化膿性鏈球菌是一種會導致多種疾病的人類致病菌。化膿性鏈球菌的許多分泌性毒力因子會與宿主組織有直接的交互作用進而產生疾病。然而，化膿性鏈球菌如何去調控自己的分泌性蛋白質體去應對各種不同的感染環境目前仍然研究不夠清楚。本論文提出膠體以及非膠體定量蛋白質體分析法去鑑定以及定量化膿性鏈球菌新的分泌性毒力因子。在膠體定量蛋白質體分析的研究中，我們針對一個調控過氧化抵抗以及致病性有關的重要調控因子PerR去進行研究。但是，目前對於PerR調控分泌性蛋白體來影響毒力卻是知道的不多。因此，我們比較了perR基因缺陷突變株以及野生株的分泌性蛋白體來探討PerR如何調控化膿性鏈球菌分泌性蛋白體的表現來影響毒力。我們收集野生株以及perR基因缺陷突變株含有分泌蛋白質的培養液提供二維電泳分析使用。表現量有差異的蛋白質點則會利用液相層析電噴灑離子化串聯式質譜分析去做蛋白質身分鑑定。經過進一步的功能性分析，我們找到一個新的PerR調控的胞外毒力因子MF3。
在非膠體定量蛋白質體研究中，我們主要探討環境酸化對於化膿性鏈球菌分泌性蛋白質體的影響。為了瞭解在酸性環境下各種時期分泌性蛋白質體的變化，我們利用非標記液相層析串聯式質譜分析的比較性分泌性蛋白質體方法去分析酸性及中性環境下的分泌性蛋白體。非標記液相層析串聯式質譜分析一共鑑定到45個被預測的分泌蛋白質，這些蛋白質都受到環境酸化的影響。Mga以及RofA/Nra也發現對於環境酸化以及生長時期會有所反應。除此之外，我們第一次提出證據指出酸性刺激以及生長時期對於化膿性鏈球菌的典型蛋白質分泌是很重要的。蛋白質交互作用的數據則指出在酸性刺激會影響營養源的取得、蛋白質合成以及纖毛的生成。有21個致病相關的分泌蛋白質會影響免疫逃脫、溶血、組織破壞以及營養取得。在這個研究中，我們也證明了一個酸性誘發表現的分泌蛋白質是一個新的毒力因子並且會影響侵入性以及免疫逃脫。相信這個研究能提供重要的資訊去描繪出對於化膿性鏈球菌在酸性環境下侵入行為的廣泛影響以及機制。
在這個論文中，我發展出兩種不同的分泌性蛋白體的分析策略，用來找尋新的化膿性鏈球菌毒力因子。這對於找尋新的以及重要的毒力因子是很有效率的，也有助於去了解新的致病機制。此外，論文中的蛋白質體數據也可能有助於發展化學性治療策略去預防或是根治化膿性鏈球菌的疾病。

Streptococcus pyogenes is an important human pathogen. Numerous virulence factors secreted by S. pyogenes interact directly a with host tissue to cause various diseases. However, how S. pyogenes manipulate its secretome in response to different infected environments remains unclear. Herein, we proposed gel-based and gel-free quantitative proteomic analyses for identification and quantification of S. pyogenes novel secreted virulence factors. In the gel-based quantitative proteomic study, we focus on an important peroxide regulator (PerR) which is associated with the peroxide resistance response and pathogenesis. But, it is little known about its regulation of the secretome involved in virulence. To investigate how PerR regulates the expression of the S. pyogenes secretome involved in virulence, a perR deficient mutant was used for comparative secretomics analysis with a wild-type strain. The conditioned medium (CM) containing secreted proteins of a wild-type strain and a perR deficient mutant at the stationary phase were collected for 2DGE analysis. Differentially-expressed protein spots were identified by LC-ESI-MS/MS. After further functional analyses, we found a novel PerR-regulated extracellular virulence factor mitogen factor3 (MF3). In gel-free proteomic study, we investigated the influence of environmental acidification on S. pyogenes secretome. To investigate temporal secretome changes under acidic environment, a comparative secretomics approach using label-free LC-MS/MS was undertaken to analyze the secretome in acidic and neutral conditions. The dynamic label-free LC-MS/MS profiling identified 45 predicted secreted proteins, which are influenced by environmental acidification. Mga and RofA/Nra were found that can respond to environmental acidification and growth-phase cues. In addition, we provided the first evidence that acidic stimuli and growth-phase cues are crucial for classical protein secretion in S. pyogenes. The protein-protein interaction data indicate that acid stimuli influence nutrient uptake, protein synthesis, and pilus formation. There are 21 pathogenesis-related secreted proteins influencing immune evasion, hemolysis, adhesion, tissue damage, and nutrient acquisition. In this study, we demonstrated that an acid-induced secreted protein is a novel virulence factor and is involved in invasion and immune evasion. We believe that our investigation provides vital information for documenting the broad influences and mechanisms underlying the invasive behavior of group A streptococci in an acidified environment.
