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Streptococcal Toxins: Role in Pathogenesis and Disease

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Streptococcal Toxins: Role in Pathogenesis and Disease Cellular Microbiology (2015) doi:10.1111/cmi.12531 Microreview Streptococcal toxins: role in pathogenesis and disease Timothy C. Barnett,1 Jason N. Cole,1,2 that play crucial roles in colonization, pathogenesis and Tania Rivera-Hernandez,1 Anna Henningham,1,2 dissemination. While there are examples of streptococcal James C. Paton,3 Victor Nizet2 and Mark J. Walker1* toxins that are represented across species boundaries, 1Australian Infectious Diseases Research Centre and many streptococcal toxins are species specific or even School of Chemistry and Molecular Biosciences, The limited to certain clonal lineages within an individual University of Queensland, St Lucia, Queensland, species. A number of these toxins have found utility as Australia. vaccine antigens or as novel therapeutics. In this review, 2Department of Pediatrics and Skaggs School of we divide our examination of streptococcal toxins into four Pharmacy and Pharmaceutical Sciences, University of groups: haemolysins, proteases, superantigens (SAgs) California San Diego, La Jolla, California, USA. and miscellaneous toxins. The best-studied individual 3Research Centre for Infectious Diseases, Department of examples from each class from across the genus Molecular and Cellular Biology, School of Biological Streptococcus are used to illustrate the function of these Sciences, University of Adelaide, Adelaide, South toxin molecules and their contribution to the disease Australia, Australia. process. Haemolysins Summary The complete lysis of red blood cells by streptococci, Group A Streptococcus (Streptococcus pyogenes), known as β-haemolysis, was first observed in 1895 and is group B Streptococcus (Streptococcus agalactiae) embodied by the characteristic zone of clearing surround- and Streptococcus pneumoniae (pneumococcus) ing bacterial colonies on the surface of blood agar medium are host-adapted bacterial pathogens among the (Ayers and Rupp, 1922; Molloy et al., 2011). This section leading infectious causes of human morbidity and summarizes our current understanding of streptococcal mortality. These microbes and related members of β-haemolysins/cytolysins (β-h/c) and their key role in the genus Streptococcus produce an array of pathogenesis (Table 1). toxins that act against human cells or tissues, resulting in impaired immune responses and Streptolysin S subversion of host physiological processes to The potent membrane-active haemolysin streptolysin S benefit the invading microorganism. This toxin (SLS) is secreted by 99% of all group A Streptococcus repertoire includes haemolysins, proteases, (GAS) isolates at stationary phase (Yoshino et al., 2010) superantigens and other agents that ultimately and is related to the class I bacteriocin family of enhance colonization and survival within the host proteinaceous toxins and antimicrobial peptides (Nizet and promote dissemination of the pathogen. et al., 2000; Cotter et al., 2005). SLS belongs to the thiazole/oxazole-modified microcin class of natural prod- ucts, a family of diverse ribosomally produced peptides that are post-translationally modified to contain thiazole Introduction and (methyl)oxazole heterocycles from cysteine, threo- The genus Streptococcus comprises several important nine and serine residues (Mitchell et al., 2009; Melby species of human and animal pathogens, most specifically et al., 2011). The activity of SLS is both temperature and adapted to survive within a single host species. As host- concentration dependent and is principally responsible for adapted pathogens, streptococcal species have evolved the characteristic zone of β-haemolysis surrounding GAS distinctive repertoires of protein and non-protein toxins colonies cultured on blood agar plates (Betschel et al., 1998; Nizet et al.,2000).SLSisencodedbythe chromosomal SLS-associated gene (sag) locus, a con- Received 29 June, 2015; revised 13 August, 2015; accepted 2 September, 2015. *For correspondence. E-mail mark.walker@uq. served nine-gene operon comprised of contiguous genes edu.au; Tel. (+61) 7 33461623; Fax (+61) 7 3365 4273. sagA to sagI (Nizet et al., 2000). The mature SLS is a © 2015 John Wiley & Sons Ltd cellular microbiology 2 T. C. Barnett et al. Table 1. Streptococcal haemolysins. Haemolysin Streptococcal species Virulence role References Streptolysin S family haemolysins Streptolysin S Streptococcus Lysis of erythrocytes, (Sierig et al., 2003; Miyoshi- pyogenes lymphocytes, neutrophils, Akiyama et al., 2005; Lin et al., platelets, sub-cellular organelles 2009) Streptococcus ND (Humar et al., 2002; dysgalactiae Hashikawa et al., 2004) ssp. equisimilis Streptococcus equi ND (Flanagan et al., 1998; ssp. equi Hashikawa et al., 2004) Streptococcus