The Shr receptor from Streptococcus pyogenes uses a cap and release mechanism to acquire heme–iron from human hemoglobin

Streptococcus pyogenes (group A Streptococcus) is a clinically important microbial pathogen that requires iron in order to proliferate. During infections, S. pyogenes uses the surface displayed Shr receptor to capture human hemoglobin (Hb) and acquires its iron-laden heme molecules. Through a poorly understood mechanism, Shr engages Hb via two structurally unique N-terminal Hb-interacting domains (HID1 and HID2) which facilitate heme transfer to proximal NEAr Transporter (NEAT) domains. Based on the results of X-ray crystallography, small angle X-ray scattering, NMR spectroscopy, native mass spectrometry, and heme transfer experiments, we propose that Shr utilizes a “cap and release” mechanism to gather heme from Hb. In the mechanism, Shr uses the HID1 and HID2 modules to preferentially recognize only heme-loaded forms of Hb by contacting the edges of its protoporphyrin rings. Heme transfer is enabled by significant receptor dynamics within the Shr–Hb complex which function to transiently uncap HID1 from the heme bound to Hb’s β subunit, enabling the gated release of its relatively weakly bound heme molecule and subsequent capture by Shr’s NEAT domains. These dynamics may maximize the efficiency of heme scavenging by S. pyogenes, enabling it to preferentially recognize and remove heme from only heme-loaded forms of Hb that contain iron.

To successfully mount infections bacterial pathogens must overcome host nutritional immunity mechanisms that limit access to iron, an essential metal nutrient required for microbial survival because it functions as a cofactor in enzymes that mediate cellular metabolism. Human hemoglobin (Hb) contains ~75 to 80% of the body’s total iron in the form of heme (iron–protoporphyrin IX) and is thus a prime nutrient source for invading microbes (1–9). Bacteria gain access to Hb’s iron-laden heme molecules when erythrocytes are ruptured by bacterial cytotoxins or when they spontaneously lyse. In gram-positive monoderm bacteria, extracellular Hb is captured by surface-displayed microbial receptors. Hb’s heme molecules are then released and transferred via microbial heme-binding chaperones across the expanse of the peptidoglycan to the membrane, where they are imported into the cell and degraded to release iron. The acquisition mechanisms that many pathogens use to bind to Hb and remove its tightly bound heme molecules are not well understood. Streptococcus pyogenes (group A Streptococcus) colonizes the skin and mucosal surfaces in humans and is estimated to cause more than 500,000 deaths annually (10–12). It causes a range of illnesses, ranging from acute pharyngitis to life-threatening diseases such as scarlet fever, bacteremia, pneumonia, necrotizing fasciitis, myonecrosis, and streptococcal toxic shock syndrome (13, 14). S. pyogenes employs the streptococcal hemoprotein receptor (Shr) to capture Hb and acquire its heme molecules, and it is an important virulence factor that when genetically deleted reduces the ability of the pathogen to grow in human blood and to cause infections in murine and zebrafish models (15–17). Strategies that interfere with the ability of S. pyogenes and other pathogenic bacteria to harvest heme from Hb could be useful in treating infections, as they would effectively starve pathogens of iron.The S. pyogenes Shr protein is a structurally unique multidomain Hb receptor that is also found in other streptococci and clostridia species (e.g., Clostridium novyi, Streptococcus iniae, Streptococcus equi, and Streptococcus dysgalactiae) (Fig. 1A). Its N-terminal region (NTR, residues 26 to 364) binds to Hb using two Hb interacting domains (HIDs), called HID1 and HID2 (formally known as DUF1533 domains) (18, 19). The HIDs are structurally novel binding modules and are joined via a structured linker domain (L) to a C-terminal region (CTR, residues 365 to 1,275) which contains two heme-binding NEAr iron Transporter domains (NEAT domains N1 and N2) that are separated by a series of leucine-rich repeats (LRR). The NTR and N1 domain within Shr (called NTR-N1) preferentially bind to holo-Hb and remove its heme (18). In vitro, heme bound by the N1 domain is then readily transferred to either the C-terminal N2 domain, or to Shp, a cell wall-associated protein that relays heme to the membrane-associated HtsABC/SiaABC transporter that pumps heme into the cytoplasm (20–22). The N2 domain in Shr may act as a storage unit, since it binds to heme with much higher affinity than N1 and does not directly transfer heme to Shp (23). Shr also interacts via its N2 domain with the human extracellular matrix (ECM) proteins fibronectin and laminin (15, 16, 18), and its exposure on the cell surface may make it a useful epitope in S. pyogenes vaccines (24, 25). However, it remains poorly understood how Shr acquires heme from Hb. Here we show using a combination of biophysical and structural methods that Shr uses its HIDs to selectively bind to the heme-loaded form of Hb, slowing the rate of heme release by directly contacting the edges of its protoporphyrin rings. However, receptor dynamics within the Shr–Hb complex act to transiently uncap the HIDs from Hb’s β subunit, enabling heme’s gated release and subsequent capture by the receptor. This “cap and release” mechanism exploits the β subunit’s inherent weaker affinity for heme (26), allowing S. pyogenes to preferentially capture only heme-saturated forms of Hb that contain iron.Open in a separate windowFig. 1.Structure of the Hb–Shr^H2 complex. (A) Domain schematic of the Shr receptor. The polypeptide constructs used in this study are shown below. (B) Crystal structure of the Hb–Shr^H2 complex. The asymmetric unit of the crystal contains two tetramers of Hb that are bound by three molecules of Shr^H2. (C and D) HID2 binds over the heme pockets in both the α and β chains of Hb. These capping interactions directly contact both the heme and globin chain, burying an average of ~153 Ų and ~408 Ų of solvent-accessible surface area, respectively. Hb contacts originate from three surface loops in HID2: β2-α1, β4-β5, and β5-β6. (E) Expanded view of the Hb-receptor interface showing interactions with the heme molecule bound to the α subunit. The heme molecules are shown in stick format with oxygen and nitrogen atoms colored red and blue, respectively. Side chains in the receptor that interact with Hb are shown in stick format. (F) Identical to panel (E), except that receptor contacts to the β subunit in Hb are shown. Hb is in its ferric form. Color scheme: α subunit (salmon), β subunit (green), and HID2 (blue).     

