A群鏈球菌 (Group A streptococcus) 是重要的人類致病菌，會造成嚴重疾病如壞死性筋膜炎與鏈球菌毒素休克症候群。以往認為A群鏈球菌是胞外致病菌，但近年來許多研究指出A群鏈球菌能入侵細胞甚至在細胞中存活。我們團隊之研究指出從侵襲性疾病之病患分離之A群鏈球菌NZ131，能在內皮細胞中增殖；而從非侵襲性疾病之病患分離之SF370菌株則不能在內皮細胞中生長。先前的研究指出鏈球菌溶血素O與co-toxin NAD-glycohydrolase (NADase) 的協同作用可延緩A群鏈球菌被角質細胞的autophagy機制清除。先前實驗室未發表之研究顯示NZ131 nga突變株無法於內皮細胞中存活，回補nga的SF370菌株則能在內皮細胞中存活，證明了有NADase表現基因nga的存在，可避免autophagolysosome清除之機制，然而，NADase是如何影響細胞清除機制仍然未知，因此，本研究擬探討NADase在內皮細胞中的作用機制。首先，以real-time RT-PCR分析nga突變株並不影響下游基因ifs及slo的mRNA表現，證實nga扮演關鍵角色。已知IFS會抑制NADase的酵素活性，進而影響A群鏈球菌在角質細胞中的存活能力。因此，我建構了IFS大量表現之菌株，以gentamicin protection assay證實A群鏈球菌在內皮細胞中增殖主要是透過NADase酵素活性所導致。同時，利用市售試劑組檢測胞內NAD＋含量，發現高活性NADase會造成胞內NAD＋/NADH ratio下降兩倍。由於NADase能水解胞內β-NAD＋，形成nicotinamide及ADP-ribose，以額外添加產物的方式來探討NADase代謝作用對A群鏈球菌與內皮細胞之影響，實驗結果發現高濃度nicotinamide會抑制NZ131及nga突變株於內皮細胞中的生長，透過外加bafilomycin A1及免疫螢光染色等實驗，證明高濃度nicotinamide會增強細胞的autophagolysosme酸化清除細菌之機制。此外，檢測胞內NAD＋含量，發現高濃度nicotinamide會以再循環方式增加胞內NAD＋含量，提升胞內NAD＋/NADH ratio。總結以上，A群鏈球菌藉由NADase使胞內NAD＋/NADH ratio下降，導致胞內能量不平衡，幫助其在內皮細胞中增殖，外加高濃度nicotinamide能增加胞內NAD＋含量，提升胞內NAD＋/NADH ratio，啟動autophagy機制，清除入侵的A群鏈球菌。

Streptococcus pyogenes (Group A streptococcus, GAS) is an important human pathogen that causes various severe diseases, such as necrotizing fasciitis and streptococcal toxic shock syndrome. Although GAS is considered as an extracellular pathogen, several studies have shown that GAS can survive within intracellular niches as well. In our study group, an invasive strain NZ131 can multiply inside human microvascular endothelial cells (HMEC-1), but noninvasive strain SF370 cannot, suggesting that unknown molecules in the invasive strain may be involved. Previous studies demonstrated that streptolysin O (SLO) and its co-toxin NAD-glycohydrolase (NADase) could protect GAS from xenophagic killing in keratinocytes. Our laboratory showed that nga encodes NADase, prevents the clearance of acidified autophagolysosome. However, how NADase associates with the cellular clearance mechanism still unknown. In this thesis, I aimed to figure out the role of enzymatic activity and the metabolic effect of NADase in intracellular multiplication. First, polar effects on the downstream genes of nga were ruled out by real-time RT-PCR. The results confirmed that nga play a key role. As known endogenous IFS inhibites NADase activity and further influences intracellular survival. I investigated the enzymatic activity of NADase by constructing IFS overexpression strain. The results showed that NZ131 engineered to secrete IFS impaired intracellular survival, suggesting that GAS multiplication depended on NADase activity. Meanwhile, the ratio of NAD＋/NADH was decreased when NZ131 infected with HMEC-1. Since NADase is able to cleave the intracellular β-NAD+ to produce nicotinamide and adenosine diphosphoribose, these substrates were added to HMEC-1 infected with NZ131 and nga mutant to investigate how the metabolic effects of NADase influence the interaction between GAS and HMEC-1. The results showed the multiplication ability of NZ131 and nga mutant in endothelial cells remained reduced when treated with nicotinamide. With bafilomycin A1 and immunofluorescence, I found that nicotinamide enhanced autophagolysosome clearance mechanism by increased the intracellular NAD+. Taken together, NADase promotes GAS multiplication within endothelial cells through interfered cellular NAD+ homeostasis, the phenomena can be improved by treating with nicotinamide at high concentration.