In this dissertation, I developed two different secretomic analytical approaches to discover novel virulence factors in S. pyogenes. It is efficient to find novel and important virulence factors for realizing the other new mechanisms of pathogenesis. Besides, these proteomic data might lead to the development of chemotherapeutic strategies to prevent or treat severe streptococcal diseases.

Agaisse H, Gominet M, Okstad OA, Kolsto AB, Lereclus D. 1999. PlcR is a pleiotropic regulator of extracellular virulence factor gene expression in Bacillus thuringiensis. Mol Microbiol 32:1043-1053.
Allhorn M, Briceno JG, Baudino L, Lood C, Olsson ML, Izui S, et al. 2010. The IGG-specific endoglycosidase EndoS inhibits both cellular and complement-mediated autoimmune hemolysis. Blood 115:5080-5088.
Aryal UK, Stockel J, Krovvidi RK, Gritsenko MA, Monroe ME, Moore RJ, et al. 2011. Dynamic proteomic profiling of a unicellular cyanobacterium Cyanothece ATCC51142 across light-dark diurnal cycles. BMC Syst Biol 5:194.
Backert S, Gressmann H, Kwok T, Zimny-Arndt U, Konig W, Jungblut PR, et al. 2005. Gene expression and protein profiling of AGS gastric epithelial cells upon infection with Helicobacter pylori. Proteomics 5:3902-3918.
Banks DJ, Porcella SF, Barbian KD, Beres SB, Philips LE, Voyich JM, et al. 2004. Progress toward characterization of the group A streptococcus metagenome: Complete genome sequence of a macrolide-resistant serotype M6 strain. J Infect Dis 190:727-738.
Becher D, Hempel K, Sievers S, Zuhlke D, Pane-Farre J, Otto A, et al. 2009. A proteomic view of an important human pathogen--towards the quantification of the entire Staphylococcus aureus proteome. PLoS One 4:e8176.
Berends ET, Horswill AR, Haste NM, Monestier M, Nizet V, von Kockritz-Blickwede M. 2010. Nuclease expression by Staphylococcus aureus facilitates escape from neutrophil extracellular traps. J Innate Immun 2:576-586.
Beres SB, Sylva GL, Barbian KD, Lei B, Hoff JS, Mammarella ND, et al. 2002. Genome sequence of a serotype M3 strain of group A streptococcus: Phage-encoded toxins, the high-virulence phenotype, and clone emergence. Proc Natl Acad Sci U S A 99:10078-10083.
Beres SB, Richter EW, Nagiec MJ, Sumby P, Porcella SF, DeLeo FR, et al. 2006. Molecular genetic anatomy of inter- and intraserotype variation in the human bacterial pathogen group A streptococcus. Proc Natl Acad Sci U S A 103:7059-7064.
Bessen DE, Manoharan A, Luo F, Wertz JE, Robinson DA. 2005. Evolution of transcription regulatory genes is linked to niche specialization in the bacterial pathogen Streptococcus pyogenes. J Bacteriol 187:4163-4172.
Brenot A, King KY, Caparon MG. 2005. The PerR regulon in peroxide resistance and virulence of Streptococcus pyogenes. Mol Microbiol 55:221-234.
Buchanan JT, Simpson AJ, Aziz RK, Liu GY, Kristian SA, Kotb M, et al. 2006. Dnase expression allows the pathogen group A streptococcus to escape killing in neutrophil extracellular traps. Curr Biol 16:396-400.
