Human Complement Regulators C4b-Binding Protein and C1 Esterase Inhibitor Interact with a Novel Outer Surface Protein of Borrelia recurrentis

The spirochete Borrelia recurrentis is the causal agent of louse-borne relapsing fever and is transmitted to humans by the infected body louse Pediculus humanus. We have recently demonstrated that the B. recurrentis surface receptor, HcpA, specifically binds factor H, the regulator of the alternative pathway of complement activation, thereby inhibiting complement mediated bacteriolysis. Here, we show that B. recurrentis spirochetes express another potential outer membrane lipoprotein, termed CihC, and acquire C4b-binding protein (C4bp) and human C1 esterase inhibitor (C1-Inh), the major inhibitors of the classical and lectin pathway of complement activation. A highly homologous receptor for C4bp was also found in the African tick-borne relapsing fever spirochete B. duttonii. Upon its binding to B. recurrentis or recombinant CihC, C4bp retains its functional potential, i.e. facilitating the factor I-mediated degradation of C4b. The additional finding that ectopic expression of CihC in serum sensitive B. burgdorferi significantly increased spirochetal resistance against human complement suggests this receptor to substantially contribute, together with other known strategies, to immune evasion of B. recurrentis

Developing core elements and checklist items for global hospital antimicrobial stewardship programmes:a consensus approach

International audienc

Yersinia enterocolitica Serum Resistance Proteins YadA and Ail Bind the Complement Regulator C4b-Binding Protein

Many pathogens are equipped with factors providing resistance against the bactericidal action of complement. Yersinia enterocolitica, a Gram-negative enteric pathogen with invasive properties, efficiently resists the deleterious action of human complement. The major Y. enterocolitica serum resistance determinants include outer membrane proteins YadA and Ail. Lipopolysaccharide (LPS) O-antigen (O-ag) and outer core (OC) do not contribute directly to complement resistance. The aim of this study was to analyze a possible mechanism whereby Y. enterocolitica could inhibit the antibody-mediated classical pathway of complement activation. We show that Y. enterocolitica serotypes O:3, O:8, and O:9 bind C4b-binding protein (C4bp), an inhibitor of both the classical and lectin pathways of complement. To identify the C4bp receptors on Y. enterocolitica serotype O:3 surface, a set of mutants expressing YadA, Ail, O-ag, and OC in different combinations was tested for the ability to bind C4bp. The studies showed that both YadA and Ail acted as C4bp receptors. Ail-mediated C4bp binding, however, was blocked by the O-ag and OC, and could be observed only with mutants lacking these LPS structures. C4bp bound to Y. enterocolitica was functionally active and participated in the factor I-mediated degradation of C4b. These findings show that Y. enterocolitica uses two proteins, YadA and Ail, to bind C4bp. Binding of C4bp could help Y. enterocolitica to evade complement-mediated clearance in the human host

Virulence of Group A Streptococci Is Enhanced by Human Complement Inhibitors

Streptococcus pyogenes, also known as Group A Streptococcus (GAS), is an important human bacterial pathogen that can cause invasive infections. Once it colonizes its exclusively human host, GAS needs to surmount numerous innate immune defense mechanisms, including opsonization by complement and consequent phagocytosis. Several strains of GAS bind to human-specific complement inhibitors, C4b-binding protein (C4BP) and/or Factor H (FH), to curtail complement C3 (a critical opsonin) deposition. This results in diminished activation of phagocytes and clearance of GAS that may lead to the host being unable to limit the infection. Herein we describe the course of GAS infection in three human complement inhibitor transgenic (tg) mouse models that examined each inhibitor (human C4BP or FH) alone, or the two inhibitors together (C4BPxFH or 'double' tg). GAS infection with strains that bound C4BP and FH resulted in enhanced mortality in each of the three transgenic mouse models compared to infection in wild type mice. In addition, GAS manifested increased virulence in C4BPxFH mice: higher organism burdens and greater elevations of pro-inflammatory cytokines and they died earlier than single transgenic or wt controls. The effects of hu-C4BP and hu-FH were specific for GAS strains that bound these inhibitors because strains that did not bind the inhibitors showed reduced virulence in the 'double' tg mice compared to strains that did bind; mortality was also similar in wild-type and C4BPxFH mice infected by non-binding GAS. Our findings emphasize the importance of binding of complement inhibitors to GAS that results in impaired opsonization and phagocytic killing, which translates to enhanced virulence in a humanized whole animal model. This novel hu-C4BPxFH tg model may prove invaluable in studies of GAS pathogenesis and for developing vaccines and therapeutics that rely on human complement activation for efficacy

