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| '''An overview of Staphylococcus epidermidis and Staphylococcus aureus with a focus on developing countries-PMID: 26142662 '''
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| Staphylococcus aureus is a Gram-positive bacterium, and it is a major pathogen in humans and animals, causing a wide variety of illnesses ranging from skin and soft tissue infections to life-threatening invasive diseases. The pathogenesis of a particular S. aureus strain is attributed to the combined effect of
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| extracellular factors and toxins, together with the invasive properties of the strain such as adherence, biofilm formation, and resistance to phagocytosis. S. aureus has long been recognized as a virulent pathogen able to cause bacteremia strongly associated with higher mortality compared to other bacterial blood stream infections [3]. The habitats of Staphylococcus are the nasal membranes and skin of warm-blooded animals, and they may cause a wide range of infections, such as skin infections, food poisoning, pneumonia, sepsis, osteomyelitis, and infectious endocarditis
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| '''Staphylococcus aureus toxins--their functions and genetics-PMID: 23541411 '''
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| In contrast to conventional peptide antigens, SAgs activate a large fraction of T lymphocytes simultaneously. Conventional antigens are taken up by antigen-presenting cells (APCs) and processed by protease digestion. The resulting antigenic peptides are bound to major histocompatibility complex (MHC) molecules and displayed on the APC surface as MHC/peptide complexes. These are recognized by T-cells via the hypervariable loops of their T-cell receptor (TCR) α and β chains. SAgs can bypass this highly specific antigen-driven interaction between T-cells and APCs. They directly cross-link certain TCR Vβ domains with conserved structures on MHC class II (MHC II) molecules expressed on professional APCs. They interact with MHC II by binding to the α-chain (antigen peptide-dependent or independent) or to a conserved histidine in the β-domain via a zinc complex (peptide-dependent) (Fraser and Proft, 2008). Furthermore, each SAg interacts with a defined TCR repertoire determined by the TCR Vβ sequences. As the human genome encodes approximately 50 TCR Vβ elements, which are unevenly represented in the T-cell pool of an individual, up to 20% of T cells can be activated by a given SAg (Proft and Fraser, 2003). In contrast, conventional peptide antigens stimulate only 1 out of 105–106 naïve T-cells (Fraser et al., 2000). The Vβ-restricted T-cell expansion is thus the hallmark of SAgs (Choi et al., 1990; Kappler et al., 1989 ; White et al., 1989) with two exceptions: (i) the SAg SEH also contacts TCR Vα chains (Petersson et al., 2003 ; Thomas et al., 2009) and (ii) the staphylococcal protein A, which is universally expressed by S. aureus, acts as a B cell SAg targeting B-cell receptors (membrane-anchored antibodies) which use the immunoglobulin-VH3 gene element (Silverman and Goodyear, 2006). In addition, many T-cell SAgs also trigger cytokine release by the APCs, which are activated via MHC-II engagement (Proft and Fraser, 2003).
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| *4.1. Role of SAgs in staphylococcal virulence
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| SAgs have been implicated in a broad range of diseases. SEs are the causative agents of staphylococcal food poisoning resulting from ingestion of contaminated food. Due to their extraordinary stability in denaturing conditions, such as heat and low pH, SEs are not completely destroyed by mild cooking or digestion of food in the stomach. Nausea, emesis, abdominal pain or cramping and diarrhea ensue after a short incubation time. The disease is usually self-limiting (Thomas et al., 2007).
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| Staphylococcal toxic shock syndrome (TSS) is characterized by high fever, rash, desquamation, vomiting, diarrhea and hypotension, frequently resulting in multiple organ failure. In TSS, S. aureus is usually localized, either at mucosal sites (vagina or nasophryx) or in abscesses ( Fraser and Proft, 2008), but the released SAgs act systemically, triggering large numbers of T-cells to produce massive amounts of pro-inflammatory cytokines, such as IL-2, IFN-γ and TNF. This cytokine storm causes the symptoms ( Bergdoll et al., 1981 ; McCormick et al., 2001). This is followed by a state of profound T-cell unresponsiveness or anergy, where the T-cells fail to proliferate or secrete IL-2 (Rellahan et al., 1990), or they even undergo cell death (Alderson et al., 1995). It has, therefore, been proposed that SAgs might confer an evolutionary advantage to S. aureus by deleting T-cells that help B-cells to mount an effective antibody response against the bacteria ( Fraser et al., 2000). This view has been challenged by the observation that SAgs themselves are potent immunogens eliciting an effective and highly specific neutralizing antibody response ( Grumann et al., 2011 ; Holtfreter et al., 2006).