Buttner K, Bernhardt J, Scharf C, Schmid R, Mader U, Eymann C, et al. 2001. A comprehensive two-dimensional map of cytosolic proteins of Bacillus subtilis. Electrophoresis 22:2908-2935.
Caparon MG, Geist RT, Perez-Casal J, Scott JR. 1992. Environmental regulation of virulence in group A streptococci: transcription of the gene encoding M protein is stimulated by carbon dioxide. J Bacteriol 174:5693-5701.
Chaussee MS, Liu J, Stevens DL, Ferretti JJ. 1996. Genetic and phenotypic diversity among isolates of Streptococcus pyogenes from invasive infections. J Infect Dis 173:901-908.
Chaussee MS, Watson RO, Smoot JC, Musser JM. 2001. Identification of Rgg-regulated exoproteins of Streptococcus pyogenes. Infect Immun 69:822-831.
Chiang-Ni C, Zheng PX, Tsai PJ, Chuang WJ, Lin YS, Liu CC, et al. 2012. Environmental pH changes, but not the LuxS signalling pathway, regulate SpeB expression in M1 group A streptococci. J Med Microbiol 61:16-22.
Chiu KH, Chang YH, Wu YS, Lee SH, Liao PC. 2011. Quantitative secretome analysis reveals that COL6A1 is a metastasis-associated protein using stacking gel-aided purification combined with iTRAQ labeling. J Proteome Res 10:1110-1125.
Cole JN, McArthur JD, McKay FC, Sanderson-Smith ML, Cork AJ, Ranson M, et al. 2006. Trigger for group A streptococcal M1T1 invasive disease. FASEB J 20:1745-1747.
Cole JN, Barnett TC, Nizet V, Walker MJ. 2011. Molecular insight into invasive group A streptococcal disease. Nat Rev Microbiol 9:724-736.
Cox J, Mann M. 2008. Maxquant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat biotechnol 26:1367-1372.
Cunningham MW. 2000. Pathogenesis of group A streptococcal infections. Clin Microbiol Rev 13:470-511.
Dalton TL, Scott JR. 2004. CovS inactivates CovR and is required for growth under conditions of general stress in Streptococcus pyogenes. J Bacteriol 186:3928-3937.
Darenberg J, Luca-Harari B, Jasir A, Sandgren A, Pettersson H, Schalen C, et al. 2007. Molecular and clinical characteristics of invasive group A streptococcal infection in Sweden. Clin Infect Dis 45:450-458.
Domon B, Aebersold R. 2006. Mass spectrometry and protein analysis. Science (New York, NY) 312:212-217.
Dong YM, Pearce EI, Yue L, Larsen MJ, Gao XJ, Wang JD. 1999. Plaque pH and associated parameters in relation to caries. Caries Res 33:428-436.
Egesten A, Eliasson M, Johansson HM, Olin AI, Morgelin M, Mueller A, et al. 2007. The CXC chemokine MIG/CXCL9 is important in innate immunity against Streptococcus pyogenes. J Infect Dis 195:684-693.
Ehlers C, Ivens UI, Moller ML, Senderovitz T, Serup J. 2001. Females have lower skin surface pH than men. A study on the surface of gender, forearm site variation, right/left difference and time of the day on the skin surface pH. Skin Res Technol 7:90-94.
Federle MJ, McIver KS, Scott JR. 1999. A response regulator that represses transcription of several virulence operons in the group A streptococcus. J Bacteriol 181:3649-3657.
Ferretti JJ, McShan WM, Ajdic D, Savic DJ, Savic G, Lyon K, et al. 2001. Complete genome sequence of an M1 strain of Streptococcus pyogenes. Proc Natl Acad Sci U S A 98:4658-4663.
Fogg GC, Caparon MG. 1997. Constitutive expression of fibronectin binding in Streptococcus pyogenes as a result of anaerobic activation of rofA. J Bacteriol 179:6172-6180.
Folio P, Chavant P, Chafsey I, Belkorchia A, Chambon C, Hebraud M. 2004. Two-dimensional electrophoresis database of Listeria monocytogenes EGDe proteome and proteomic analysis of mid-log and stationary growth phase cells. Proteomics 4:3187-3201.
