Understanding How Lipopolysaccharide Impacts CD4 T Cell Immunity

Lipopolysaccharide (LPS) is a natural adjuvant synthesized by gram-negative bacteria that has profound effects on CD4 T cell responses. LPS stimulates cells through Toll-like receptor 4 (TLR4), causing the release of inflammatory cytokines and upregulation of costimulatory molecules on antigen presenting cells. The combination of signals from antigen, costimulation, and cytokines allow CD4 T cells to overcome suppressive barriers and accumulate in large numbers. T cells that are primed in an LPS-stimulated environment are programmed for long-term survival following clonal expansion. LPS is well-known for generating Th1 responses, however, under appropriate conditions it can also support differentiation into other T helper lineages, demonstrating its pleiotropic nature. Although molecular analyses have provided insights into how immune responses are controlled by LPS in vivo, its powerful adjuvant activity is also associated with toxicity. Research on partial TLR4 agonists such as monophosphoryl lipid A have demonstrated that toxicity and immunogenicity are not always linked, making them useful candidates for human vaccines. In this sense, many years of LPS research have ultimately contributed to vaccine design, and the next generation may involve studying how the balance between different CD4 T cell subsets is controlled

Obesity and the microbiome in atopic dermatitis: Therapeutic implications for PPAR-γ agonists

Atopic dermatitis (AD) is an inflammatory skin disease characterized by epidermal barrier disruption, Th2 immune responses to skin allergens and microbial dysbiosis within affected lesions. Studies within the past decade have revealed genetic and environmental factors contributing to AD in children. Obesity is a metabolic disorder that often manifests early in life and is associated with reduced bacterial diversity, leading to skin colonization with lipophilic bacteria and intestinal colonization with pro-inflammatory species. These changes impair epithelial barriers and promote Th17 responses, which may worsen the severity of AD symptoms. While few studies have examined the contribution of microbiota in obesity-induced allergies, there is emerging evidence that PPAR-γ may be an effective therapeutic target. This review discusses the microbiome in pediatric AD, treatment with probiotics, how disease is altered by obesity and potential therapeutic effects of PPAR-γ agonists. While healthy skin contains diverse species adapted for specific niches, lesional skin is highly colonized with Staphylococcus aureus which perpetuates the inflammatory reaction. Treatments for AD should help to restore microbial diversity in the skin and intestine, as well as epithelial barrier function. Pre-clinical models have shown that PPAR-γ agonists can suppress Th17 responses, IgE production and mast cell function, while improving the epidermal barrier and microbial homeostasis. Overall, PPAR-γ agonists may be effective in a subset of patients with AD, and future studies should distinguish their metabolic and anti-inflammatory effects in order to inform the best therapies

Aspergillus fumigatus preexposure worsens pathology and improves control of Mycobacterium abscessus pulmonary infection in mice

ABSTRACT Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Mutations in this chloride channel lead to mucus accumulation, subsequent recurrent pulmonary infections, and inflammation, which, in turn, cause chronic lung disease and respiratory failure. Recently, rates of nontuberculous mycobacterial (NTM) infections in CF patients have been increasing. Of particular relevance is infection with Mycobacterium abscessus , which causes a serious, life-threatening disease and constitutes one of the most antibiotic-resistant NTM species. Interestingly, an increased prevalence of NTM infections is associated with worsening lung function in CF patients who are also coinfected with Aspergillus fumigatus . We established a new mouse model to investigate the relationship between A. fumigatus and M. abscessus pulmonary infections. In this model, animals exposed to A. fumigatus and coinfected with M. abscessus exhibited increased lung inflammation and decreased mycobacterial burden compared with those of mice infected with M. abscessus alone. This increased control of M. abscessus infection in coinfected mice was mucus independent but dependent on both transcription factors T-box 21 (Tbx21) and retinoic acid receptor (RAR)-related orphan receptor gamma t (RORγ-t), master regulators of type 1 and type 17 immune responses, respectively. These results implicate a role for both type 1 and type 17 responses in M. abscessus control in A. fumigatus -coinfected lungs. Our results demonstrate that A. fumigatus , an organism found commonly in CF patients with NTM infection, can worsen pulmonary inflammation and impact M. abscessus control in a mouse model. </jats:p

Cytokine Regulation in Human CD4 T Cells by the Aryl Hydrocarbon Receptor and Gq-Coupled Receptors