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| The role of SAgs in other forms of sepsis is less well defined. In animal models, SAgs and LPS, a major component of the outer membrane of Gram-negative bacteria and highly potent stimulator of the innate immune system, most effectively synergize in the induction of lethal shock (Blank et al., 1997 ; Schlievert, 1982). This observation prompted the development of the two-hit model of septic shock (Bannan et al., 1999), which was later generalized by Holtfreter and Bröker: A first hit by SAgs or other potent T cell stimuli is potentiated by a second hit by pathogen-associated molecular patterns (PAMPs), which activate the innate immune system. This sequence of events culminates in a dramatic, often lethal activation of the whole immune system (Holtfreter and Bröker, 2005). The sequence of events varies in the different accounts.
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| Kawasaki disease is an acute febrile disease in children that resembles TSS. A role for SAgs has been suggested (Yarwood et al., 2000). Intravenous immunoglobulin therapy is highly effective when given early, suggesting that the agent is a toxin that is neutralized by anti-toxin antibodies contained in pooled human serum.
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| Finally, a prominent role for SAgs is being discussed in skin and airway allergies. For atopic dermatitis, a correlation between clinical severity and colonization with SEA- and SEB-producing S. aureus as well as with IgE specific for SEA and SEB was documented in one study, but not confirmed in others ( Bunikowski et al., 1999 ; Zollner et al., 2000). Bronchial asthma afflicts around 300 million people worldwide, thus belonging to the most common diseases. In allergic asthma, the triggers are known inhalative allergens (=allergy-driving antigens), while the causative agents of non-allergic or intrinsic asthma, around 10% of cases, are not known. Intrinsic asthma is often of late onset (3rd–4th decade of life) and takes a severe disease course, which is refractory to established treatment strategies. Chronic rhinosinusitis, a pronounced inflammation of the mucosal tissue of the nose and sinuses, with or without the development of polyps, is also very frequent and often accompanied by intrinsic asthma. Since many patients possess high titres of SAg-specific IgE in their serum or locally in the polyps, several research groups promote the opinion that allergic reactions to S. aureus SAgs drive or at least amplify chronic airway inflammation ( Bachert et al., 2010; Bachert et al., 2008; Barnes, 2009; Gevaert et al., 2005 ; Zhang et al., 2011).
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| 5. The evolution of the S. aureus toxin gene families
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| Toxin gene clustering and sequence homologies imply evolution from ancestral genes by gene duplication and variation. These features are prominent in the families of leukotoxins, ETs, and SAgs. The enterotoxin gene cluster (egc), discovered on a staphylococcal genomic island (νSaβ) by the group of Jarraud, is given here as an example ( Jarraud et al., 2001 ; Letertre et al., 2003). Egc SAgs are the most prevalent SAg genes in commensal and invasive S. aureus isolates, with frequencies ranging between 46% and 66% in different strain collections ( Becker et al., 2004; Fueyo et al., 2005; Holtfreter et al., 2007 ; Monecke et al., 2009). Most egc-positive S. aureus strains harbor five SAg genes (seg, sei, selm, seln, and selo) and the pseudogenes ψent1 and ψent2 ( Jarraud et al., 2001). The egc is unusually variable. The S. aureus clonal cluster CC30, for example, harbors an additional SAg gene, designated selu, a fusion product of ψent1 and ψent2 ( Holtfreter et al., 2007; Letertre et al., 2003 ; Thomas et al., 2006). Given that the members of the egc display considerable sequence differences and each of the egc SAgs shows closest similarity to SAgs encoded outside the egc, Jarraud et al. proposed that the egc functions as an “enterotoxin gene nursery” ( Jarraud et al., 2001).
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