Froehlich BJ, Bates C, Scott JR. 2009. Streptococcus pyogenes CovrS mediates growth in iron starvation and in the presence of the human cationic antimicrobial peptide ll-37. J Bacteriol 191:673-677.
Gase K, Ferretti JJ, Primeaux C, McShan WM. 1999. Identification, cloning, and expression of the CAMP factor gene (cfa) of group A streptococci. Infect Immun 67:4725-4731.
Gautier V, Mouton-Barbosa E, Bouyssie D, Delcourt N, Beau M, Girard JP, et al. 2012. Label-free quantification and shotgun analysis of complex proteomes by one-dimensional SDS-PAGE/nanoLC-MS: evaluation for the large scale analysis of inflammatory human endothelial cells. Mol Cell Proteomics 11:527-539.
Gerber SA, Rush J, Stemman O, Kirschner MW, Gygi SP. 2003. Absolute quantification of proteins and phosphoproteins from cell lysates by tandem MS. Proc Natl Acad Sci U S A 100:6940-6945.
Gibson CM, Mallett TC, Claiborne A, Caparon MG. 2000. Contribution of NADH oxidase to aerobic metabolism of Streptococcus pyogenes. J Bacteriol 182:448-455.
Gingras AC, Gstaiger M, Raught B, Aebersold R. 2007. Analysis of protein complexes using mass spectrometry. Nat Rev Mol Cell Biol 8:645-654.
Graham MR, Smoot LM, Migliaccio CA, Virtaneva K, Sturdevant DE, Porcella SF, et al. 2002. Virulence control in group A streptococcus by a two-component gene regulatory system: Global expression profiling and in vivo infection modeling. Proc Natl Acad Sci U S A 99:13855-13860.
Green NM, Zhang S, Porcella SF, Nagiec MJ, Barbian KD, Beres SB, et al. 2005. Genome sequence of a serotype M28 strain of group A streptococcus: potential new insights into puerperal sepsis and bacterial disease specificity. J Infect Dis 192:760-770.
Gryllos I, Grifantini R, Colaprico A, Cary ME, Hakansson A, Carey DW, et al. 2008. PerR confers phagocytic killing resistance and allows pharyngeal colonization by group A streptococcus. PLoS Pathog 4:e1000145.
Hasegawa T, Torii K, Hashikawa S, Iinuma Y, Ohta M. 2002. Cloning and characterization of two novel DNases from Streptococcus pyogenes. Arch Microbiol 177:451-456.
Hoe NP, Ireland RM, DeLeo FR, Gowen BB, Dorward DW, Voyich JM, et al. 2002. Insight into the molecular basis of pathogen abundance: group A streptococcus inhibitor of complement inhibits bacterial adherence and internalization into human cells. Proc Natl Acad Sci U S A 99:7646-7651.
Holden MT, Scott A, Cherevach I, Chillingworth T, Churcher C, Cronin A, et al. 2007. Complete genome of acute rheumatic fever-associated serotype M5 Streptococcus pyogenes strain manfredo. J Bacteriol 189:1473-1477.
Hollands A, Aziz RK, Kansal R, Kotb M, Nizet V, Walker MJ. 2008. A naturally occurring mutation in ropB suppresses SpeB expression and reduces M1T1 group A streptococcal systemic virulence. PLoS One 3:e4102.
Hondorp ER, McIver KS. 2007. The Mga virulence regulon: infection where the grass is greener. Mol Microbiol 66:1056-1065.
Horstmann RD, Sievertsen HJ, Leippe M, Fischetti VA. 1992. Role of fibrinogen in complement inhibition by streptococcal M protein. Infect Immun 60:5036-5041.
Ji Y, McLandsborough L, Kondagunta A, Cleary PP. 1996. C5a peptidase alters clearance and trafficking of group A streptococci by infected mice. Infect Immun 64:503-510.
Johansson BP, Levander F, von Pawel-Rammingen U, Berggard T, Bjorck L, James P. 2005. The protein expression of Streptococcus pyogenes is significantly influenced by human plasma. J Proteome Res 4:2302-2311.
Kappeler KV, Anbalagan S, Dmitriev AV, McDowell EJ, Neely MN, Chaussee MS. 2009. A naturally occurring Rgg variant in serotype M3 Streptococcus pyogenes does not activate speB expression due to altered specificity of DNA binding. Infect Immun 77:5411-5417.