Evaluation of red blood cell transfusion threshold in the management of brain-dead organ donors

The disparity between the demand and supply of organs has necessitated an expansion of the criteria for organ donation. Consequently, numerous guidelines have been proposed for managing brain-dead organ donors (BDODs) to improve their organ function and the organ procurement rate. Therefore, we aimed to evaluate the previously recommended threshold for red blood cell transfusion in BDODs. Medical records of BDODs were retrospectively reviewed from January 2012 to December 2021. We enrolled BDODs who stayed for more than 24 hours at an hospital organ procurement organization. We analyzed their organ function and the rate of organ procurement according to the hemoglobin concentration. A total of 111 BDODs were enrolled and divided into the following 2 groups: hemoglobin (Hb) ≥ 10 g/dL (45.0 %) and Hb < 10 g/dL (55.0 %). There were no significant differences between the groups in the total bilirubin, creatinine, arterial blood lactate, and the rate of organ procurement. A correlation analysis did not reveal any association between the hemoglobin concentration and organ function of the BDODs. Hemoglobin concentration of 10 g/dL cannot be considered a threshold for red blood cell transfusion. Furthermore, organ function is not correlated with a hemoglobin concentration > 7 g/dL. Restrictive transfusion strategy is appropriate for BDOD management.     

2型糖尿病合并高血压患者的社区综合干预效果评价

目的了解上海市浦东新区社区管理2型糖尿病患者的糖化血红蛋白(HbA1c)的达标情况,初步探讨影响HbA1c达标的相关因素。方法分层随机选取浦东新区8家社区卫生服务中心管理的2型糖尿病患者400例进行问卷调查,根据《中国2型糖尿病防治指南》的控制目标HbA1c < 7.0%为标准,将被调查者分为达标组和未达标组,采用多因素logistic回归分析影响HbA1c达标的相关因素。结果共回收有效问卷387份,HbA1c达标患者93例,达标率为24.03%;经多因素logistic分析,居住地、病程、饮食、HbA1c监测和腰臀比(WHR)是影响HbA1c达标的独立相关因素。结论浦东新区社区管理的2型糖尿病患者HbA1c达标率较低,影响浦东新区2型糖尿病患者HbA1c达标的可能因素有居住地、病程、饮食、HbA1c监测和WHR。     

Plasma hemoglobin concentration was related to estimated glomerular filtration rate in elderly patients with ischemic Cardiomyopatny