Barltrop, J. A., T. C. Owen, A. H. Cory and J. G. Cory. 5-(3-carboxymethoxyphenyl)-2-(4,5-dimethylthiazolyl)-3-(4-sulfophenyl)tetrazolium, inner salt (MTS) and related analogs of 3-(4,5-dimethylthiazolyl)-2,5-diphenyltetrazolium bromide (MTT) reducing to purple water-soluble formazans As cell-viability indicators. Bioorganic & Medicinal Chemistry Letters 1(11): 611-614. 1991.
Barnett, T. C., D. Liebl, L. M. Seymour, C. M. Gillen, J. Y. Lim, C. N. Larock, M. R. Davies, B. L. Schulz, V. Nizet, R. D. Teasdale and M. J. Walker. The globally disseminated M1T1 clone of group A streptococcus evades autophagy for intracellular replication. Cell Host Microbe 14(6): 675-682. 2013.
Bastiat-Sempe, B., J. F. Love, N. Lomayesva and M. R. Wessels. Streptolysin O and NAD-glycohydrolase prevent phagolysosome acidification and promote group A streptococcus survival in macrophages. MBio 5(5): e01690-01614. 2014.
Berridge, M. V. and A. S. Tan. Characterization of the cellular reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT): subcellular localization, substrate dependence, and involvement of mitochondrial electron transport in MTT reduction. Arch Biochem Biophys 303(2): 474-482. 1993.
Bhakdi, S., J. Tranum-Jensen and A. Sziegoleit. Mechanism of membrane damage by streptolysin-O. Infect Immun 47(1): 52-60. 1985.
Bisno A. L., M. O. Brito and C. M. Collins. Molecular basis of group A streptococcal virulence. Lancet Infect Dis 3(4): 191-200. 2003.
Bricker, A. L., V. J. Carey and M. R. Wessels. Role of NADase in virulence in experimental invasive group A streptococcal infection. Infect Immun 73(10): 6562-6566. 2005.
Bricker, A. L., C. Cywes, C. D. Ashbaugh and M. R. Wessels. NAD+-glycohydrolase acts as an intracellular toxin to enhance the extracellular survival of group A streptococci. Mol Microbiol 44(1): 257-269. 2002.
Carapetis JR, S. A., E. K. Mulholland, M. Weber. The global burden of group A streptococcal diseases. Lancet Infect Dis. 5(11): 685-694. 2005.
Carlson, A. S., A. Kellner, A. W. Bernheimer and E. B. Freeman. A streptococcal enzyme that acts specifically upon diphosphopyridine nucleotide: characterization of the enzyme and its separation from streptolysin O. J Exp Med 106(1): 15-26. 1957.
Chandrasekaran, S. and M. G. Caparon. The Streptococcus pyogenes NAD+ glycohydrolase modulates epithelial cell PARylation and HMGB1 release. Cell Microbiol 17(9): 1376-1390. 2015.
Chen, Y. Y., C. T. Huang, S. M. Yao, Y. C. Chang, P. W. Shen, C. Y. Chou and S. Y. Li. Molecular epidemiology of group A streptococcus causing scarlet fever in northern Taiwan, 2001-2002. Diagn Microbiol Infect Dis 58(3): 289-295. 2007.
Cone, L. A., D. R. Woodard, P. M. Schlievert and G. S. Tomory. Clinical and bacteriologic observations of a toxic shock-like syndrome due to Streptococcus pyogenes. N Engl J Med 317(3): 146-149. 1987.
Cory, A. H., T. C. Owen, J. A. Barltrop and J. G. Cory. Use of an aqueous soluble tetrazolium/formazan assay for cell growth assays in culture. Cancer Commun 3(7): 207-212. 1991.
Cunningham, M. W. Pathogenesis of group A streptococcal infections. Clin Microbiol Rev 13(3): 470-511. 2000.
Dmitriev, A. V., E. J. McDowell, K. V. Kappeler, M. A. Chaussee, L. D. Rieck and M. S. Chaussee. The Rgg regulator of Streptococcus pyogenes influences utilization of nonglucose carbohydrates, prophage induction, and expression of the NAD-glycohydrolase virulence operon. J Bacteriol 188(20): 7230-7241. 2006.
