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      Staphylococcal Superantigens Spark Host-Mediated Danger Signals

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          Abstract

          Staphylococcal enterotoxin B (SEB) of Staphylococcus aureus, and related superantigenic toxins produced by myriad microbes, are potent stimulators of the immune system causing a variety of human diseases from transient food poisoning to lethal toxic shock. These protein toxins bind directly to specific Vβ regions of T-cell receptors (TCR) and major histocompatibility complex (MHC) class II on antigen-presenting cells, resulting in hyperactivation of T lymphocytes and monocytes/macrophages. Activated host cells produce excessive amounts of proinflammatory cytokines and chemokines, especially tumor necrosis factor α, interleukin 1 (IL-1), IL-2, interferon γ (IFNγ), and macrophage chemoattractant protein 1 causing clinical symptoms of fever, hypotension, and shock. Because of superantigen-induced T cells skewed toward TH1 helper cells, and the induction of proinflammatory cytokines, superantigens can exacerbate autoimmune diseases. Upon TCR/MHC ligation, pathways induced by superantigens include the mitogen-activated protein kinase cascades and cytokine receptor signaling, resulting in activation of NFκB and the phosphoinositide 3-kinase/mammalian target of rapamycin pathways. Various mouse models exist to study SEB-induced shock including those with potentiating agents, transgenic mice and an “SEB-only” model. However, therapeutics to treat toxic shock remain elusive as host response genes central to pathogenesis of superantigens have only been identified recently. Gene profiling of a murine model for SEB-induced shock reveals novel molecules upregulated in multiple organs not previously associated with SEB-induced responses. The pivotal genes include intracellular DNA/RNA sensors, apoptosis/DNA damage-related molecules, immunoproteasome components, as well as antiviral and IFN-stimulated genes. The host-wide induction of these, and other, antimicrobial defense genes provide evidence that SEB elicits danger signals resulting in multi-organ damage and toxic shock. Ultimately, these discoveries might lead to novel therapeutics for various superantigen-based diseases.

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          Invasive methicillin-resistant Staphylococcus aureus infections in the United States.

          As the epidemiology of infections with methicillin-resistant Staphylococcus aureus (MRSA) changes, accurate information on the scope and magnitude of MRSA infections in the US population is needed. To describe the incidence and distribution of invasive MRSA disease in 9 US communities and to estimate the burden of invasive MRSA infections in the United States in 2005. Active, population-based surveillance for invasive MRSA in 9 sites participating in the Active Bacterial Core surveillance (ABCs)/Emerging Infections Program Network from July 2004 through December 2005. Reports of MRSA were investigated and classified as either health care-associated (either hospital-onset or community-onset) or community-associated (patients without established health care risk factors for MRSA). Incidence rates and estimated number of invasive MRSA infections and in-hospital deaths among patients with MRSA in the United States in 2005; interval estimates of incidence excluding 1 site that appeared to be an outlier with the highest incidence; molecular characterization of infecting strains. There were 8987 observed cases of invasive MRSA reported during the surveillance period. Most MRSA infections were health care-associated: 5250 (58.4%) were community-onset infections, 2389 (26.6%) were hospital-onset infections; 1234 (13.7%) were community-associated infections, and 114 (1.3%) could not be classified. In 2005, the standardized incidence rate of invasive MRSA was 31.8 per 100,000 (interval estimate, 24.4-35.2). Incidence rates were highest among persons 65 years and older (127.7 per 100,000; interval estimate, 92.6-156.9), blacks (66.5 per 100,000; interval estimate, 43.5-63.1), and males (37.5 per 100,000; interval estimate, 26.8-39.5). There were 1598 in-hospital deaths among patients with MRSA infection during the surveillance period. In 2005, the standardized mortality rate was 6.3 per 100,000 (interval estimate, 3.3-7.5). Molecular testing identified strains historically associated with community-associated disease outbreaks recovered from cultures in both hospital-onset and community-onset health care-associated infections in all surveillance areas. Invasive MRSA infection affects certain populations disproportionately. It is a major public health problem primarily related to health care but no longer confined to intensive care units, acute care hospitals, or any health care institution.
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            The IL-1 family: regulators of immunity.

            Over recent years it has become increasingly clear that innate immune responses can shape the adaptive immune response. Among the most potent molecules of the innate immune system are the interleukin-1 (IL-1) family members. These evolutionarily ancient cytokines are made by and act on innate immune cells to influence their survival and function. In addition, they act directly on lymphocytes to reinforce certain adaptive immune responses. This Review provides an overview of both the long-established and more recently characterized members of the IL-1 family. In addition to their effects on immune cells, their involvement in human disease and disease models is discussed.
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              Cell death.

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                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/240816
                URI : http://frontiersin.org/people/u/40838
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                02 February 2016
                2016
                : 7
                : 23
                Affiliations
                [1] 1Department of Immunology, Molecular Translational Sciences Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick , Frederick, MD, USA
                [2] 2Biology Department, Wilson College , Chambersburg, PA, USA
                Author notes

                Edited by: Katharina F. Kubatzky, University Hospital Heidelberg, Germany

                Reviewed by: Howard M. Johnson, University of Florida, USA; Klaus Heeg, University of Heidelberg, Germany

                *Correspondence: Teresa Krakauer, teresa.krakauer.civ@ 123456mail.mil ; Bradley G. Stiles, brad.stiles@ 123456wilson.edu

                Specialty section: This article was submitted to Microbial Immunology, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2016.00023
                4735405
                26870039
                85c5718d-ef2b-4bcb-a2f0-77e281da0aa8
                Copyright © 2016 Krakauer, Pradhan and Stiles.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 01 October 2015
                : 18 January 2016
                Page count
                Figures: 0, Tables: 2, Equations: 0, References: 182, Pages: 14, Words: 13061
                Categories
                Immunology
                Review

                Immunology
                seb,superantigens,toxic shock,damage response,therapy,animal models
                Immunology
                seb, superantigens, toxic shock, damage response, therapy, animal models

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