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Cho, Kyu Hong
KYU HONG CHO
Ph.D., University of Illinois at Urbana-Champaign
Office: Science Building 231
My research focuses on the regulation mechanisms of virulence factors of the Gram-positive human pathogen Streptococcus pyogenes. S. pyogenes, also known as Group A Streptococcus (GAS), inhabits the pharyngeal mucosal surfaces of approximately 10% to 20% of the human population. This organism can cause a variety of diseases such as mild superficial infections (impetigo, pharyngitis also known as strep throat), toxigenic diseases (scarlet fever, toxic-shock syndrome), sequelae (rheumatic heart disease, glomerulonephritis), and invasive diseases (cellulitis, necrotizing fasciitis). To the public, this pathogen is also known as a “flesh-eating bacterium” because it can destroy the tissues between the skin and muscle very rapidly causing necrotizing fasciitis that has an approximately 30% mortality rate. A recent survey estimated that severe GAS diseases including post-infectious sequelae and invasive infections cause over a half million annual deaths globally. The goal of my research is to identify streptococcal molecules or pathways influencing the virulence of the bacterium and to understand the molecular mechanisms of the pathways to provide knowledge that can be used to develop therapeutic measures.
c-di-AMP signaling pathway in S. pyogenes. Cyclic nucleotides act as second messenger molecules in both prokaryotes and eukaryotes and play essential roles in signaling pathways that sense environmental changes such as stress, temperature, nutrition, pH, etc. Cyclic di-adenosine monophosphate (c-di-AMP) was recently discovered in bacteria and involved in regulation of fundamental cellular processes such as fatty acid synthesis, potassium ion transport, cell wall homeostasis, etc., and perturbation of intracellular c-di-AMP level reduces the virulence of bacterial pathogens. c-di-AMP binds to specific molecules such as proteins and riboswitches and changes their structures and/or function. To control intracellular c-di-AMP level, S. pyogenes employs a c-di-AMP synthase DacA and two degrading enzymes GdpP and Pde2. Our study revealed that deletion of any enzyme involved in the c-di-AMP biogenesis reduced the virulence of S. pyogenes. Especially the production of the secreted protease toxin SpeB, the major virulence factor for necrotizing fasciitis, is controlled by c-di-AMP, so understanding how c-di-AMP controls SpeB production could be the basis for the development of effective anti-virulence drugs against S. pyogenes infection. Our aims of this project are to i) determine the regulation mechanism for SpeB biogenesis by c-di-AMP, ii) discover c-di-AMP binding proteins in S. pyogenes, and iii) study the proteins to understand the overall c-di-AMP signaling pathway in S. pyogenes.
S. pyogenes small regulatory RNAs. S. pyogenes not only produces virulence factors such as adhesins and toxins, but also regulates them in an exquisite manner to survive in a variety of environments in host tissues. Recent studies have shown that small non-coding regulatory RNAs (sRNAs) have an important role in S. pyogenes pathogenesis by regulating virulence factor expression at a translational level. Previously, we performed a systematic search for sRNAs in S. pyogenes using bioinformatics and experimental verification. Our approach led to the discovery of 7 novel streptococcal sRNAs. We are studying these new sRNAs to identify their target mRNAs and their roles in S. pyogenes pathogenesis. Currently, we employ a next-generation sequencing technology, RNA-Seq, and bioinformatics tools to determine their target mRNAs.