Objectlves To stuaythe relationship between plasma hemoglobin concentration and estimated glomerular filtration rate (eGFR)in elderly patients with ischemic cardiomyopathy (ICM).Methods Clinical data of patients with coronary heart disease who weredischarged from The First Affiliated Hospital,Chongqing Medicai University between 2005 and 2007 were analyzed retrospectively.Echocardiography resuIts.plasma hemoglobin and creatinine concentration were abstracted from the medical records.The study included235 Chinese Han patients with age 60 years and older with angiography confwmed coronary heart disease.silent myocardial ischemia orangina pectoris,of whom 154 had ICM defined as left ventricular end-diastolic diameter(LVDd),male≥56mm,female≥51 mm(63.51±7.70 mm)measured by M-mode echocardiography.The differences in plasma hemoglobin concentration were analyzed retrospec-were no significant changes in plasma hemoglobin concentration and eGFR;however,plasma hernoglobin concentration was related toeGFR significantly positively in elderly patients with ICM due to coronary heart disease.     

Visit-to-visit glycated hemoglobin A1c variability in adults with type 2 diabetes: a systematic review and meta-analysis

Background:Current practice uses the latest measure of glycated hemoglobin (HbAlc) to facilitate clinical decision-making. Studies have demonstrated that HbAlc variability links the risk of death and complications of diabetes. However, the role of HbAlc variability is unclear in clinical practice. This systematic review summarized the evidence of visit-to-visit HbAlc variability regarding different metrics in micro- and macro-vascular complications and death in people with type 2 diabetes.Methods:We searched PubMed, EMBASE (via OVID), and Cochrane Central Register (CENTRAL, via OVID) for studies investigating the association between HbAlc variability and adverse outcomes in patients with type 2 diabetes and performed random-effects meta-analysis stratified by HbAlc variability metrics in terms of standard deviation (SD), coefficient of variation (CV), and HbAlc variability score (HVS).Results:In people with type 2 diabetes, the highest quantile of all three HbAlc variability metrics (HbAlc-standard deviation [HbAlc-SD], HbAlc-coefficient of variance [HbAlc-CV], and HVS) is associated with increased risks of all-cause mortality, cardiovascular events, progression to chronic kidney disease, amputation, and peripheral neuropathy. For example, the hazard ratio of HbAlc-SD on all-cause mortality was l.89 with 95% confidence interval (95% CI) l.46–2.45 (HbAlc-CV l.47, 95% CI l.26–l.72; HVS l.67, 95% CI l.34–2.09).Conclusions:High HbAlc variability leads to micro- and macro-vascular complications of type 2 diabetes and related death. People with type 2 diabetes and high HbAlc variability need additional attention and care for the potential adverse outcomes.     

糖化血红蛋白不同组份的临床价值探讨

目的探讨糖化血红蛋白不同组份的临床价值。方法应用D-10糖化血红蛋白分析仪（高效液相色谱法）分析186例糖尿病（DM）患者全血中7种糖化血红蛋白组份[糖化血红蛋白A1亚组份（HbA1c、HbA1a、HbA1b）、抗碱血红蛋白（HbF）、不明蛋白组份（unknow）、蛋白组份3（P3）和不稳定糖化血红蛋白（LA1c_CHb-1）]水平。同时检测患者血糖（Glu）、C肽（C—P）、三酰甘油（TG）、总胆固醇（TC）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）、载脂蛋白A—I（apoA—I）、载脂蛋白B（apo B）和脂蛋白（a）[LP（a）]。结果Glu、HbA1a、HbA1b、HbF、P3和unknow与HbA1c呈正相关（P〈0．05）,LA1c_CHb-1、C—P与HbA1c成负相关（P〈0．05）。186例DM患者HbA1c与血脂7项均无明显相关性,但其中101例男性患者HbA1c与总胆固醇（TC）呈正相关（r=0．333,P〈0．05）。结论除HbA1c外,HbA1a、HbA1b、HbF和P3在DM疗效评估中具有重要作用。DM患者,尤其是男性患者,在控制血糖的同时应辅以降脂治疗。     

