, with the vagus nerve and sympathetic innervation of numerous organs now known to modulate immune cell function and therefore dictate immunological outcomes during health and disease. Here we review the evidence for neuro-immune communication in response to bacterial pathogens, and the discuss the consequences to host morbidity and mortality during infection of the gastrointestinal tract. Copyright © 2020 American Society for Microbiology.The parasites and eggs of helminths, including schistosomes, are associated with factors that can modulate the nature and outcomes of host immune responses, particularly enhancing type 2 immunity and impairing the effects of type 1 and type 17 immunity. The main species of schistosomes that cause infection in humans are capable of generating a microenvironment that allows survival of the parasite by evasion of the immune response. Schistosome infections are associated with beneficial effects on chronic immune disorders that include allergies, autoimmune diseases, and alloimmune responses. Recently, there has been increasing research interest in the role of schistosomes in immunoregulation during human infection, but the mechanisms underlying these roles continue to be investigated. Further studies may identify potential opportunities to develop new treatments for immune disease. In this review we provide an update on the advances in our understanding of schistosome-associated modulation of the cells of the innate and adaptive immune systems as well as the potential role of schistosome-associated factors as therapeutic modulators of immune disorders, including allergies, autoimmune disease and transplant immunopathology. We also discuss potential opportunities in targeting schistosome-induced immunoregulation for future translation to the clinic. Copyright © 2020 American Society for Microbiology.OBJECTIVE In previous studies, neoadjuvant chemotherapy followed by interval debulking surgery was not inferior to primary cytoreductive surgery as initial treatment for advanced epithelial ovarian cancer. Our study aimed to compare surgical and survival outcomes between the two treatments in a large national database. Menadione in vitro METHODS Data were extracted from the National Cancer Database from January 2004 to December 2015. Patients with FIGO (International Federation of Gynecologists and Obstetricians) stage III-IV epithelial ovarian cancer and known sequence of treatment were included primary cytoreductive (surgery=26 717 and neoadjuvant chemotherapy=9885). Tubal and primary peritoneal cancer diagnostic codes were not included. Residual disease after treatment was defined based on recorded data R0 defined as microscopic or no residual disease; R1 defined as macroscopic residual disease. Multivariate Cox proportional HR was used for survival analysis. Multivariate logistic regression analysis was utilized to compare rimary cytoreductive surgery (95% CI 2.46 to 5.64). The 90-day mortality was higher for neoadjuvant chemotherapy in multivariate analysis (HR 1.31, 95% CI 1.06 to 1.61) but similar to primary cytoreductive surgery after excluding high-risk patients. CONCLUSIONS Most patients with advanced epithelial ovarian cancer may benefit from primary cytoreductive surgery. Patients treated with neoadjuvant chemotherapy should be those with co-morbidities unfit for surgery. © IGCS and ESGO 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.BACKGROUND Chronic breathlessness has devastating consequences. The minimal clinically important difference (MCID) for current intensity has been estimated as 9 mm on a 100 mm visual analogue scale (VAS). We aimed to determine MCIDs for commonly used dimensions and recall periods the current unpleasantness and current, average, best and worst intensity of the last 24 h for chronic breathlessness. METHODS This was a secondary analysis of a randomised controlled trial of morphine versus placebo during seven days in people with chronic breathlessness from severe disease. The breathlessness scores were self-reported using a diary each evening on 100 mm VAS. The MCID for improvement in each score was estimated using anchor based and distribution based methods. RESULTS 283 participants (mean age 74.2 years; 63% males; 58% COPD; 87.0% mMRC 3-4) were included. Anchor-based MCIDs for breathlessness scores ranged from -13.9 mm to -9.5 mm. The MCIDs were similar when using different anchors and across all participants, and participants with more severe BREATHLESSNESS (mMRC 3-4), respectively. Distribution based effect sizes were small (-4.7 to -6.3 mm), moderate (-9.4 to -12.5 mm) and large effect (-15.0 to -20.0 mm). Sample sizes for trials using the different scores were proposed. MCIDs of absolute change were more stable than using relative change from baseline. CONCLUSION An improvement of about 10 mm on a 100 mm VAS is likely to be clinically meaningful across commonly used measures of chronic breathlessness (current intensity, unpleasantness, and average, best and worst intensity over the last 24 h) - to evaluate clinical benefit and effects in therapeutic trials. Copyright ©ERS 2020.Patients with COVID19 present a broad spectrum of clinical presentation. Whereas hypoxemia is the marker of severity, different strategies of management should be customised to five specific individual phenotypes. Many intubated patients present with phenotype 4, characterised by pulmonary hypoxic vasoconstriction, being associated with severe hypoxemia with "normal" (>40 mL·cm-1 H20) lung compliance and likely represents pulmonary microvascular thrombosis. Phenotype 5 is often associated with high plasma procalcitonin, and has low pulmonary compliance, being a result of co-infection or acute lung injury after non-invasive ventilation. Identifying these clinical phenotypes and applying a personalised approach would benefit in optimisation of therapies and improving outcomes. Copyright ©ERS 2020.RATIONALE Environmental tobacco smoke exposure (ETS) increases asthma risk in children. There is limited knowledge of prenatal ETS for adult onset asthma. OBJECTIVES To determine the association between prenatal ETS and adult onset asthma. MEASUREMENTS AND MAIN RESULTS Questionnaire and clinical data of 5200 people, free of physician-diagnosed asthma by the age 31 years, of Northern Finland Birth Cohort 1966 Study was used. The association of maternal smoking during the last three months of pregnancy with onset of physician-diagnosed asthma and with lung function in adult offspring were studied by adjusted multivariate regression analyses. The cumulative incidence of physician-diagnosed asthma between the ages of 31 and 46 years was 5.1% among men and 8.8% among women. Gestational smoke exposure was associated with adult onset asthma among the offspring (adjusted odds ratio 1.54, 95% confidence interval 1.04-2.29), namely among offspring who reported either past non-diagnosed asthma (odds ratio 9.63, 95% confidence interval 2.