The innate immune response plays a crucial role in satisfactory host resolution of bacterial infection. In response to chemotactic signals, neutrophils are early responding cells that migrate in large numbers to sites of infection. The recent discovery of secreted neutrophil extracellular traps (NETs) composed of DNA and histones opened a novel dimension in our understanding of the microbial killing capacity of these specialized leukocytes. M1 serotype strains of the pathogen Group A Streptococcus (GAS) are associated with invasive infections including necrotizing fasciitis (NF) and express a potent DNase (Sda1). Here we apply a molecular genetic approach of allelic replacement mutagenesis, single gene complementation, and heterologous expression to demonstrate that DNase Sda1 is both necessary and sufficient to promote GAS neutrophil resistance and virulence in a murine model of NF. Live fluorescent microscopic cell imaging and histopathological analysis are used to establish for the first time a direct linkage between NET degradation and bacterial pathogenicity. Inhibition of GAS DNase activity with G-actin enhanced neutrophil clearance of the pathogen in vitro and reduced virulence in vivo. The results demonstrate a significant role for NETs in neutrophil-mediated innate immunity, and at the same time identify a novel therapeutic target against invasive GAS infection.
Most invasive bacterial infections are caused by species that more commonly colonize the human host with minimal symptoms. Although phenotypic or genetic correlates underlying a bacterium's shift to enhanced virulence have been studied, the in vivo selection pressure governing such shifts are poorly understood. The globally disseminated M1T1 clone of group A Streptococcus (GAS) is linked with rare but life-threatening syndromes of necrotizing fasciitis and toxic shock syndrome. Mutations in the GAS control of virulence regulatory sensor kinase (covRS) operon are associated with severe invasive disease, abolishing expression of a broad spectrum cysteine protease (SpeB)2,3 and allowing the recruitment and activation of host plasminogen on the bacterial surface. Here we describe how bacteriophage-encoded GAS DNase (Sda1), which facilitates the pathogen's escape from neutrophil extracellular traps (NETs)5,6, serves as a selective force for covRS mutation. The results provide a paradigm whereby natural selection exerted by the innate immune system generate hypervirulent bacterial variants with increased risk of systemic dissemination. Keywords CMMB Disciplines Life Sciences | Physical Sciences and Mathematics | Social and Behavioral Sciences Publication DetailsThis article was originally published as Walker, MJ et al, DNase Sda1 provides selection pressure for a switch to invasive group A streptococcal infection, Nature Medicine 13, 2007, 981- GAS is estimated to cause ~700 million cases of self-limited throat or skin infection each year worldwide 7 . Invasive GAS disease occurs in approximately 1/1,000 cases, with associated mortality of 25% 7 . Epidemic invasive disease is associated with the emergence of the globally disseminated GAS M1T1 clone 1,8 , which is distinguished from related strains by acquisition of prophages encoding virulence determinants such as superantigen SpeA and DNase Sda1 9,10 . In the M1T1 GAS clone, the transition from local to systemic infection can be linked to mutations in the two-component covRS regulator. The effect of these mutations is a distinct shift in the transcriptional 3 profile of invasive GAS isolates compared to mucosal (throat) isolates 3 . The covRS mutation and changes in gene expression are recapitulated upon subcutaneous challenge of mice and analysis of GAS disseminating to the spleen in comparison with those in the original inocolum 3 . Prominent changes in the transcriptional profile of invasive GAS isolates include a strong up-regulation of the DNase gene sda1, and a marked decrease in expression of the gene encoding the cysteine protease SpeB 3 .Sda1 is a virulence factor that protects GAS against neutrophil killing by degrading the DNA framework of NETs 5,6 . Abolishment of SpeB expression allows accumulation and activation of the broad spectrum host protease plasmin on the GAS bacterial surface 4 . A clinical correlation of GAS invasive disease severity and diminished SpeB expression has been established 2 .To elucidate the selection pressure for the rap...
Infrastructure, processes of care and outcome measurements are the cornerstone of quality care for pediatric trauma. This review aims to evaluate current evidence on system organization and concentration of pediatric expertise in the delivery of pediatric trauma care. It discusses key quality indicators for all phases of care, from pre-hospital to post-discharge recovery. In particular, it highlights the importance of measuring quality of life and psychosocial recovery for the injured child.
Objective: Translumbar embolization (TLE) of type II endoleaks has been described for the treatment of enlarging aneurysms following EVAR. This technique is reported to have a very high rate of technical success and durability. The purpose of this study is to review our experience with TLE in controlling type II endoleaks, in arresting the increase in aneurysm growth, and limiting the need for subsequent intervention.Methods: A retrospective case review was performed on 13 patients with CT and/or angiographically confirmed type II endoleaks who underwent TLE at two institutions. Patients were treated with combinations of stainless-steal coils, Onyx, Cyanoacrylate (NBCA), thrombin, and/or poly vinyl alcohol (PVA) beads. Success was defined as clear resolution of the type II endoleak and/or an aneurysm diameter that was either stable or decreasing. Failure of the technique was defined as any persistent leak, an enlarging aneurysm sac, or the need for secondary intervention.Results: Thirteen patients underwent TLE for type II endoleaks associated with aneurysm enlargement. In two patients who underwent translumbar puncture, no endoleak could be identified, and no treatment was performed. TLE was successful in only 5 (45.5%) of the remaining 11 patients. Six patients (54.5%) had unsuccessful TLE. Of the 6 treatment failures; 2 patients required repeat interventions, 2 required open surgical repair (1 for rupture), 1 suffered colonic ischemia requiring resection, and 1 patient has a persistent type II endoleak.Conclusions: Our experience contrasts with previously published studies in that fewer than half of the patients treated had successful resolution of their endoleak with TLE alone. Although TLE is a useful technique for the management of type II endoleaks, many patients will require subsequent procedures. Close surveillance of patients after TLE is imperative to identify the patients who will require additional intervention. The practice gap addressed is the difficulty in obtaining adequate results using TLE in treating endoleaks. A small number of previously published studies showed high success rates. By identifying a lower success rate for TLE, we hope to impress the importance of vigorous surveillance after the procedure. JOURNAL OF VASCULAR SURGERY Volume 52, Number 2 Abstracts 529
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.