2型糖尿病患者糖化血红蛋白及餐后血糖与尿清蛋白排泄率的关系

目的探讨2型糖尿病(T2DM)病人糖化血红蛋白(HBA1c)、餐后2 h血糖(2hPBG)与12 h尿清蛋白排泄率(UAE)的关系。方法选择113例空腹血糖(FBG)控制达标的T2DM患者及54例体检正常人群。HbA1c检测用高效液相色谱法,2 hPBG检测用葡萄糖氧化酶法,尿清蛋白检测用放射免疫法,记录12 h尿量,计算出UAE。按照HbA1c及2 h PBG水平将113例患者分为A组(HbA1c<7%且PBG<10 mmol/L),B组(HbA1c<7%且PBG≥10 mmol/L),C组(HbA1c>7%且PBG<10mmol/L)和D组(HbA1c≥7%且PBG≥10 mmol/L)。结果113例T2DM患者UAE均高于正常对照组(P<0.01)。D组UAE水平明高于A,B,C组(P<0.01,P<0.05,P<0.01);A组UAE水平明显低于C组(P<0.05)。B组与A,C组UAE无差异(P>0.05)。结论T2DM病人FBG控制达标后,餐后血糖及HbA1c控制不良仍会加重尿清蛋白排泄。因此强化血糖控制要重视HbA1c和餐后血糖的监测及达标。     

黄连素对不同中医证型2型糖尿病降糖作用临床研究

目的观察黄连素对不同中医证型2型糖尿病的临床疗效。方法选择阴虚热盛型、湿热困脾型、气阴两虚型及瘀血阻络型2型糖尿病各30例,在原降糖治疗基础上予黄连素0.5 g,餐前15 min口服,每日3次,疗程3个月。观察各组空腹血糖、餐后2 h血糖、糖化血红蛋白等以评定降糖疗效;观察中医证候积分,以评定中医证候疗效。结果黄连素对湿热困脾型组的降糖作用及中医证候疗效明显优于其他3个证型组(P<0.05,P<0.01)。结论黄连素对湿热困脾型2型糖尿病患者降糖作用明显。     

肾移植受者发生移植后糖尿病的危险因素分析及预测模型的构建

目的  分析肾移植受者发生移植后糖尿病（PTDM）的危险因素,建立PTDM预测模型并评价其预测价值。方法  回顾性分析915例肾移植受者的临床资料。根据有否发生PTDM,分为PTDM组（78例）和非PTDM组（837例）。收集受者的主要指标,对肾移植受者发生PTDM的危险因素进行单因素和多因素分析; 建立PTDM预测模型并评价其预测价值。结果  糖尿病家族史、体质量指数（BMI）、术前餐后2 h血糖、术前糖化血红蛋白是肾移植受者发生PTDM的独立危险因素。PTDM预测模型为logit（P）=2.199×糖尿病家族史（有=1,无=0）+0.109×BMI+0.151×餐后2 h血糖（mmol/L）+0.508×糖化血红蛋白（%）-9.123。受试者工作特征（ROC）曲线结果显示,联合4种预测因子预测肾移植受者发生PTDM的曲线下面积（AUC）为0.830[95%可信区间（CI）0.786~0.873],界值为0.0608,灵敏度为0.821,特异度为0.700,约登指数为0.521（P < 0.05）。结论  糖尿病家族史、BMI、术前餐后2 h血糖、术前糖化血红蛋白是肾移植受者发生PTDM的独立危险因素。联合4种预测因子的PTDM预测模型具有较好的预测价值。     

2型糖尿病患者血糖控制欠佳时脂蛋白(a)与糖化血红蛋白的关系

目的:探讨2型糖尿病(DM)患者血糖控制欠佳时脂蛋白(a)[Lp(a)]的水平及其与糖化血红蛋白(HbA 1c)的关系。方法:采用免疫胶乳凝集抑制法检测HbA 1c,采用免疫比浊法对30例HbA 1c高于正常的2型糖尿病患者和30例正常对照者的脂蛋白(a)进行测定。结果:2型DM糖化血红蛋白(GHb)升高组和正常对照组的血浆Lp(a)分布均呈偏态;2型DM GHb升高组Lp(a)显著高于正常对照组(P<0.01);根据HbA 1c水平将2型DM GHb升高组分成三组,三组间脂蛋白(a)的差异无统计学意义(P>0.05);2型DM GHb升高组Lp(a)与HbA 1c无相关性(P>0.05)。结论:2型糖尿病患者血糖控制欠佳时脂蛋白(a)的水平与糖化血红蛋白的水平无关。