Kazmi SU, Kansal R, Aziz RK, Hooshdaran M, Norrby-Teglund A, Low DE, et al. 2001. Reciprocal, temporal expression of SpeA and SpeB by invasive M1T1 group A streptococcal isolates in vivo. Infect Immun 69:4988-4995.
Kreikemeyer B, McIver KS, Podbielski A. 2003. Virulence factor regulation and regulatory networks in Streptococcus pyogenes and their impact on pathogen-host interactions. Trends Microbiol 11:224-232.
Kruger M, Moser M, Ussar S, Thievessen I, Luber CA, Forner F, et al. 2008. SILAC mouse for quantitative proteomics uncovers Kindlin-3 as an essential factor for red blood cell function. Cell 134:353-364.
Kunitomo E, Terao Y, Okamoto S, Rikimaru T, Hamada S, Kawabata S. 2008. Molecular and biological characterization of histidine triad protein in group A streptococci. Microbes Infect 10:414-423.
Kuo CF, Wu JJ, Lin KY, Tsai PJ, Lee SC, Jin YT, et al. 1998. Role of streptococcal pyrogenic exotoxin B in the mouse model of group A streptococcal infection. Infect Immun 66:3931-3935.
Lancefield RC. 1933. A serological differentiation of human and other groups of hemolytic streptococci. J Exp Med 57:571-595.
Lefebure T, Stanhope MJ. 2007. Evolution of the core and pan-genome of streptococcus: positive selection, recombination, and genome composition. Genome Bio 8:R71.
Li J, Zhu H, Feng W, Liu M, Song Y, Zhang X, et al. 2013. Regulation of inhibition of neutrophil infiltration by the two-component regulatory system CovRS in subcutaneous murine infection with group A streptococcus. Infect Immun 81:974-983.
Liu M, Zhu H, Li J, Garcia CC, Feng W, Kirpotina LN, et al. 2012. Group A streptococcus secreted esterase hydrolyzes platelet-activating factor to impede neutrophil recruitment and facilitate innate immune evasion. PLoS Pathog 8:e1002624.
Loughman JA, Caparon M. 2006. Regulation of SpeB in Streptococcus pyogenes by pH and NaCl: a model for in vivo gene expression. J Bacteriol 188:399-408.
Luber CA, Cox J, Lauterbach H, Fancke B, Selbach M, Tschopp J, et al. 2010. Quantitative proteomics reveals subset-specific viral recognition in dendritic cells. Immunity 32:279-289.
Malmstrom J, Beck M, Schmidt A, Lange V, Deutsch EW, Aebersold R. 2009. Proteome-wide cellular protein concentrations of the human pathogen Leptospira interrogans. Nature 460:762-765.
Manetti AG, Koller T, Becherelli M, Buccato S, Kreikemeyer B, Podbielski A, et al. 2010. Environmental acidification drives S. pyogenes pilus expression and microcolony formation on epithelial cells in a FCT-dependent manner. PLoS One 5:e13864.
Mariappan V, Vellasamy KM, Thimma JS, Hashim OH, Vadivelu J. 2010. Identification of immunogenic proteins from Burkholderia cepacia secretome using proteomic analysis. Vaccine 28:1318-1324.
McIver KS, Heath AS, Green BD, Scott JR. 1995a. Specific binding of the activator Mga to promoter sequences of the emm and scpA genes in the group A streptococcus. J Bacteriol 177:6619-6624.
McIver KS, Heath AS, Scott JR. 1995b. Regulation of virulence by environmental signals in group A streptococci: influence of osmolarity, temperature, gas exchange, and iron limitation on emm transcription. Infect Immun 63:4540-4542.
McIver KS, Scott JR. 1997. Role of mga in growth phase regulation of virulence genes of the group A streptococcus. J Bacteriol 179:5178-5187.
Mehta S, McGeer A, Low DE, Hallett D, Bowman DJ, Grossman SL, et al. 2006. Morbidity and mortality of patients with invasive group A streptococcal infections admitted to the ICU. Chest 130:1679-1686.
Minodier P, Bidet P, Rallu F, Tapiero B, Bingen E, Ovetchkine P. 2009. Clinical and microbiologic characteristics of group A streptococcal necrotizing fasciitis in children. Pediatr Infect Dis J 28:541-543.
