The Role of Hypoxia-Inducible Factor in the Immune Response to Infection /

The twentieth century saw great improvements in our ability to control infectious diseases through the use of antibiotics and vaccinations. In recent decades, however, some of these improvements have eroded as pathogens evolve antibiotic resistance. Further progress in controlling infectious disease will likely require not just new antibiotics, but also strategies to strengthen and target the host immune response more effectively. To this end, a more nuanced understanding of host immune response regulation is necessary. One key regulatory factor is hypoxia-inducible factor (HIF), which plays a pivotal role in the antimicrobial function of myeloid cells. Here we explore the role of HIF in other aspects of the immune response to infection, and evaluate its potential as a target for new anti-infective therapies. Using a genetic model in which Hif-1[alpha] was ablated specifically in dendritic cells, we studied the role of HIF in initiating the T-cell response. We found that HIF was important for the expression of antigen-presenting and costimulatory surface molecules, the ability to stimulate T cell proliferation, and the overall response to vaccination. Furthermore, pharmacological augmentation of HIF improved both the humoral and cell-mediated response to vaccination, indicating that HIF could be a target for vaccine adjuvants. Previous work by the Nizet lab and others has shown that HIF is crucial for the control of skin infections. Like HIF, the active form of vitamin D increases in the skin upon exposure to molecular signals of infection, leading to increased antimicrobial activity of skin epithelial and immune cells. We used a human skin cell line to elucidate the relationship between HIF and vitamin D in the regulation of skin immunity. We found that vitamin D increases HIF expression and function, and HIF modulates vitamin D-induced expression of the antimicrobial peptide LL-37. These data provide the first suggestion that drugs which augment HIF may help treat infections in vitamin D-deficient patients. It is clear that HIF plays an important and complex role in the immune response to infection. As our understanding of HIF grows, we will be better able to manipulate the host immune response to prevent or control infectious disease

The Role of Hypoxia-Inducible Factor in the Immune Response to Infection /

The twentieth century saw great improvements in our ability to control infectious diseases through the use of antibiotics and vaccinations. In recent decades, however, some of these improvements have eroded as pathogens evolve antibiotic resistance. Further progress in controlling infectious disease will likely require not just new antibiotics, but also strategies to strengthen and target the host immune response more effectively. To this end, a more nuanced understanding of host immune response regulation is necessary. One key regulatory factor is hypoxia-inducible factor (HIF), which plays a pivotal role in the antimicrobial function of myeloid cells. Here we explore the role of HIF in other aspects of the immune response to infection, and evaluate its potential as a target for new anti-infective therapies. Using a genetic model in which Hif-1[alpha] was ablated specifically in dendritic cells, we studied the role of HIF in initiating the T-cell response. We found that HIF was important for the expression of antigen-presenting and costimulatory surface molecules, the ability to stimulate T cell proliferation, and the overall response to vaccination. Furthermore, pharmacological augmentation of HIF improved both the humoral and cell-mediated response to vaccination, indicating that HIF could be a target for vaccine adjuvants. Previous work by the Nizet lab and others has shown that HIF is crucial for the control of skin infections. Like HIF, the active form of vitamin D increases in the skin upon exposure to molecular signals of infection, leading to increased antimicrobial activity of skin epithelial and immune cells. We used a human skin cell line to elucidate the relationship between HIF and vitamin D in the regulation of skin immunity. We found that vitamin D increases HIF expression and function, and HIF modulates vitamin D-induced expression of the antimicrobial peptide LL-37. These data provide the first suggestion that drugs which augment HIF may help treat infections in vitamin D-deficient patients. It is clear that HIF plays an important and complex role in the immune response to infection. As our understanding of HIF grows, we will be better able to manipulate the host immune response to prevent or control infectious disease

Streptolysin O Rapidly Impairs Neutrophil Oxidative Burst and Antibacterial Responses to Group A Streptococcus