Ghosh, J., P. J. Anderson, S. Chandrasekaran and M. G. Caparon. Characterization of Streptococcus pyogenes beta-NAD+ glycohydrolase: re-evaluation of enzymatic properties associated with pathogenesis. J Biol Chem 285(8): 5683-5694. 2010.
Goldmann, O., I. Sastalla, M. Wos-Oxley, M. Rohde and E. Medina. Streptococcus pyogenes induces oncosis in macrophages through the activation of an inflammatory programmed cell death pathway. Cell Microbiol 11(1): 138-155. 2009.
Guse, A. H., C. P. da Silva, I. Berg, A. L. Skapenko, K. Weber, P. Heyer, M. Hohenegger, G. A. Ashamu, H. Schulze-Koops, B. V. Potter and G. W. Mayr. Regulation of calcium signalling in T lymphocytes by the second messenger cyclic ADP-ribose. Nature 398(6722): 70-73. 1999.
Hafner Česen, M., K. Pegan, A. Špes and B. Turk. Lysosomal pathways to cell death and their therapeutic applications. Exp Cell Res 318(11): 1245-1251. 2012.
Hakansson, A., C. C. Bentley, E. A. Shakhnovic and M. R. Wessels. Cytolysin-dependent evasion of lysosomal killing. Proc Natl Acad Sci U S A 102(14): 5192-5197. 2005.
Hara, N., K. Yamada, T. Shibata, H. Osago, T. Hashimoto and M. Tsuchiya. Elevation of cellular NAD levels by nicotinic acid and involvement of nicotinic acid phosphoribosyltransferase in human cells. J Biol Chem 282(34): 24574-24582. 2007.
Hayat, M. A. Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging: Volume 8- Human Diseases. Academic Press 2015.
Hertzén E, J. L., R. Wallin, H. Schmidt, M. Kroll, A. P. Rehn, M. Kotb, M. Mörgelin and A. Norrby-Teglund. M1 protein-dependent intracellular trafficking promotes persistence and replication of Streptococcus pyogenes in macrophages. J Innate Immun. 2(6): 534-545. 2010.
Hu, C. R. Li, J. S. Ma, Y. J. Lau, K. C. Lu and H. W. Yu. Clinical and genetic analysis of invasive and non-invasive group A streptococcal infections in central Taiwan. J Microbiol Immunol Infect 38(2): 105-111. 2005.
Jang, S. Y., H. T. Kang and E. S. Hwang. Nicotinamide-induced mitophagy: event mediated by high NAD+/NADH ratio and SIRT1 protein activation. J Biol Chem 287(23): 19304-19314. 2012.
Kang, H. T. and E. S. Hwang. Nicotinamide enhances mitochondria quality through autophagy activation in human cells. Aging Cell 8(4): 426-438. 2009.
Kao, C. H., P. Y. Chen, F. L. Huang, C. W. Chen, C. S. Chi, Y. H. Lin, C. Y. Shih, B. S.
Kimoto, H., Y. Fujii, S. Hirano, Y. Yokota and A. Taketo. Genetic and biochemical properties of streptococcal NAD-glycohydrolase inhibitor. J Biol Chem 281(14): 9181-9189. 2006.
Kimoto, H., Y. Fujii, Y. Yokota and A. Taketo. Molecular characterization of NADase-streptolysin O operon of hemolytic streptococci. Biochim Biophys Acta 1681(2-3): 134-149. 2005.
Kobayashi, S. Choose delicately and reuse adequately: The newly revealed process of autophagy. Biol Pharm Bull 38(8): 1098-1103. 2015.
Kreikemeyer, B., K. S. McIver and A. Podbielski. Virulence factor regulation and regulatory networks in Streptococcus pyogenes and their impact on pathogen-host interactions. Trends Microbiol 11(5): 224-232. 2003.
Kyme, P., N. H. Thoennissen, C. W. Tseng, G. B. Thoennissen, A. J. Wolf, K. Shimada, U. O. Krug, K. Lee, C. Müller-Tidow, W. E. Berdel, W. D. Hardy, A. F. Gombart, H. P. Koeffler and G. Y. Liu. C/EBPε mediates nicotinamide-enhanced clearance of Staphylococcus aureus in mice. J Clin Invest 122(9): 3316-3329. 2012.
Lancefield, R. C. Current knowledge of type-specific M antigens of group A streptococci. J Immunol. 89: 307-313. 1962.