Causal mechanisms proposed for the Alcohol Harm Paradox - a systematic review

Background and Aims The Alcohol Harm Paradox (AHP) posits that disadvantaged groups suffer from higher rates of alcohol-related harm compared with advantaged groups, despite reporting similar or lower levels of consumption on average. The causes of this relationship remain unclear. This study aimed to identify explanations proposed for the AHP. Secondary aims were to review the existing evidence for those explanations and investigate whether authors linked explanations to one another. Methods Systematic review. We searched MEDLINE (1946-January 2021), EMBASE (1974 – January 2021) and PsycINFO (1967 – January 2021), supplemented via manual searching of grey literature. Included papers either explored the causes of the AHP or investigated the relationship between alcohol consumption, alcohol-related harm, and socioeconomic position. Papers were set in Organisation for Economic Co-operation and Development high income countries. Explanations extracted for analysis could be evidenced in the empirical results or suggested by researchers in their narrative. Inductive thematic analysis was applied to group explanations. Results Seventy-nine papers met the inclusion criteria and initial coding revealed these papers contained 41 distinct explanations for the AHP. Following inductive thematic analysis, these explanations were grouped into 16 themes within six broad domains: Individual, Lifestyle, Contextual, Disadvantage, Upstream and Artefactual. Explanations related to risk behaviours, which fit within the Lifestyle domain, were the most frequently proposed (n=51) and analysed (n=21). Conclusions While there are many potential explanations for the Alcohol Harm Paradox, most research focuses on risk behaviours while other explanations lack empirical testing

Analysis of magnetic field measurement results for the AGS Booster magnets

Magnetic field measurements have been made on nearly 200 conventional magnets that have been installed in the AGS Booster and its associated transfer lines. The measurements were intended to monitor the quality of the magnets being produced and to check the performance of each magnet before installation. The magnetic measurements effort led to certain improvements in the manufacturing process, which ten subsequently produced very good, very uniform magnets. The integrated dipole fields of the 36 booster dipoles are uniform to 1.5 parts in ten thousand. The magnetic measurements indicate that the quadrupoles were manufactured to an accuracy of 3 ten thousandths of an inch, which is better than we can physically measure. 3 refs., 2 figs., 4 tabs

A beam scraper using a linear motor

A beam scraper using a linear motor drive has been developed for use in the AGS at Brookhaven National Laboratory. The device is used to measure beam size by moving a target to a predetermined location and measuring the intercepted beam with nearby loss monitors or by noting the decrease in the circulating beam current. This device has excellent vacuum characteristics, as the motor and sensor coils are outside the vacuum, coupled magnetically to the moving parts which are inside. There are no bellows or dynamic seals required. The position-time profile is controlled by a closed-loop servo system which uses position feedback. 2 refs., 4 figs

Design and operation of the AGS Booster Ionization Profile Monitor

The AGS Booster Ionization Profile Monitor (IPM) must operate in a vacuum of about 3 {times} 10{sup {minus}11} Torr. The ultra-high vacuum imposes certain requirements on detector gain and restrictions on construction techniques. Each detector is a two-stage micro-channel plate with an integral substrate containing sixty-four printed anodes. Formed electrodes provide uniform collection fields without the use of resistors, which would be unacceptable in these vacuum conditions. An ultra-violet light calibrates the detector in its permanent mounting. An extra set of electrodes performs a first order correction to the perturbations imposed by the horizontal and vertical collection electrodes. This paper will present details of the design of the profile monitor and recent operational results. 4 refs., 6 figs

Rodinian Collisional and Escape Tectonics in the Hudson Highlands, New York

A new multidisciplinary research collaboration to study the western Hudson Highlands, New York, has unraveled a complex Rodinian tectonic history that will be illustrated by visiting key locations on this trip. New sensitive high-resolution ion microprobe (SHRIMP) data demonstrates a cryptic suture between a ca. 1.2-1.1 Ga island arc and sedimentary rocks from a deeply incised craton (Amazonia?). The 1.05 Ga collision between these two terranes produced westward-directed fold nappes, granulite facies metamorphism and the dominant subhorizontal gneissic foliation. Tectonic surge granite sheets were emplaced into the nappes. Bimodal (diorite and granite) plutons intruded the area prior to the onset of a steeply SE-dipping 35-kmwide dextral shear system that resulted from tectonic escape. Extensive iron remobilization and mineralization accompanied the shearing and post-kinematic pegmatite plutons mark the end of activity at ca. 980 Ma