Effector Memory Th1 CD4 T Cells Are Maintained in a Mouse Model of Chronic Malaria

Protection against malaria often decays in the absence of infection, suggesting that protective immunological memory depends on stimulation. Here we have used CD4+ T cells from a transgenic mouse carrying a T cell receptor specific for a malaria protein, Merozoite Surface Protein-1, to investigate memory in a Plasmodium chabaudi infection. CD4+ memory T cells (CD44hiIL-7Rα+) developed during the chronic infection, and were readily distinguishable from effector (CD62LloIL-7Rα−) cells in acute infection. On the basis of cell surface phenotype, we classified memory CD4+ T cells into three subsets: central memory, and early and late effector memory cells, and found that early effector memory cells (CD62LloCD27+) dominated the chronic infection. We demonstrate a linear pathway of differentiation from central memory to early and then late effector memory cells. In adoptive transfer, CD44hi memory cells from chronically infected mice were more effective at delaying and reducing parasitemia and pathology than memory cells from drug-treated mice without chronic infection, and contained a greater proportion of effector cells producing IFN-γ and TNFα, which may have contributed to the enhanced protection. These findings may explain the observation that in humans with chronic malaria, activated effector memory cells are best maintained in conditions of repeated exposure

A Sterol-Regulatory Element Binding Protein Is Required for Cell Polarity, Hypoxia Adaptation, Azole Drug Resistance, and Virulence in Aspergillus fumigatus

At the site of microbial infections, the significant influx of immune effector cells and the necrosis of tissue by the invading pathogen generate hypoxic microenvironments in which both the pathogen and host cells must survive. Currently, whether hypoxia adaptation is an important virulence attribute of opportunistic pathogenic molds is unknown. Here we report the characterization of a sterol-regulatory element binding protein, SrbA, in the opportunistic pathogenic mold, Aspergillus fumigatus. Loss of SrbA results in a mutant strain of the fungus that is incapable of growth in a hypoxic environment and consequently incapable of causing disease in two distinct murine models of invasive pulmonary aspergillosis (IPA). Transcriptional profiling revealed 87 genes that are affected by loss of SrbA function. Annotation of these genes implicated SrbA in maintaining sterol biosynthesis and hyphal morphology. Further examination of the SrbA null mutant consequently revealed that SrbA plays a critical role in ergosterol biosynthesis, resistance to the azole class of antifungal drugs, and in maintenance of cell polarity in A. fumigatus. Significantly, the SrbA null mutant was highly susceptible to fluconazole and voriconazole. Thus, these findings present a new function of SREBP proteins in filamentous fungi, and demonstrate for the first time that hypoxia adaptation is likely an important virulence attribute of pathogenic molds

A Role for the Unfolded Protein Response (UPR) in Virulence and Antifungal Susceptibility in Aspergillus fumigatus

Filamentous fungi rely heavily on the secretory pathway, both for the delivery of cell wall components to the hyphal tip and the production and secretion of extracellular hydrolytic enzymes needed to support growth on polymeric substrates. Increased demand on the secretory system exerts stress on the endoplasmic reticulum (ER), which is countered by the activation of a coordinated stress response pathway termed the unfolded protein response (UPR). To determine the contribution of the UPR to the growth and virulence of the filamentous fungal pathogen Aspergillus fumigatus, we disrupted the hacA gene, encoding the major transcriptional regulator of the UPR. The ΔhacA mutant was unable to activate the UPR in response to ER stress and was hypersensitive to agents that disrupt ER homeostasis or the cell wall. Failure to induce the UPR did not affect radial growth on rich medium at 37°C, but cell wall integrity was disrupted at 45°C, resulting in a dramatic loss in viability. The ΔhacA mutant displayed a reduced capacity for protease secretion and was growth-impaired when challenged to assimilate nutrients from complex substrates. In addition, the ΔhacA mutant exhibited increased susceptibility to current antifungal agents that disrupt the membrane or cell wall and had attenuated virulence in multiple mouse models of invasive aspergillosis. These results demonstrate the importance of ER homeostasis to the growth and virulence of A. fumigatus and suggest that targeting the UPR, either alone or in combination with other antifungal drugs, would be an effective antifungal strategy