Lancefield, R. C. and V. P. Dole. The properties of T antigens extracted from group A hemolytic streptococci. J Exp Med 84(5): 449-471. 1946.
LaPenta, D., C. Rubens, E. Chi and P. P. Cleary. Group A streptococci efficiently invade human respiratory epithelial cells. PNAS USA 91(25): 12115-12119. 1994.
Laub, M. T. and M. Goulian. Specificity in two-component signal transduction pathways. Annu Rev Genet 41: 121-145. 2007.
Lee, J., S. Giordano and J. Zhang. Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling. Biochem J 441(2): 523-540. 2012.
Levine, B. Eating oneself and uninvited guests: autophagy-related pathways in cellular defense. Cell 120(2): 159-162. 2005.
Levine, B., N. Mizushima and H. W. Virgin. Autophagy in immunity and inflammation. Nature 469(7330): 323-335. 2011.
Limbago, B., V. Penumalli, B. Weinrick and J. R. Scott. Role of streptolysin O in a mouse model of invasive group A streptococcal disease. Infect Immun 68(11): 6384-6390. 2000.
Lin, J.-N., L.-L. Chang, C.-H. Lai, H.-H. Lin and Y.-H. Chen. Emergence of Streptococcus pyogenes emm102 causing toxic shock syndrome in southern Taiwan during 2005–2012. PLoS ONE 8(12): e81700. 2013a.
Lin, J. N., L. L. Chang, C. H. Lai, H. H. Lin and Y. H. Chen. Group A streptococcal necrotizing fasciitis in the emergency department. J Emerg Med 45(5): 781-788. 2013b.
Lu, S. L., C. F. Kuo, H. W. Chen, Y. S. Yang, C. C. Liu, R. Anderson, J. J. Wu and Y. S. Lin. Insufficient acidification of autophagosomes facilitates group A streptococcus survival and growth in endothelial cells. MBio 6(5): e01435-01415. 2015.
Luk, E. Y., J. Y. Lo, A. Z. Li, M. C. Lau, T. K. Cheung, A. Y. Wong, M. M. Wong, C. W. Wong, S. K. Chuang and T. Tsang. Scarlet fever epidemic, Hong Kong, 2011. Emerg Infect Dis 18(10): 1658-1661. 2012.
MacKay, D., J. Hathcock and E. Guarneri. Niacin: chemical forms, bioavailability, and health effects. Nutr Rev 70(6): 357-366. 2012.
Madden, J. C., N. Ruiz and M. Caparon. Cytolysin-mediated translocation (CMT): a functional equivalent of type III secretion in gram-positive bacteria. Cell 104(1): 143-152. 2001.
Magni, G., G. Orsomando, N. Raffelli and S. Ruggieri. Enzymology of mammalian NAD metabolism in health and disease. Front Biosci 13: 6135-6154. 2008.
Martin, J. M., M. Green, K. A. Barbadora and E. R. Wald. Group A streptococci among school-aged children: clinical characteristics and the carrier state. Pediatrics 114(5): 1212-1219. 2004.
McIver, K. S. and J. R. Scott. Role of mga in growth phase regulation of virulence genes of the group A streptococcus. J Bacteriol 179(16): 5178-5187. 1997.
Meehl, M. A., J. S. Pinkner, P. J. Anderson, S. J. Hultgren and M. G. Caparon. A novel endogenous inhibitor of the secreted streptococcal NAD-glycohydrolase. PLoS Pathog 1(4): e35. 2005.
Mesquita, I., P. Varela, A. Belinha, J. Gaifem, M. Laforge, B. Vergnes, J. Estaquier and R. Silvestre. Exploring NAD+ metabolism in host-pathogen interactions. Cell Mol Life Sci 73(6): 1225-1236. 2016.
Michos, A., I. Gryllos, A. Hakansson, A. Srivastava, E. Kokkotou and M. R. Wessels. Enhancement of streptolysin O activity and intrinsic cytotoxic effects of the group A streptococcal toxin, NAD-glycohydrolase. J Biol Chem 281(12): 8216-8223. 2006.
Mizushima, N., Y. Ohsumi and T. Yoshimori. Autophagosome formation in mammalian cells. Cell Struct Funct. 27(6): 421-429. 2002.
Moreira, D., V. Rodrigues, M. Abengozar, L. Rivas, E. Rial, M. Laforge, X. Li, M. Foretz, B. Viollet, J. Estaquier, A. Cordeiro da Silva and R. Silvestre. Leishmania infantum modulates host macrophage mitochondrial metabolism by hijacking the SIRT1-AMPK axis. PLoS Pathog 11(3): e1004684. 2015.
