Understanding Escherichia coli Urinary Tract Infection: A Niche Perspective

Urinary tract infections (UTIs) are among the most common bacterial infections worldwide, costing greater than $2 billion in healthcare costs and lost wages yearly in America alone. The lifetime risk for a woman exceeds 50% with 25-40% of these suffering recurrent infections. Two of the most important risk factors for recurrent UTI are prior UTIs and sexual intercourse. Over 80% of UTIs are caused by uropathogenic Escherichia coli (UPEC), which binds and invades superficial facet cells lining the bladder surface. UPEC expresses extracellular fibers called type 1 pili with a terminal mannose-binding adhesin, FimH, which interacts with mannosylated uroplakin residues on the urothelium. UPEC replicates in the cytoplasm of bladder cells into biofilm-like intracellular bacterial communities (IBCs) in a protected niche. In C3H/HeN mice, a robust, systemic, immune response at 24 hours precedes the development of persistent bacteriuria and chronic cystitis, which lasts indefinitely. A less robust immune response results in resolution of the infection. I determined the population dynamics during UPEC infection with a set of 40 variants of a clinical isolate, UTI89, each with a unique genetic sequence detectable by multiplex PCR. I identified a significant population bottleneck during the first 24 hours coinciding with the inflammatory response. Furthermore, I tested a panel of FimH alleles under positive selection and found several that impacted the ability of UPEC strains to form IBCs and promote chronic cystitis. These pathoadaptive alleles govern the ability of FimH to bind mannose by dynamically interconverting between a compact, low-affinity conformation and an elongated, high-affinity state. This dynamic equilibrium is crucial for virulence as alleles locked in either conformation are attenuated. I also developed a model of frequent inoculation of UPEC into the urinary tract to investigate the clinical link between frequent sexual intercourse and UTI risk. By inoculating mice twice during acute infection, I found a dramatic increase in the proportion of mice that experienced chronic cystitis. Taken together, this thesis defines bacterial and behavioral factors that increase the risk for chronic and recurrent UTI, providing rationale for the development of novel therapeutics targeting bacterial invasion to limit infection by excluding UPEC from intracellular niches

Global Air Quality and Health Co-benefits of Mitigating Near-Term Climate Change through Methane and Black Carbon Emission Controls

Background: Tropospheric ozone and black carbon (BC), a component of fine particulate matter (PM ≤ 2.5 µm in aerodynamic diameter; PM:2.5), are associated with premature mortality and they disrupt global and regional climate. Objectives: We examined the air quality and health benefits of 14 specific emission control measures targeting BC and methane, an ozone precursor, that were selected because of their potential to reduce the rate of climate change over the next 20–40 years.: Methods: We simulated the impacts of mitigation measures on outdoor concentrations of PM2.5 and ozone using two composition-climate models, and calculated associated changes in premature PM2.5- and ozone-related deaths using epidemiologically derived concentration–response functions. Results: We estimated that, for PM:2.5 and ozone, respectively, fully implementing these measures could reduce global population-weighted average surface concentrations by 23–34% and 7–17% and avoid 0.6–4.4 and 0.04–0.52 million annual premature deaths globally in 2030. More than 80% of the health benefits are estimated to occur in Asia. We estimated that BC mitigation measures would achieve approximately 98% of the deaths that would be avoided if all BC and methane mitigation measures were implemented, due to reduced BC and associated reductions of nonmethane ozone precursor and organic carbon emissions as well as stronger mortality relationships for PM2.5 relative to ozone. Although subject to large uncertainty, these estimates and conclusions are not strongly dependent on assumptions for the concentration–response function. Conclusions: In addition to climate benefits, our findings indicate that the methane and BC emission control measures would have substantial co-benefits for air quality and public health worldwide, potentially reversing trends of increasing air pollution concentrations and mortality in Africa and South, West, and Central Asia. These projected benefits are independent of carbon dioxide mitigation measures. Benefits of BC measures are underestimated because we did not account for benefits from reduced indoor exposures and because outdoor exposure estimates were limited by model spatial resolution.

Guidelines for Modeling and Reporting Health Effects of Climate Change Mitigation Actions.