Thermoregulation of capsule production The S. pyogenes capsule is an adhesin involved in initial colonization on the mucosal surfaces of the throat or on the skin. The capsule is composed of hyaluronic acid, which binds to CD44 located on the surface of keratinocytes on the pharyngeal mucosa and the skin, where the temperature is normally lower than the internal body temperature. The hyaluronic acid capsule is synthesized by the products of the capsule biosynthetic operon comprised of the hasA, hasB, and hasC genes. Transcription of the hasABC operon is under the control of a single upstream promoter that is regulated by the CovRS two-component regulatory system, in which CovR is the response regulator and CovS is the sensor kinase. Although it is well established that the capsule is critical for initial colonization and invasiveness of the pathogen, the mechanism of capsule thermoregulation is mostly unknown. For the last several years, we have made the following progress in understanding the role of capsule thermoregulation and its molecular mechanism: 1) In addition to the transcriptional regulation by the CovRS two-component system, the production of the capsule is further thermoregulated at a post-transcriptional level. 2) Extracellular hyaluronidase activity is not involved in capsule thermoregulation. 3) Among naturally occurring invasive mucoid strains, approximately 20% of them exhibit thermoregulated capsule production. 4) CvfA (RNase Y), an endoribonuclease in the RNA degradosome, is involved in capsule thermoregulation. 5) A streptococcal prophage øHSC5.3 is involved in capsule thermoregulation.
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Fahmi T, Faozia S, Port G, & Cho KH. 2019. The second messenger c-di-AMP regulates diverse cellular pathways involved in stress response, biofilm formation, cell wall homeostasis, SpeB expression, and virulence in Streptococcus pyogenes. Infect Immun 87:e00147-19. https://doi.org/10.1128/IAI.00147-19.
Cho KH, Port G, Caparon M. 2019. Genetics of Group A Streptococcus. Microbiol Spectrum 7(1):GPP3-0056-2018. doi:10 .1128/microbiolspec.GPP3-0056-2018.
Yoe WS, Arya R, Kim KK, Jeong J, Cho KH & Bae T. 2018. The FDA-approved anti-cancer drugs, streptozotocin and floxuridine, reduce the virulence of Staphylococcus aureus. Scientific Report. 8(1):2521. doi: 10.1038/s41598-018-20617-5
Rath E, Pitman S, Cho KH & Bai Y. 2017. Identification of streptococcal small RNAs that are putative targets of RNase III through bioinformatics analysis of RNA sequencing data. BMC Bioinformatics, 18(Suppl 14):540 DOI 10.1186/s12859-017-1897-0
Fahmi T, Port GC & Cho KH. 2017. c-di-AMP: An essential molecule in the signaling pathways that regulate the viability and virulence of Gram-positive bacteria. Genes. 8(8): pii: E197. doi: 10.3390/genes8080197
Nicholls C, Kump A, Ford S, Gonser S & Cho KH. 2017. Draft genome sequence of a Streptococcus pyogenes strain M3KCL. Genome Announcement
Cho KH. 2017. The structure and function of the Gram (+) bacterial RNA degradosome. Front. Microbiol. 8:154. doi: 10.3389/fmicb.2017.00154
Brown L, Kim JH & Cho KH. 2016. Presence of a prophage determines temperature-dependent capsule production in Streptococcus pyogenes HSC5. Genes 7(10). doi: 10.3390/genes7100074.
Roy A, Hashmi S, Li Z, Dement AD, Cho KH, & Kim JH. 2016. The glucose metabolite methylglyoxal inhibits expression of the glucose transport genes by inactivating the cell surface glucose sensor Rgt2 and Snf3 in yeast. Mol Biol Cell. 27(5): 862-71. doi: 10.1091/mbc.E15-11-0789.
Pitman S & Cho KH. 2015. The mechanism of virulence regulation by small noncoding RNAs in low GC gram-positive pathogens. Int. J. Mol. Sci. 16(12): 29797–29814. doi: 10.3390/ijms161226194
Cho KH & Kim JH. 2015. Cis-encoded noncoding antisense RNAs in streptococci and other low GC Gram (+) bacterial pathogens. Front. Genet. 6: 110. doi: 10.3389/fgene.2015.00110
Roy A, Dement AD, Cho KH & Kim JH. 2015. Assessing glucose uptake through the yeast hexose transporter 1 (Hxt1). PLOS ONE 10(3): e0121985. doi: 10.1371/journal.pone.0121985.
Roy, A., Kim Y.B., Cho, K.H. & Kim, J.H. 2014. Glucose starvation-induced turnover of the yeast glucose transporter Hxt1. Biochim Biophys Acta 1840(9):2878-2885.
