Predictive Virtual Infection Modeling of Fungal Immune Evasion in Human Whole Blood. Prauße Maria T E,Lehnert Teresa,Timme Sandra,Hünniger Kerstin,Leonhardt Ines,Kurzai Oliver,Figge Marc Thilo Frontiers in immunology Bloodstream infections by the human-pathogenic fungi and increasingly occur in hospitalized patients and are associated with high mortality rates. The early immune response against these fungi in human blood comprises a concerted action of humoral and cellular components of the innate immune system. Upon entering the blood, the majority of fungal cells will be eliminated by innate immune cells, i.e., neutrophils and monocytes. However, recent studies identified a population of fungal cells that can evade the immune response and thereby may disseminate and cause organ dissemination, which is frequently observed during candidemia. In this study, we investigate the so far unresolved mechanism of fungal immune evasion in human whole blood by testing hypotheses with the help of mathematical modeling. We use a previously established state-based virtual infection model for whole-blood infection with to quantify the immune response and identified the fungal immune-evasion mechanism. While this process was assumed to be spontaneous in the previous model, we now hypothesize that the immune-evasion process is mediated by host factors and incorporate such a mechanism in the model. In particular, we propose, based on previous studies that the fungal immune-evasion mechanism could possibly arise through modification of the fungal surface by as of yet unknown proteins that are assumed to be secreted by activated neutrophils. To validate or reject any of the immune-evasion mechanisms, we compared the simulation of both immune-evasion models for different infection scenarios, i.e., infection of whole blood with either or under non-neutropenic and neutropenic conditions. We found that under non-neutropenic conditions, both immune-evasion models fit the experimental data from whole-blood infection with and . However, differences between the immune-evasion models could be observed for the infection outcome under neutropenic conditions with respect to the distribution of fungal cells across the immune cells. Based on these predictions, we suggested specific experimental studies that might allow for the validation or rejection of the proposed immune-evasion mechanism. 10.3389/fimmu.2018.00560

How neutrophils kill fungi. Gazendam Roel P,van de Geer Annemarie,Roos Dirk,van den Berg Timo K,Kuijpers Taco W Immunological reviews Neutrophils play a critical role in the prevention of invasive fungal infections. Whereas mouse studies have demonstrated the role of various neutrophil pathogen recognition receptors (PRRs), signal transduction pathways, and cytotoxicity in the murine antifungal immune response, much less is known about the killing of fungi by human neutrophils. Recently, novel primary immunodeficiencies have been identified in patients with a susceptibility to fungal infections. These human 'knock-out' neutrophils expand our knowledge to understand the role of PRRs and signaling in human fungal killing. From the studies with these patients it is becoming clear that neutrophils employ fundamentally distinct mechanisms to kill Candida albicans or Aspergillus fumigatus. 10.1111/imr.12454

Neutrophils flash their GLUTs to beat back detestable fungi. Cell host & microbe Neutrophils enforce frontline immunity to fungal infection. Potent neutrophil effector functions require vast amounts of cytosolic glucose. Li et al. describe how neutrophils, upon interaction with Candida albicans, modulate the new synthesis and membrane localization of Glucose Transporter 1 (GLUT1) to facilitate glucose entry and meet neutrophils' metabolic needs. 10.1016/j.chom.2022.03.027

Eradicating, retaining, balancing, swarming, shuttling and dumping: a myriad of tasks for neutrophils during fungal infection. Urban Constantin F,Backman Emelie Current opinion in microbiology Opportunistic, invasive mycoses in immunocompromised patients remain challenging for health care with unacceptably high levels of morbidity and mortality. Neutrophils are essential in host protection against invasive mycoses. Upon development of acute infection, neutrophils are recruited from circulation to the infected tissue, where they exert a considerable variety of effector functions with the ultimate task to eradicate invading microbes. Effector functions include recognition, phagocytosis and intracellular killing of microorganisms via oxidative and non-oxidative mechanisms, excretion of antimicrobial factors from intracellular storages (degranulation), release of neutrophil extracellular traps (NETs) and of extracellular vesicles (EVs), as well as generation of cytokines and chemokines to modulate immune responses. Herein, we describe recent findings which further our understanding of the roles of neutrophils during opportunistic fungal infections which could serve as starting point for the development of immune-targeted interventions to improve clinical management of affected individuals. 10.1016/j.mib.2020.09.011