Th17 cells contribute to host defense on mucosal surfaces but also provoke autoimmune diseases when directed against self-antigens. Identifying therapeutic targets that regulate Th17 cell differentiation and/or cytokine production has considerable value. Here, we study the aryl hydrocarbon receptor (AhR)-dependent transcriptome in human CD4 T cells treated with Th17-inducing cytokines. We show that the AhR reciprocally regulates IL-17 and IL-22 production in human CD4 T cells. Global gene expression analysis revealed that AhR ligation decreased IL21 expression, correlating with delayed upregulation of RORC during culture with Th17-inducing cytokines. Several of the AhR-dependent genes have known roles in cellular assembly, organization, development, growth and proliferation. We further show that expression of GPR15, GPR55 and GPR68 positively correlates with IL-22 production in the presence of the AhR agonist FICZ. Activation of GPR68 with the lorazepam derivative ogerin resulted in suppression of IL-22 and IL-10 secretion by T cells, with no effect on IL-17. Under neutral Th0 conditions, ogerin and the Gq/11 receptor inhibitor YM254890 blunted IL-22 induction by FICZ. These data reveal the AhR-dependent transcriptome in human CD4 T cells and suggest the mechanism through which the AhR regulates T cell function may be partially dependent on Gq-coupled receptors including GPR68

IL-17RA Is Required for CCL2 Expression, Macrophage Recruitment, and Emphysema in Response to Cigarette Smoke

Chronic Obstructive Pulmonary Disease (COPD) is characterized by airspace enlargement and peribronchial lymphoid follicles; however, the immunological mechanisms leading to these pathologic changes remain undefined. Here we show that cigarette smoke is a selective adjuvant that augments in vitro and in vivo Th17, but not Th1, cell differentiation via the aryl hydrocarbon receptor. Smoke exposed IL-17RA−/− mice failed to induce CCL2 and MMP12 compared to WT mice. Remarkably, in contrast to WT mice, IL-17RA−/− mice failed to develop emphysema after 6 months of cigarette smoke exposure. Taken together, these data demonstrate that cigarette smoke is a potent Th17 adjuvant and that IL-17RA signaling is required for chemokine expression necessary for MMP12 induction and tissue emphysema

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Understanding How Lipopolysaccharide Impacts CD4 T-Cell Immunity

Lipopolysaccharide (LPS) is a natural adjuvant synthesized by gram-negative bacteria that has profound effects on CD4 T cell responses. LPS stimulates cells through Toll-like receptor 4 (TLR4), causing the release of inflammatory cytokines and upregulation of costimulatory molecules on antigen presenting cells. The combination of signals from antigen, costimulation, and cytokines allow CD4 T cells to overcome suppressive barriers and accumulate in large numbers. T cells that are primed in an LPS-stimulated environment are programmed for long-term survival following clonal expansion. LPS is well-known for generating Th1 responses, however, under appropriate conditions it can also support differentiation into other T helper lineages, demonstrating its pleiotropic nature. Although molecular analyses have provided insights into how immune responses are controlled by LPS in vivo, its powerful adjuvant activity is also associated with toxicity. Research on partial TLR4 agonists such as monophosphoryl lipid A have demonstrated that toxicity and immunogenicity are not always linked, making them useful candidates for human vaccines. In this sense, many years of LPS research have ultimately contributed to vaccine design, and the next generation may involve studying how the balance between different CD4 T cell subsets is controlled

Allicin- inspired pyridyl disulfides as antimicrobial agents for multidrug-resistant Staphylococcus aureus

A chemical library comprised of nineteen synthesized pyridyl disulfides that emulate the chemical reactivity of allicin (garlic) was evaluated for antimicrobial activity against a panel of pathogenic bacteria. Gram-positive species including vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus (VISA, VRSA) demonstrated the highest level of susceptibility toward analogs with S-alkyl chains of 7–9 carbons in length. Further biological studies revealed that the disulfides display synergy with vancomycin against VRSA, cause dispersal of S. aureus biofilms, exhibit low cytotoxicity, and decelerate S. aureus metabolism. In final analysis, pyridyl disulfides represent a novel class of mechanism-based antibacterial agents that have a potential application as antibiotic adjuvants in combination therapy of S. aureus infections with reduced vancomycin susceptibility