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

A computational model of invasive aspergillosis in the lung and the role of iron

BACKGROUND: Invasive aspergillosis is a severe infection of immunocompromised hosts, caused by the inhalation of the spores of the ubiquitous environmental molds of the Aspergillus genus. The innate immune response in this infection entails a series of complex and inter-related interactions between multiple recruited and resident cell populations with each other and with the fungal cell; in particular, iron is critical for fungal growth. RESULTS: A computational model of invasive aspergillosis is presented here; the model can be used as a rational hypothesis-generating tool to investigate host responses to this infection. Using a combination of laboratory data and published literature, an in silico model of a section of lung tissue was generated that includes an alveolar duct, adjacent capillaries, and surrounding lung parenchyma. The three-dimensional agent-based model integrates temporal events in fungal cells, epithelial cells, monocytes, and neutrophils after inhalation of spores with cellular dynamics at the tissue level, comprising part of the innate immune response. Iron levels in the blood and tissue play a key role in the fungus’ ability to grow, and the model includes iron recruitment and consumption by the different types of cells included. Parameter sensitivity analysis suggests the model is robust with respect to unvalidated parameters, and thus is a viable tool for an in silico investigation of invasive aspergillosis. CONCLUSIONS: Using laboratory data from a mouse model of invasive aspergillosis in the context of transient neutropenia as validation, the model predicted qualitatively similar time course changes in fungal burden, monocyte and neutrophil populations, and tissue iron levels. This model lays the groundwork for a multi-scale dynamic mathematical model of the immune response to Aspergillus species. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12918-016-0275-2) contains supplementary material, which is available to authorized users

Optimisation of Perioperative Cardiovascular Management to Improve Surgical Outcome II (OPTIMISE II) trial: study protocol for a multicentre international trial of cardiac output-guided fluid therapy with low-dose inotrope infusion compared with usual care in patients undergoing major elective gastrointestinal surgery.

INTRODUCTION: Postoperative morbidity and mortality in older patients with comorbidities undergoing gastrointestinal surgery are a major burden on healthcare systems. Infections after surgery are common in such patients, prolonging hospitalisation and reducing postoperative short-term and long-term survival. Optimal management of perioperative intravenous fluids and inotropic drugs may reduce infection rates and improve outcomes from surgery. Previous small trials of cardiac-output-guided haemodynamic therapy algorithms suggested a modest reduction in postoperative morbidity. A large definitive trial is needed to confirm or refute this and inform widespread clinical practice. METHODS: The Optimisation of Perioperative Cardiovascular Management to Improve Surgical Outcome II (OPTIMISE II) trial is a multicentre, international, parallel group, open, randomised controlled trial. 2502 high-risk patients undergoing major elective gastrointestinal surgery will be randomly allocated in a 1:1 ratio using minimisation to minimally invasive cardiac output monitoring to guide protocolised administration of intravenous fluid combined with low-dose inotrope infusion, or usual care. The trial intervention will be carried out during and for 4 hours after surgery. The primary outcome is postoperative infection of Clavien-Dindo grade II or higher within 30 days of randomisation. Participants and those delivering the intervention will not be blinded to treatment allocation; however, outcome assessors will be blinded when feasible. Participant recruitment started in January 2017 and is scheduled to last 3 years, within 50 hospitals worldwide. ETHICS/DISSEMINATION: The OPTIMISE II trial has been approved by the UK National Research Ethics Service and has been approved by responsible ethics committees in all participating countries. The findings will be disseminated through publication in a widely accessible peer-reviewed scientific journal. TRIAL REGISTRATION NUMBER: ISRCTN39653756.The OPTIMISE II trial is supported by Edwards Lifesciences (Irvine, CA) and the UK National Institute for Health Research through RMP’s NIHR Professorship

Systematic planning to optimize investments in hydrogen infrastructure deployment

The introduction of hydrogen infrastructure and fuel cell vehicles (FCVs) to gradually replace gasoline internal combustion engine vehicles can provide environment and energy security benefits. The deployment of hydrogen fueling infrastructure to support the demonstration and commercialization of FCVs remains a critical barrier to transitioning to hydrogen as a transportation fuel. This study utilizes an engineering methodology referred to as the Spatially and Temporally Resolved Energy and Environment Tool (STREET) to demonstrate how systematic planning can optimize early investments in hydrogen infrastructure in a way that supports and encourages growth in the deployment of FCVs while ensuring that the associated environment and energy security benefits are fully realized. Specifically, a case study is performed for the City of Irvine, California - a target area for FCV deployment - to determine the optimized number and location of hydrogen fueling stations required to provide a bridge to FCV commercialization, the preferred rollout strategy for those stations, and the environmental impact associated with three near-term scenarios for hydrogen production and distribution associated with local and regional sources of hydrogen available to the City. Furthermore, because the State of California has adopted legislation imposing environmental standards for hydrogen production, results of the environmental impact assessment for hydrogen production and distribution scenarios are measured against the California standards. The results show that significantly fewer hydrogen fueling stations are required to provide comparable service to the existing gasoline infrastructure, and that key community statistics are needed to inform the preferred rollout strategy for the stations. Well-to-wheel (WTW) greenhouse gas (GHG) emissions, urban criteria pollutants, energy use, and water use associated with hydrogen and FCVs can be significantly reduced in comparison to the average parc of gasoline vehicles regardless of whether hydrogen is produced and distributed with an emphasis on conventional resources (e.g., natural gas), or on local, renewable resources. An emphasis on local renewable resources to produce hydrogen further reduces emissions, energy use, and water use associated with hydrogen and FCVs compared to an emphasis on conventional resources. All three hydrogen production and distribution scenarios considered in the study meet California's standards for well-to-wheel GHG emissions, and well-to-tank emissions of urban ROG and NOX. Two of the three scenarios also meet California's standard that 33% of hydrogen must be produced from renewable feedstocks. Overall, systematic planning optimizes both the economic and environmental impact associated with the deployment of hydrogen infrastructure and FCVs. © 2010 Professor T. Nejat Veziroglu