Reduced exposure to vasopressors through permissive hypotension to reduce mortality in critically ill people aged 65 and over: the 65 RCT. Health technology assessment (Winchester, England) BACKGROUND:Vasopressors are administered to critical care patients to avoid hypotension, which is associated with myocardial injury, kidney injury and death. However, they work by causing vasoconstriction, which may reduce blood flow and cause other adverse effects. A mean arterial pressure target typically guides administration. An individual patient data meta-analysis (Lamontagne F, Day AG, Meade MO, Cook DJ, Guyatt GH, Hylands M, Pooled analysis of higher versus lower blood pressure targets for vasopressor therapy septic and vasodilatory shock. 2018;:12-21) suggested that greater exposure, through higher mean arterial pressure targets, may increase risk of death in older patients. OBJECTIVE:To estimate the clinical effectiveness and cost-effectiveness of reduced vasopressor exposure through permissive hypotension (i.e. a lower mean arterial pressure target of 60-65 mmHg) in older critically ill patients. DESIGN:A pragmatic, randomised clinical trial with integrated economic evaluation. SETTING:Sixty-five NHS adult general critical care units. PARTICIPANTS:Critically ill patients aged ≥ 65 years receiving vasopressors for vasodilatory hypotension. INTERVENTIONS:Intervention - permissive hypotension (i.e. a mean arterial pressure target of 60-65 mmHg). Control (usual care) - a mean arterial pressure target at the treating clinician's discretion. MAIN OUTCOME MEASURES:The primary clinical outcome was 90-day all-cause mortality. The primary cost-effectiveness outcome was 90-day incremental net monetary benefit. Secondary outcomes included receipt and duration of advanced respiratory and renal support, mortality at critical care and acute hospital discharge, and questionnaire assessment of cognitive decline and health-related quality of life at 90 days and 1 year. RESULTS:Of 2600 patients randomised, 2463 (permissive hypotension,  = 1221; usual care,  = 1242) were analysed for the primary clinical outcome. Permissive hypotension resulted in lower exposure to vasopressors than usual care [mean duration 46.0 vs. 55.9 hours, difference -9.9 hours (95% confidence interval -14.3 to -5.5 hours); total noradrenaline-equivalent dose 31.5 mg vs. 44.3 mg, difference -12.8 mg (95% CI -18.0 mg to -17.6 mg)]. By 90 days, 500 (41.0%) patients in the permissive hypotension group and 544 (43.8%) patients in the usual-care group had died (absolute risk difference -2.85%, 95% confidence interval -6.75% to 1.05%;  = 0.154). Adjustment for prespecified baseline variables resulted in an odds ratio for 90-day mortality of 0.82 (95% confidence interval 0.68 to 0.98) favouring permissive hypotension. There were no significant differences in prespecified secondary outcomes or subgroups; however, patients with chronic hypertension showed a mortality difference favourable to permissive hypotension. At 90 days, permissive hypotension showed similar costs to usual care. However, with higher incremental life-years and quality-adjusted life-years in the permissive hypotension group, the incremental net monetary benefit was positive, but with high statistical uncertainty (£378, 95% confidence interval -£1347 to £2103). LIMITATIONS:The intervention was unblinded, with risk of bias minimised through central allocation concealment and a primary outcome not subject to observer bias. The control group event rate was higher than anticipated. CONCLUSIONS:In critically ill patients aged ≥ 65 years receiving vasopressors for vasodilatory hypotension, permissive hypotension did not significantly reduce 90-day mortality compared with usual care. The absolute treatment effect on 90-day mortality, based on 95% confidence intervals, was between a 6.8-percentage reduction and a 1.1-percentage increase in mortality. FUTURE WORK:Future work should (1) update the individual patient data meta-analysis, (2) explore approaches for evaluating heterogeneity of treatment effect and (3) explore 65 trial conduct, including use of deferred consent, to inform future trials. TRIAL REGISTRATION:Current Controlled Trials ISRCTN10580502. FUNDING:This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 25, No. 14. See the NIHR Journals Library website for further project information. 10.3310/hta25140