BACKGROUND: Modeling suggests that climate change mitigation actions can have substantial human health benefits that accrue quickly and locally. Documenting the benefits can help drive more ambitious and health-protective climate change mitigation actions; however, documenting the adverse health effects can help to avoid them. Estimating the health effects of mitigation (HEM) actions can help policy makers prioritize investments based not only on mitigation potential but also on expected health benefits. To date, however, the wide range of incompatible approaches taken to developing and reporting HEM estimates has limited their comparability and usefulness to policymakers. OBJECTIVE: The objective of this effort was to generate guidance for modeling studies on scoping, estimating, and reporting population health effects from climate change mitigation actions. METHODS: An expert panel of HEM researchers was recruited to participate in developing guidance for conducting HEM studies. The primary literature and a synthesis of HEM studies were provided to the panel. Panel members then participated in a modified Delphi exercise to identify areas of consensus regarding HEM estimation. Finally, the panel met to review and discuss consensus findings, resolve remaining differences, and generate guidance regarding conducting HEM studies. RESULTS: The panel generated a checklist of recommendations regarding stakeholder engagement: HEM modeling, including model structure, scope and scale, demographics, time horizons, counterfactuals, health response functions, and metrics; parameterization and reporting; approaches to uncertainty and sensitivity analysis; accounting for policy uptake; and discounting. DISCUSSION: This checklist provides guidance for conducting and reporting HEM estimates to make them more comparable and useful for policymakers. Harmonization of HEM estimates has the potential to lead to advances in and improved synthesis of policy-relevant research that can inform evidence-based decision making and practice. https://doi.org/10.1289/EHP6745

Simultaneously mitigating near-term climate change and improving human health and food security

Tropospheric ozone and black carbon (BC) contribute to both degraded air quality and global warming. We considered ~400 emission control measures to reduce these pollutants by using current technology and experience. We identified 14 measures targeting methane and BC emissions that reduce projected global mean warming ~0.5°C by 2050. This strategy avoids 0.7 to 4.7 million annual premature deaths from outdoor air pollution and increases annual crop yields by 30 to 135 million metric tons due to ozone reductions in 2030 and beyond. Benefits of methane emissions reductions are valued at $700 to$5000 per metric ton, which is well above typical marginal abatement costs (less than $250). The selected controls target different sources and influence climate on shorter time scales than those of carbon dioxide–reduction measures. Implementing both substantially reduces the risks of crossing the 2°C threshold

Guidelines for Modeling and Reporting Health Effects of Climate Change Mitigation Actions.

BACKGROUND: Modeling suggests that climate change mitigation actions can have substantial human health benefits that accrue quickly and locally. Documenting the benefits can help drive more ambitious and health-protective climate change mitigation actions; however, documenting the adverse health effects can help to avoid them. Estimating the health effects of mitigation (HEM) actions can help policy makers prioritize investments based not only on mitigation potential but also on expected health benefits. To date, however, the wide range of incompatible approaches taken to developing and reporting HEM estimates has limited their comparability and usefulness to policymakers. OBJECTIVE: The objective of this effort was to generate guidance for modeling studies on scoping, estimating, and reporting population health effects from climate change mitigation actions. METHODS: An expert panel of HEM researchers was recruited to participate in developing guidance for conducting HEM studies. The primary literature and a synthesis of HEM studies were provided to the panel. Panel members then participated in a modified Delphi exercise to identify areas of consensus regarding HEM estimation. Finally, the panel met to review and discuss consensus findings, resolve remaining differences, and generate guidance regarding conducting HEM studies. RESULTS: The panel generated a checklist of recommendations regarding stakeholder engagement: HEM modeling, including model structure, scope and scale, demographics, time horizons, counterfactuals, health response functions, and metrics; parameterization and reporting; approaches to uncertainty and sensitivity analysis; accounting for policy uptake; and discounting. DISCUSSION: This checklist provides guidance for conducting and reporting HEM estimates to make them more comparable and useful for policymakers. Harmonization of HEM estimates has the potential to lead to advances in and improved synthesis of policy-relevant research that can inform evidence-based decision making and practice. https://doi.org/10.1289/EHP6745

Resequencing Study Confirms That Host Defense and Cell Senescence Gene Variants Contribute to the Risk of Idiopathic Pulmonary Fibrosis.

To access publisher's full text version of this article click on the hyperlink belowRationale: Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung. Objectives: To develop an integrated understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease. Methods: We performed deep targeted resequencing (3.69 Mb of DNA) in cases (n = 3,624) and control subjects (n = 4,442) across genes and regions previously associated with disease. We tested for associations between disease and 1) individual common variants via logistic regression and 2) groups of rare variants via sequence kernel association tests. Measurements and Main Results: Statistically significant common variant association signals occurred in all 10 of the regions chosen based on genome-wide association studies. The strongest risk variant is the MUC5B promoter variant rs35705950, with an odds ratio of 5.45 (95% confidence interval, 4.91-6.06) for one copy of the risk allele and 18.68 (95% confidence interval, 13.34-26.17) for two copies of the risk allele (P = 9.60 × 10-295). In addition to identifying for the first time that rare variation in FAM13A is associated with disease, we confirmed the role of rare variation in the TERT and RTEL1 gene regions in the risk of IPF, and found that the FAM13A and TERT regions have independent common and rare variant signals. Conclusions: A limited number of common and rare variants contribute to the risk of idiopathic pulmonary fibrosis in each of the resequencing regions, and these genetic variants focus on biological mechanisms of host defense and cell senescence.National Center for Research Resources National Heart, Lung, and Blood Institut