Moscoso M, Garcia E, Lopez R. 2006. Biofilm formation by Streptococcus pneumoniae: role of choline, extracellular DNA, and capsular polysaccharide in microbial accretion. J Bacteriol 188:7785-7795.
Mueller LN, Rinner O, Schmidt A, Letarte S, Bodenmiller B, Brusniak MY, et al. 2007. SuperHirn - a novel tool for high resolution LC-MS-based peptide/protein profiling. Proteomics 7:3470-3480.
Mulcahy H, Charron-Mazenod L, Lewenza S. 2010. Pseudomonas aeruginosa produces an extracellular deoxyribonuclease that is required for utilization of DNA as a nutrient source. Environ Microbiol 12:1621-1629.
Musser JM, Hauser AR, Kim MH, Schlievert PM, Nelson K, Selander RK. 1991. Streptococcus pyogenes causing toxic-shock-like syndrome and other invasive diseases: clonal diversity and pyrogenic exotoxin expression. Proc Natl Acad Sci U S A 88:2668-2672.
Musser JM, DeLeo FR. 2005. Toward a genome-wide systems biology analysis of host-pathogen interactions in group A streptococcus. Am J Pathol 167:1461-1472.
Musser JM, Shelburne SA, 3rd. 2009. A decade of molecular pathogenomic analysis of group A streptococcus. J Clin Invest 119:2455-2463.
Nakagawa I, Kurokawa K, Yamashita A, Nakata M, Tomiyasu Y, Okahashi N, et al. 2003. Genome sequence of an M3 strain of Streptococcus pyogenes reveals a large-scale genomic rearrangement in invasive strains and new insights into phage evolution. Genome Res 13:1042-1055.
Nakamura T, Hasegawa T, Torii K, Hasegawa Y, Shimokata K, Ohta M. 2004. Two-dimensional gel electrophoresis analysis of the abundance of virulent exoproteins of group A streptococcus caused by environmental changes. Arch Microbiol 181:74-81.
Nakano K, Fujita K, Nishimura K, Nomura R, Ooshima T. 2005. Contribution of biofilm regulatory protein A of Streptococcus mutans, to systemic virulence. Microbes Infect 7:1246-1255.
Neuner JM, Hamel MB, Phillips RS, Bona K, Aronson MD. 2003. Diagnosis and management of adults with pharyngitis. A cost-effectiveness analysis. Ann Intern Med 139:113-122.
O'Brien KL, Beall B, Barrett NL, Cieslak PR, Reingold A, Farley MM, et al. 2002. Epidemiology of invasive group A streptococcus disease in the United States, 1995-1999. Clin Infect Dis 35:268-276.
Ogunniyi AD, Grabowicz M, Mahdi LK, Cook J, Gordon DL, Sadlon TA, et al. 2009. Pneumococcal histidine triad proteins are regulated by the Zn2+-dependent repressor AdcR and inhibit complement deposition through the recruitment of complement factor H. FASEB J 23:731-738.
Olsen RJ, Musser JM. 2010. Molecular pathogenesis of necrotizing fasciitis. Annu Rev Pathol 5:1-31.
Pancholi V, Boel G, Jin H. 2010. Streptococcus pyogenes Ser/Thr kinase-regulated cell wall hydrolase is a cell division plane-recognizing and chain-forming virulence factor. J Biol Chem 285:30861-30874.
Peant B, LaPointe G. 2004. Identification and characterization of a conserved nuclease secreted by strains of the Lactobacillus casei group. J Appl Microbiol. 96:367-374.
Podbielski A, Leonard BA. 1998. The group A streptococcal dipeptide permease (Dpp) is involved in the uptake of essential amino acids and affects the expression of cysteine protease. Mol Microbiol 28:1323-1334.
Podbielski A, Woischnik M, Leonard BA, Schmidt KH. 1999. Characterization of nra, a global negative regulator gene in group A streptococci. Mol Microbiol 31:1051-1064.
Proft T, Sriskandan S, Yang L, Fraser JD. 2003. Superantigens and streptococcal toxic shock syndrome. Emerg Infect Dis 9:1211-1218.