Moreland, N. J., C. S. Waddington, D. A. Williamson, S. Sriskandan, P. R. Smeesters, T. Proft, A. C. Steer, M. J. Walker, E. N. Baker, M. G. Baker, D. Lennon, R. Dunbar, J. Carapetis and J. D. Fraser. Working towards a group A streptococcal vaccine: report of a collaborative Trans-Tasman workshop. Vaccine 32(30): 3713-3720. 2014.
Murray, M. F., M. Nghiem and A. Srinivasan. HIV infection decreases intracellular nicotinamide adenine dinucleotide [NAD]. Biochem Biophys Res Commun 212(1): 126-131. 1995.
Murray, M. F. Nicotinamide: an oral antimicrobial agent with activity against both Mycobacterium tuberculosis and human immunodeficiency virus. Clin Infect Dis 36(4): 453-460. 2003.
Nagamune, H., K. Ohkura and H. Ohkuni. Molecular basis of group A streptococcal pyrogenic exotoxin B. J Infect Chemother 11(1): 1-8. 2005.
Nakagawa, I., A. Amano, N. Mizushima, A. Yamamoto, H. Yamaguchi, T. Kamimoto, A. Nara, J. Funao, M. Nakata, K. Tsuda, S. Hamada and T. Yoshimori. Autophagy defends cells against invading group A streptococcus. Science 306(5698): 1037-1040. 2004.
O'Loughlin, R. E., A. Roberson, P. R. Cieslak, R. Lynfield, K. Gershman, A. Craig, B. A. Albanese, M. M. Farley, N. L. Barrett, N. L. Spina, B. Beall, L. H. Harrison, A. Reingold, C. Van Beneden; Active Bacterial Core Surveillance Team. The epidemiology of invasive group A streptococcal infection and potential vaccine implications: United States, 2000-2004. Clin Infect Dis. 45(7): 853-862. 2007.
O'Seaghdha, M. and M. R. Wessels. Streptolysin O and its co-toxin NAD-glycohydrolase protect group A streptococcus from Xenophagic killing. PLoS Pathog 9(6): e1003394. 2013.
Patel, A. S., L. Lin, A. Geyer, J. A. Haspel, C. H. An, J. Cao, I. O. Rosas and D. Morse. Autophagy in idiopathic pulmonary fibrosis. PLoS ONE 7(7): e41394. 2012.
Pfaffl, M. W. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29(9): e45. 2001.
Revollo, J. R., A. Korner, K. F. Mills, A. Satoh, T. Wang, A. Garten, B. Dasgupta, Y. Sasaki, C. Wolberger, R. R. Townsend, J. Milbrandt, W. Kiess and S. Imai. Nampt/PBEF/Visfatin regulates insulin secretion in beta cells as a systemic NAD biosynthetic enzyme. Cell Metab 6(5): 363-375. 2007.
Rohde, M., E. Müller, G. S. Chhatwal and S. R. Talay. Host cell caveolae act as an entry-port for group A streptococci. Cell Microbiol. 5(5): 323-342. 2003.
Rolfe, H. M. A review of nicotinamide: treatment of skin diseases and potential side effects. J Cosmet Dermatol 13(4): 324-328. 2014.
Santic, M., M. Molmeret, K. E. Klose and Y. Abu Kwaik. Francisella tularensis travels a novel, twisted road within macrophages. Trends Microbiol. 14(1): 37-44. 2006.
Shibutani, S. T., T. Saitoh, H. Nowag, C. Munz and T. Yoshimori. Autophagy and autophagy-related proteins in the immune system. Nat Immunol 16(10): 1014-1024. 2015.
Smith, C. L., J. Ghosh, J. S. Elam, J. S. Pinkner, S. J. Hultgren, M. G. Caparon and T. Ellenberger. Structural basis of Streptococcus pyogenes immunity to its NAD+ glycohydrolase toxin. Structure 19(2): 192-202. 2011.
Staali, L., Bauer, S., Mörgelin, M., L. Björck and H. Tapper. Streptococcus pyogenes expressing M and M-like surface proteins are phagocytosed but survive inside human neutrophils. Cell Microbiol. 5(4): 253-265. 2003.
Steer, A. C., I. Law, L. Matatolu, B. W. Beall and J. R. Carapetis. Global emm type distribution of group A streptococci: systematic review and implications for vaccine development. Lancet Infect Dis 9(10): 611-616. 2009.