Lysis of erythrocytes, neutrophils, (Locke et al., 2007) iniae lymphocytes Streptococcus ND (Richards et al., 2012) canis Streptococcus ND (Tabata et al., 2013; anginosus ssp. Asam et al., 2015) anginosus Streptococcus ND (Tabata et al., 2014) constellatus ssp. constellatus Cholesterol-dependent cytolysins Streptolysin O S. pyogenes Disrupts cytoplasmic integrity of (Limbago et al., 2000; erythrocytes, leukocytes, Sierig et al., 2003; macrophages, platelets, epithelial cells Brosnahan et al., 2009; Timmer et al., 2009) Translocates NAD-glycohydrolase (Madden et al., 2001) (Streptococcus pyogenes NAD- glycohydrolase) toxin into epithelial cells S. canis ND (Richards et al., 2012) S. dysgalactiae ND (Tanaka et al., 2008) ssp. equisimilis Pneumolysin Streptococcus Contributes to proliferation in (Berry et al., 1989b; pneumoniae whole blood, and colonization of Kadioglu et al., 2000; the nasopharynx and lungs Reiss et al., 2011) Suilysin Streptococcus suis Cytotoxic to endothelial cells, (Allen et al., 2001; epithelial cells, macrophages and Lun et al., 2003) neutrophils β-Haemolysin/cytolysin Streptococcus Induces proinflammatory (Ring et al., 2002; agalactiae responses by human brain Doran et al., 2003; microvascular endothelial cells, Liu et al., 2004; neuronal and hepatocyte apoptosis, Reiss et al., 2011) promotes intrauterine colonization Intermedilysin Streptococcus Forms cytotoxic pores in CD59-positive (Sukeno et al., 2005) intermedius cells, promotes adherence to and invasion of human liver cells ND, not determined. ~2.7kDa oxygen-stable and broad-spectrum cytolytic lysing a broad spectrum of host cells including erythro- toxin that forms hydrophilic pores in cholesterol-containing cytes (red blood cells), lymphocytes, neutrophils, plate- cytoplasmic membranes to induce irreversible osmotic lets, sub-cellular organelles (e.g. lysosomes and lysis of host cells (Todd, 1938; Bernheimer, 1967; mitochondria) and several other mammalian cell types Ginsburg, 1999; Carr et al., 2001). The plasma membrane (Ofek et al., 1970; Betschel et al., 1998), but not bacteria damage caused by pore-forming toxins induces signalling with intact cell walls (Bernheimer, 1966). In a murine cascades in the host cell to promote membrane repair, model of cutaneous infection, GAS strains lacking SLS metal ion homeostasis and a low-energy state whereby activity were less virulent than the wild-type (WT) isogenic protein synthesis is arrested (Gonzalez et al., 2008, 2011). parental strain (Betschel et al., 1998; Mitchell et al., 2009). The sagA gene encodes pre-SLS, while the downstream Soft tissue damage in mice associated with bacterial genes are required for post-translational modifications, proliferation, inflammation, vascular injury and formation of heterocycle formation, processing and export of the necrotic lesions also depends on the activity of SLS in GAS, mature SLS exotoxin (Nizet et al., 2000; Nizet, 2002; group G Streptococcus (GGS) and Streptococcus iniae Molloy et al., 2011). SLS enhances GAS pathogenicity by (Betschel et al., 1998; Limbago et al., 2000; Fuller et al., © 2015 John Wiley & Sons Ltd, Cellular Microbiology Streptococcal toxins role in pathogenesis and disease 3 2002; Humar et al., 2002; Sierig et al., 2003). SLS may with GAS SLS (Fuller et al., 2002; Locke et al., 2007) and interact synergistically with other virulence factors (e.g. M lyses erythrocytes, neutrophils, lymphocytes and several protein and streptolysin O (SLO)) and host factors (e.g. tissue culture cell lines. Heterologous expression of the S. neutrophil proteases and reactive oxygen species) to induce iniae sagA gene in a non-haemolytic ΔsagA mutant of tissue necrosis and promote the development of necrotizing serotype M49 GAS restored haemolytic activity (Fuller fasciitis in humans (Humar et al., 2002). et al., 2002; Locke et al., 2007). S. iniae SLS promotes Recently, SLS and SLO have been shown to induce neither adherence and invasion of epithelial cells nor endoplasmic reticulum (ER) stress and an unfolded resistance to opsonophagocytosis (Locke et al., 2007). protein response (UPR) in host cells to reduce the surplus However, a SagA-deficient mutant is highly attenuated for of unfolded proteins. The activation of UPR plays a key virulence (Locke et al., 2007). role in cellular defences against bacterial pore-forming Intermedilysin toxins and is an important downstream target of the p38 mitogen-activated protein kinase pathway (Bischof et al., Streptococcus intermedius, Streptococcus constellatus 2008), a central pathway of cellular immunity. In a and Streptococcus anginosus are members of the mechanism that is yet to be fully understood, UPR results Anginosus group of streptococci (AGS) that colonize the in the transcriptional upregulation of asns,agene oral cavity, upper respiratory, gastrointestinal and female
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