Ricci S, Janulczyk R, Bjorck L. 2002. The regulator PerR is involved in oxidative stress response and iron homeostasis and is necessary for full virulence of Streptococcus pyogenes. Infect Immun 70:4968-4976.
Rippke F, Schreiner V, Schwanitz HJ. 2002. The acidic milieu of the horny layer: new findings on the physiology and pathophysiology of skin pH. Am J Clin Dermatol 3:261-272.
Ross PL, Huang YN, Marchese JN, Williamson B, Parker K, Hattan S, et al. 2004. Multiplexed protein quantitation in Saccharomyces cerevisiae using amine-reactive isobaric tagging reagents. Mol Cell Proteomics 3:1154-1169.
Ryan KR, Shapiro L. 2003. Temporal and spatial regulation in prokaryotic cell cycle progression and development. Annu Rev Biochem 72:367-394.
Scott J, Thompson-Mayberry P, Lahmamsi S, King CJ, McShan WM. 2008. Phage-associated mutator phenotype in group A streptococcus. J Bacteriol 190:6290-6301.
Sharkawy A, Low DE, Saginur R, Gregson D, Schwartz B, Jessamine P, et al. 2002. Severe group A streptococcal soft-tissue infections in Ontario: 1992-1996. Clin Infect Dis 34:454-460.
Shelburne SA 3rd, Sumby P, Sitkiewicz I, Okorafor N, Granville C, Patel P, et al. 2006. Maltodextrin utilization plays a key role in the ability of group A streptococcus to colonize the oropharynx. Infect Immun 74:4605-4614.
Shelburne SA 3rd, Keith D, Horstmann N, Sumby P, Davenport MT, Graviss EA, et al. 2008. A direct link between carbohydrate utilization and virulence in the major human pathogen group A streptococcus. Proc Natl Acad Sci U S A 105:1698-1703.
Simmen HP, Battaglia H, Giovanoli P, Hanseler E, Blaser J. 1995a. Biochemical analysis of peritoneal fluid in patients with and without bacterial infection. Eur J Surg 161:23-27.
Simmen HP, Giovanoli P, Battaglia H, Wust J, Meyer VE. 1995b. Soft tissue infections of the upper extremities with special consideration of abscesses in parenteral drug abusers. A prospective study. J Hand Surg 20:797-800.
Smoot JC, Barbian KD, Van Gompel JJ, Smoot LM, Chaussee MS, Sylva GL, et al. 2002. Genome sequence and comparative microarray analysis of serotype M18 group A streptococcus strains associated with acute rheumatic fever outbreaks. Proc Natl Acad Sci U S A 99:4668-4673.
Smoot LM, Smoot JC, Graham MR, Somerville GA, Sturdevant DE, Migliaccio CA, et al. 2001. Global differential gene expression in response to growth temperature alteration in group A streptococcus. Proc Natl Acad Sci U S A 98:10416-10421.
Steer AC, Lamagni T, Curtis N, Carapetis JR. 2012. Invasive group A streptococcal disease: epidemiology, pathogenesis and management. Drugs 72:1213-1227.
Steiner K, Malke H. 2000. Life in protein-rich environments: the relA-Independent response of Streptococcus pyogenes to amino acid starvation. Mol Microbiol 38:1004-1016.
Steiner K, Malke H. 2001. relA-independent amino acid starvation response network of Streptococcus pyogenes. J Bacteriol 183:7354-7364.
Stemmann O, Zou H, Gerber SA, Gygi SP, Kirschner MW. 2001. Dual inhibition of sister chromatid separation at metaphase. Cell 107:715-726.
Stevens DL. 2000. Streptococcal toxic shock syndrome associated with necrotizing fasciitis. Annu Rev Med 51:271-288.
Sumby P, Barbian KD, Gardner DJ, Whitney AR, Welty DM, Long RD, et al. 2005. Extracellular deoxyribonuclease made by group A streptococcus assists pathogenesis by enhancing evasion of the innate immune response. Proc Natl Acad Sci U S A 102:1679-1684.
Szklarczyk D, Franceschini A, Kuhn M, Simonovic M, Roth A, Minguez P, et al. 2011. The STRING database in 2011: functional interaction networks of proteins, globally integrated and scored. Nucleic Acids Res 39:D561-568.