Group A Streptococcus (GAS) causes a wide range of human infections, ranging from simple pharyngitis to life-threatening necrotizing fasciitis and toxic shock syndrome. A globally disseminated clone of M1T1 GAS has been associated with an increase in severe, invasive GAS infections in recent decades. The secreted GAS pore-forming toxin streptolysin O (SLO), which induces eukaryotic cell lysis in a cholesterol-dependent manner, is highly upregulated in the GAS M1T1 clone during bloodstream dissemination. SLO is known to promote GAS resistance to phagocytic clearance by neutrophils, a critical first element of host defense against invasive bacterial infection. Here we examine the role of SLO in modulating specific neutrophil functions during their early interaction with GAS. We find that SLO at subcytotoxic concentrations and time points is necessary and sufficient to suppress neutrophil oxidative burst, in a manner reversed by free cholesterol and anti-SLO blocking antibodies. In addition, SLO at subcytotoxic concentrations blocked neutrophil degranulation, interleukin-8 secretion and responsiveness, and elaboration of DNA-based neutrophil extracellular traps (NETs), cumulatively supporting a key role for SLO in GAS resistance to immediate neutrophil killing. A non-toxic SLO derivate elicits protective immunity against lethal GAS challenge in a murine infection model. We conclude that SLO exerts a novel cytotoxic-independent function at early stages of invasive infections (< 30 min), contributing to GAS escape from neutrophil clearance

Empagliflozin in Patients with Chronic Kidney Disease

Background The effects of empagliflozin in patients with chronic kidney disease who are at risk for disease progression are not well understood. The EMPA-KIDNEY trial was designed to assess the effects of treatment with empagliflozin in a broad range of such patients. Methods We enrolled patients with chronic kidney disease who had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m(2) of body-surface area, or who had an eGFR of at least 45 but less than 90 ml per minute per 1.73 m(2) with a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 200. Patients were randomly assigned to receive empagliflozin (10 mg once daily) or matching placebo. The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to &lt; 10 ml per minute per 1.73 m(2), a sustained decrease in eGFR of &amp; GE;40% from baseline, or death from renal causes) or death from cardiovascular causes. Results A total of 6609 patients underwent randomization. During a median of 2.0 years of follow-up, progression of kidney disease or death from cardiovascular causes occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% confidence interval [CI], 0.64 to 0.82; P &lt; 0.001). Results were consistent among patients with or without diabetes and across subgroups defined according to eGFR ranges. The rate of hospitalization from any cause was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.86; 95% CI, 0.78 to 0.95; P=0.003), but there were no significant between-group differences with respect to the composite outcome of hospitalization for heart failure or death from cardiovascular causes (which occurred in 4.0% in the empagliflozin group and 4.6% in the placebo group) or death from any cause (in 4.5% and 5.1%, respectively). The rates of serious adverse events were similar in the two groups. Conclusions Among a wide range of patients with chronic kidney disease who were at risk for disease progression, empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes than placebo

Health-status outcomes with invasive or conservative care in coronary disease

BACKGROUND In the ISCHEMIA trial, an invasive strategy with angiographic assessment and revascularization did not reduce clinical events among patients with stable ischemic heart disease and moderate or severe ischemia. A secondary objective of the trial was to assess angina-related health status among these patients. METHODS We assessed angina-related symptoms, function, and quality of life with the Seattle Angina Questionnaire (SAQ) at randomization, at months 1.5, 3, and 6, and every 6 months thereafter in participants who had been randomly assigned to an invasive treatment strategy (2295 participants) or a conservative strategy (2322). Mixed-effects cumulative probability models within a Bayesian framework were used to estimate differences between the treatment groups. The primary outcome of this health-status analysis was the SAQ summary score (scores range from 0 to 100, with higher scores indicating better health status). All analyses were performed in the overall population and according to baseline angina frequency. RESULTS At baseline, 35% of patients reported having no angina in the previous month. SAQ summary scores increased in both treatment groups, with increases at 3, 12, and 36 months that were 4.1 points (95% credible interval, 3.2 to 5.0), 4.2 points (95% credible interval, 3.3 to 5.1), and 2.9 points (95% credible interval, 2.2 to 3.7) higher with the invasive strategy than with the conservative strategy. Differences were larger among participants who had more frequent angina at baseline (8.5 vs. 0.1 points at 3 months and 5.3 vs. 1.2 points at 36 months among participants with daily or weekly angina as compared with no angina). CONCLUSIONS In the overall trial population with moderate or severe ischemia, which included 35% of participants without angina at baseline, patients randomly assigned to the invasive strategy had greater improvement in angina-related health status than those assigned to the conservative strategy. The modest mean differences favoring the invasive strategy in the overall group reflected minimal differences among asymptomatic patients and larger differences among patients who had had angina at baseline

Initial invasive or conservative strategy for stable coronary disease

BACKGROUND Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, 121.8 percentage points; 95% CI, 124.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used