Roy, A., Jouandot II, D., Cho, K.H. & Kim, J.H. 2014. Understanding the mechanism of glucose-induced relief of Rgt1-mediated repression in yeast. FEBS Open Bio. 4:105-111.
Cho, K.H., Wright J., Svencionis, J. & Kim, J.H. 2013. The prince and the pauper. Which one is real? The problem of secondary mutation during mutagenesis in Streptococcus pyogenes. Virulence 4(8): 1-2.
Cho, K.H. & Kang, S. O. 2013. Streptococcus pyogenes GdpP, the c-di-AMP phosphodiesterase, influences SpeB maturation and virulence. PLOS ONE 8(7): e69425. doi:10.1371/journal.pone.0069425.
Kim, J.H., Roy, A., Jouandot, D. 2nd & Cho, K.H. 2013. The glucose-signaling network in yeast. Biochimica et Biophysica Acta. 1830(11):5204-10
Tesorero, R.A., Yu, N., Wright, J.O., Svencionis, J.P., Cheng Q., Kim, J.H. & Cho, K.H. 2013. Novel regulatory small RNAs in Streptococcus pyogenes. PLOS ONE. 8(6):e64021. doi:10.1371/Journal.pone.0064021.
Roy, A., Shin Y.J., Cho, K.H. & Kim, J.H. 2013. Mth1 Regulates Expression of the Glucose Transporter Genes by Modulating the Interaction of Rgt1 with Ssn6-Tup1 in yeast. Molecular Biology of the Cell 24(9):1493-503.
Kang, S.O., Tesorero, R.A., Wright, J.O., Lee, H., Beall, B. & Cho, K.H. 2012. Thermoregulation of capsule production by Streptococcus pyogenes. PLOS ONE. 7(5):e37367. Doi:10.1371/journal.pone.0037367.
Kang, S.O., Caparon, M.G. & Cho, K.H. 2010. Virulence Gene regulation by CvfA, a putative RNase: the CvfA-enolase complex in Streptococcus pyogenes links nutritional stress, growth phase control and virulence gene expression. Infect Immun. 78(6):2754-67.
Cho, K.H. & Caparon, M.G. 2008. tRNA modification mutants as candidate live attenuated strains of Streptococcus pyogenes. Infect Immun. 76(7):3176-86.
Cho, K.H. & Caparon, M.G. 2006. Genetics of group A streptococci. In: Gram-positive pathogens (2Eds.), pages 59-73. ASM Press.
Cho, K.H. & Caparon, M.G. 2005. Patterns of virulence gene expression differ between biofilm and tissue community of Streptococcus pyogenes. Mol Micro. 57(6):1545-56.
Nyberg, P., Sakai, T., Cho, K.H., Caparon, M.G., Fassler, R. & Bjorck, L. 2004. Interactions with fibronectin attenuate the virulence of Streptococcus pyogenes. EMBO J. 19,23(10):2166-74.
Cho, K.H. & Salyers, A.A. 2001. Biochemical analysis of interactions between outer membrane proteins that contribute to starch utilization by Bacteroides thetaiotaomicron. J. Bacteriol. 183:7224-30.
Cho, K.H., Cho, D.L., Wang, G. & Salyers, A.A. 2001. New regulatory gene that contributes to control ofBacteroides thetaiotaomicron starch utilization genes. J. Bacteriol. 183:7198-205.
Shipman, J.A., Cho, K.H., Siegel, H.A. & Salyers, A.A. 1999. Physiological characterization of SusG, an outer membrane protein essential for starch utilization by Bacteroides thetaiotaomicron. J. Bacteriol. 181:7206-11.
Cho, K. H., Cho, Y.K., Hong, S.S. & Lee, H.S. 1995. Optimization for lactic acid production with isolated microorganisms showing high productivity. Kor. J. Appl. Microbiol. Biotechnol. 23:6-11.
Cho, Y.K., Cho, K.H., Hong, S.S. & Lee, H.S. 1995. Optimization of medium components for lactic acid production. Kor. J. Appl. Microbiol. Biotechnol. 23:12-16.