Tanaka M, Hasegawa T, Okamoto A, Torii K, Ohta M. 2005. Effect of antibiotics on group A streptococcus exoprotein production analyzed by two-dimensional gel electrophoresis. Antimicrob Agents Chemother 49:88-96.
Tart AH, Walker MJ, Musser JM. 2007. New understanding of the group A streptococcus pathogenesis cycle. Trends Microbiol 15:318-325.
Thulin P, Johansson L, Low DE, Gan BS, Kotb M, McGeer A, et al. 2006. Viable group A streptococci in macrophages during acute soft tissue infection. PLoS Med 3:e53.
Trost M, Wehmhoner D, Karst U, Dieterich G, Wehland J, Jansch L. 2005. Comparative proteome analysis of secretory proteins from pathogenic and nonpathogenic Listeria species. Proteomics 5:1544-1557.
Tsou CC, Chiang-Ni C, Lin YS, Chuang WJ, Lin MT, Liu CC, et al. 2010. Oxidative stress and metal ions regulate a ferritin-like gene, dpr, in Streptococcus pyogenes. Int J Med Microbiol : IJMM 300:259-264.
VanBogelen RA, Neidhardt FC. 1990. Ribosomes as sensors of heat and cold shock in Escherichia coli. Proc Natl Acad Sci U S A 87:5589-5593.
Walker MJ, Hollands A, Sanderson-Smith ML, Cole JN, Kirk JK, Henningham A, et al. 2007. Dnase Sda1 provides selection pressure for a switch to invasive group A streptococcal infection. Nat Med 13:981-985.
Washburn MP, Wolters D, Yates JR, 3rd. 2001. Large-scale analysis of the yeast proteome by multidimensional protein identification technology. Nat Biotechnol 19:242-247.
Wasinger VC, Cordwell SJ, Cerpa-Poljak A, Yan JX, Gooley AA, Wilkins MR, et al. 1995. Progress with gene-product mapping of the mollicutes: Mycoplasma genitalium. Electrophoresis 16:1090-1094.
Waters CM, Bassler BL. 2005. Quorum sensing: cell-to-cell communication in bacteria. Annu Rev Cell Dev Biol 21:319-346.
Wen YT, Chang YC, Lin LC, Liao PC. 2011a. Collection of in vivo-like liver cell secretome with alternative sample enrichment method using a hollow fiber bioreactor culture system combined with tangential flow filtration for secretomics analysis. Anal Chim Acta 684:72-79.
Wen YT, Tsou CC, Kuo HT, Wang JS, Wu JJ, Liao PC. 2011b. Differential secretomics of Streptococcus pyogenes reveals a novel peroxide regulator (PerR)-regulated extracellular virulence factor mitogen factor 3 (MF3). Mol Cell Proteomics 10:M110.007013.
Wessels MR, Moses AE, Goldberg JB, DiCesare TJ. 1991. Hyaluronic acid capsule is a virulence factor for mucoid group A streptococci. Proc Natl Acad Sci U S A 88:8317-8321.
Xia Q, Hendrickson EL, Wang T, Lamont RJ, Leigh JA, Hackett M. 2007. Protein abundance ratios for global studies of prokaryotes. Proteomics 7:2904-2919.
Xu C, Wang S, Ren H, Lin X, Wu L, Peng X. 2005. Proteomic analysis on the expression of outer membrane proteins of Vibrio alginolyticus at different sodium concentrations. Proteomics 5:3142-3152.
Yam KC, D'Angelo I, Kalscheuer R, Zhu H, Wang JX, Snieckus V, et al. 2009. Studies of a ring-cleaving dioxygenase illuminate the role of cholesterol metabolism in the pathogenesis of Mycobacterium tuberculosis. PLoS Pathog 5:e1000344.
Ying T, Wang H, Li M, Wang J, Wang J, Shi Z, et al. 2005. Immunoproteomics of outer membrane proteins and extracellular proteins of Shigella flexneri 2a 2457T. Proteomics 5:4777-4793.
Zheng PX, Chung KT, Chiang-Ni C, Wang SY, Tsai PJ, Chuang WJ, et al. 2013. Complete genome sequence of emm1 Streptococcus pyogenes A20, a strain with an intact two-component system, covrs, isolated from a patient with necrotizing fasciitis. Genome Announc 1: e00149-12.