Projecting full build-out environmental impacts and roll-out strategies associated with viable hydrogen fueling infrastructure strategies

A transition from gasoline internal combustion engine vehicles to hydrogen fuel cell electric vehicles (FCEVs) is likely to emerge as a major component of the strategy to meet future greenhouse gas reduction, air quality, fuel independence, and energy security goals. Advanced infrastructure planning can minimize the cost of hydrogen infrastructure while assuring that energy and environment benefits are achieved. This study presents a comprehensive advanced planning methodology for the deployment of hydrogen infrastructure, and applies the methodology to delineate fully built-out infrastructure strategies, assess the associated energy and environment impacts, facilitate the identification of an optimal infrastructure roll-out strategy, and identify the potential for renewable hydrogen feedstocks. The South Coast Air Basin of California, targeted by automobile manufacturers for the first regional commercial deployment of FCEVs, is the focus for the study. The following insights result from the application of the methodology:Compared to current gasoline stations, only 11%-14% of the number of hydrogen fueling stations can provide comparable accessibility to drivers in a targeted region.To meet reasonable capacity demand for hydrogen fueling, approximately 30% the number of hydrogen stations are required compared to current gasoline stations.Replacing gasoline vehicles with hydrogen FCEVs has the potential to (1) reduce the emission of greenhouse gases by more than 80%, reduce energy requirements by 42%, and virtually eliminate petroleum consumption from the passenger vehicle sector, and (2) significantly reduce urban concentrations of ozone and PM2.5.Existing sources of biomethane in the California South Coast Air Basin can provide up to 30% of the hydrogen fueling demand for a fully built-out hydrogen FCEV scenario.A step-wise transition of judiciously located existing gasoline stations to dispense and accommodate the increasing demand for hydrogen addresses proactively key infrastructure deployment challenges including a viable business model, zoning, permitting, and public acceptance. © 2011, Hydrogen Energy Publications, LLC. Published by Elsevier Ltd. All rights reserved

Projecting full build-out environmental impacts and roll-out strategies associated with viable hydrogen fueling infrastructure strategies

A transition from gasoline internal combustion engine vehicles to hydrogen fuel cell electric vehicles (FCEVs) is likely to emerge as a major component of the strategy to meet future greenhouse gas reduction, air quality, fuel independence, and energy security goals. Advanced infrastructure planning can minimize the cost of hydrogen infrastructure while assuring that energy and environment benefits are achieved. This study presents a comprehensive advanced planning methodology for the deployment of hydrogen infrastructure, and applies the methodology to delineate fully built-out infrastructure strategies, assess the associated energy and environment impacts, facilitate the identification of an optimal infrastructure roll-out strategy, and identify the potential for renewable hydrogen feedstocks. The South Coast Air Basin of California, targeted by automobile manufacturers for the first regional commercial deployment of FCEVs, is the focus for the study. The following insights result from the application of the methodology:Compared to current gasoline stations, only 11%-14% of the number of hydrogen fueling stations can provide comparable accessibility to drivers in a targeted region.To meet reasonable capacity demand for hydrogen fueling, approximately 30% the number of hydrogen stations are required compared to current gasoline stations.Replacing gasoline vehicles with hydrogen FCEVs has the potential to (1) reduce the emission of greenhouse gases by more than 80%, reduce energy requirements by 42%, and virtually eliminate petroleum consumption from the passenger vehicle sector, and (2) significantly reduce urban concentrations of ozone and PM2.5.Existing sources of biomethane in the California South Coast Air Basin can provide up to 30% of the hydrogen fueling demand for a fully built-out hydrogen FCEV scenario.A step-wise transition of judiciously located existing gasoline stations to dispense and accommodate the increasing demand for hydrogen addresses proactively key infrastructure deployment challenges including a viable business model, zoning, permitting, and public acceptance. © 2011, Hydrogen Energy Publications, LLC. Published by Elsevier Ltd. All rights reserved