Stevens, D. L., D. B. Salmi, E. R. McIndoo and A. E. Bryant. Molecular epidemiology of nga and NAD glycohydrolase/ADP-ribosyltransferase activity among Streptococcus pyogenes causing streptococcal toxic shock syndrome. J Infect Dis 182(4): 1117-1128. 2000.
Stevens D. L., T. M. Winship J, R. Swarts, K. M. Ries, P. M. Schlievert, and E. Kaplan. Severe group A streptococcal infections associated with a toxic shock-like syndrome and scarlet fever toxin A. N Engl J Med. 321(1): 1-7. 1989.
Sun, J., A. Siroy, R. K. Lokareddy, A. Speer, K. S. Doornbos, G. Cingolani and M. Niederweis. The tuberculosis necrotizing toxin kills macrophages by hydrolyzing NAD. Nat Struct Mol Biol 22(9): 672-678. 2015.
Tatsuno, I., M. Isaka, M. Minami and T. Hasegawa. NADase as a target molecule of in vivo suppression of the toxicity in the invasive M-1 group A streptococcal isolates. BMC Microbiol 10: 144. 2010.
Tatsuno, I., J. Sawai, A. Okamoto, M. Matsumoto, M. Minami, M. Isaka, M. Ohta and T. Hasegawa. Characterization of the NAD-glycohydrolase in streptococcal strains. Microbiology 153(Pt 12): 4253-4260. 2007.
Thulin P, J. L., D. E. Low, B. S. Gan, M. Kotb, A. McGeer, A. Norrby-Teglund. Viable group A streptococci in macrophages during acute soft tissue infection. PLoS Med. 3(3): e53. 2006.
Timmer, A. M., J. C. Timmer, M. A. Pence, L. C. Hsu, M. Ghochani, T. G. Frey, M. Karin, G. S. Salvesen and V. Nizet. Streptolysin O promotes group A streptococcus immune evasion by accelerated macrophage apoptosis. J Biol Chem 284(2): 862-871. 2009.
Umapathy, N. S., E. A. Zemskov, J. Gonzales, B. A. Gorshkov, S. Sridhar, T. Chakraborty, R. Lucas and A. D. Verin. Extracellular beta-nicotinamide adenine dinucleotide (beta-NAD) promotes the endothelial cell barrier integrity via PKA- and EPAC1/Rac1-dependent actin cytoskeleton rearrangement. J Cell Physiol 223(1): 215-223. 2010.
Yamamoto, A., Y. Tagawa, T. Yoshimori, Y. Moriyama, R. Masaki and Y. Tashiro. Bafilomycin A1 prevents maturation of autophagic vacuoles by inhibiting fusion between autophagosomes and lysosomes in rat hepatoma cell line, H-4-II-E cells. Cell Struct Funct 23(1): 33-42. 1998.
Yang, P., X. Peng, D. Zhang, S. Wu, Y. Liu, S. Cui, G. Lu, W. Duan, W. Shi, S. Liu, J. Li and Q. Wang. Characteristics of group A streptococcus strains circulating during scarlet fever epidemic, Beijing, China, 2011. Emerg Infect Dis 19(6): 909-915. 2013.
Yoon, J. Y., D. R. An, H.-J.Yoon, H. S. Kim, S. J. Lee, H. N. Im, J. Y. Jang and S. W. Suh. High-resolution crystal structure of Streptococcus pyogenes β-NAD+ glycohydrolase in complex with its endogenous inhibitor IFS reveals a highly water-rich interface. J Synchrotron Radiat 20(Pt 6): 962–967. 2013.
You, Y. H., Y. Y. Song, X. M. Yan, H. B. Wang, M. H. Zhang, X. X. Tao, L. L. Li, Y. X. Zhang, X. H. Jiang, B. H. Zhang, H. Zhou, D. Xiao, L. M. Jin, Z. J. Feng, F. J. Luo and J. Z. Zhang. Molecular epidemiological characteristics of Streptococcus pyogenes strains involved in an outbreak of scarlet fever in China, 2011. Biomed Environ Sci 26(11): 877-885. 2013.
Zerez, C. R., E. F. Roth, Jr., S. Schulman and K. R. Tanaka. Increased nicotinamide adenine dinucleotide content and synthesis in Plasmodium falciparum-infected human erythrocytes. Blood 75(8): 1705-1710. 1990.