Environmental pH and peptide signaling control virulence of Streptococcus pyogenes via a quorum-sensing pathway

Do, Hackwon; Makthal, Nishanth; VanderWal, Arica R.; Saavedra, Matthew Ojeda; Olsen, Randall J.; Musser, James M.; Kumaraswami, Muthiah

doi:10.1038/s41467-019-10556-8

Title: Environmental pH and peptide signaling control virulence of Streptococcus pyogenes via a quorum-sensing pathway

Journal Article · 13 June 2019 · Nature Communications

DOI: https://doi.org/10.1038/s41467-019-10556-8 · OSTI ID:1624160

Do, Hackwon ^[1]; Makthal, Nishanth ^[2]; VanderWal, Arica R. ^[2]; Saavedra, Matthew Ojeda ^[2]; Olsen, Randall J. ^[3]; Musser, James M. ^[4];

^[5]

Houston Methodist Research Institute, Houston, TX (United States). Center for Molecular and Translational Human Infectious Diseases Research; Houston Methodist Research Institute, Houston, TX (United States). Dept. of Pathology and Genomic Medicine
Houston Methodist Research Institute, Houston, TX (United States). Center for Molecular and Translational Human Infectious Diseases Research; Houston Methodist Research Institute, Houston, TX (United States). Dept. of Pathology and Genomic Medicine
Houston Methodist Research Institute, Houston, TX (United States). Center for Molecular and Translational Human Infectious Diseases Research; Houston Methodist Research Institute, Houston, TX (United States). Dept. of Pathology and Genomic Medicine; Weill Medical College of Cornell University, New York, NY (United States). Dept. of Pathology and Laboratory Medicine
Houston Methodist Research Institute, Houston, TX (United States). Center for Molecular and Translational Human Infectious Diseases Research; Houston Methodist Research Institute, Houston, TX (United States). Dept. of Pathology and Genomic Medicine; Weill Medical College of Cornell University, New York, NY (United States). Dept. of Pathology and Laboratory Medicine
Houston Methodist Research Institute, Houston, TX (United States). Center for Molecular and Translational Human Infectious Diseases Research; Houston Methodist Research Institute, Houston, TX (United States). Dept. of Pathology and Genomic Medicine

Bacteria control gene expression in concert with their population density by a process called quorum sensing, which is modulated by bacterial chemical signals and environmental factors. In the human pathogen Streptococcus pyogenes, production of secreted virulence factor SpeB is controlled by a quorum-sensing pathway and environmental pH. The quorum-sensing pathway consists of a secreted leaderless peptide signal (SIP), and its cognate receptor RopB. Here, we report that the SIP quorum-sensing pathway has a pH-sensing mechanism operative through a pH-sensitive histidine switch located at the base of the SIP-binding pocket of RopB. Environmental acidification induces protonation of His144 and reorganization of hydrogen bonding networks in RopB, which facilitates SIP recognition. The convergence of two disparate signals in the SIP signaling pathway results in induction of SpeB production and increased bacterial virulence. Our findings provide a model for investigating analogous crosstalk in other microorganisms.

View Accepted Manuscript (DOE)

Cite

Export

Save

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC); National Institutes of Health (NIH); National Research Foundation of Korea, Ministry of Education

Grant/Contract Number:: AC03-76SF00098; 1R01AI109096-01A1; 2017R1A6A3A03008353

OSTI ID:: 1624160

Journal Information:: Nature Communications, Vol. 10, Issue 1; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

Citation Metrics:

Cited by: 32 works

Citation information provided by
Web of Science

References (114)

Inactivation of the C protein antigen gene, bca, by a novel shuttle/suicide vector results in attenuation of virulence and immunity in group B Streptococcus Li, J.; Kasper, D. L.; Ausubel, F. M. Proceedings of the National Academy of Sciences, Vol. 94, Issue 24 https://doi.org/10.1073/pnas.94.24.13251	journal	November 1997
Peptide Signaling in the Staphylococci Thoendel, Matthew; Kavanaugh, Jeffrey S.; Flack, Caralyn E. Chemical Reviews, Vol. 111, Issue 1 https://doi.org/10.1021/cr100370n	journal	January 2011
Structure and Proposed Mechanism for the pH-Sensing Helicobacter pylori Chemoreceptor TlpB Goers Sweeney, Emily; Henderson, J. Nathan; Goers, John Structure, Vol. 20, Issue 7 https://doi.org/10.1016/j.str.2012.04.021	journal	July 2012
The Combined Use of the Thermofluor Assay and ThermoQ Analytical Software for the Determination of Protein Stability and Buffer Optimization as an Aid in Protein Crystallization Phillips, Kevin; de la Peña, Andres Hernandez Current Protocols in Molecular Biology, Vol. 94, Issue 1 https://doi.org/10.1002/0471142727.mb1028s94	journal	April 2011
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 Kang, Song Ok; Caparon, Michael G.; Cho, Kyu Hong Infection and Immunity, Vol. 78, Issue 6 https://doi.org/10.1128/iai.01370-09	journal	April 2010
Pathogenesis of Group A Streptococcal Infections Cunningham, Madeleine W. Clinical Microbiology Reviews, Vol. 13, Issue 3 https://doi.org/10.1128/CMR.13.3.470	journal	July 2000
Molecular Pathogenesis of Necrotizing Fasciitis Olsen, Randall J.; Musser, James M. Annual Review of Pathology: Mechanisms of Disease, Vol. 5, Issue 1 https://doi.org/10.1146/annurev-pathol-121808-102135	journal	January 2010
PHENIX: a comprehensive Python-based system for macromolecular structure solution. Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.45787	text	January 2010
Regulation of SpeB in Streptococcus pyogenes by pH and NaCl: a Model for In Vivo Gene Expression Loughman, Jennifer A.; Caparon, Michael Journal of Bacteriology, Vol. 188, Issue 2 https://doi.org/10.1128/JB.188.2.399-408.2006	journal	January 2006
The Majority of 9,729 Group A Streptococcus Strains Causing Disease Secrete SpeB Cysteine Protease: Pathogenesis Implications Olsen, Randall J.; Raghuram, Anjali; Cantu, Concepcion Infection and Immunity, Vol. 83, Issue 12 https://doi.org/10.1128/iai.00989-15	journal	September 2015
Bacterial Stress Responses during Host Infection Fang, Ferric C.; Frawley, Elaine R.; Tapscott, Timothy Cell Host & Microbe, Vol. 20, Issue 2 https://doi.org/10.1016/j.chom.2016.07.009	journal	August 2016
MolProbity: all-atom contacts and structure validation for proteins and nucleic acids B., Chen, Vincent; C., Richardson, David; S., Richardson, Jane The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/m2an-p252	text	January 2007
Structural basis for the activation mechanism of the PlcR virulence regulator by the quorum-sensing signal peptide PapR Grenha, R.; Slamti, L.; Nicaise, M. Proceedings of the National Academy of Sciences, Vol. 110, Issue 3 https://doi.org/10.1073/pnas.1213770110	journal	December 2012
Impact of Environmental Cues on Staphylococcal Quorum Sensing and Biofilm Development Kavanaugh, Jeffrey S.; Horswill, Alexander R. Journal of Biological Chemistry, Vol. 291, Issue 24 https://doi.org/10.1074/jbc.R116.722710	journal	April 2016
pH of pus collected from periapical abscesses Nekoofar, M. H.; Namazikhah, M. S.; Sheykhrezae, M. S. International Endodontic Journal, Vol. 42, Issue 6 https://doi.org/10.1111/j.1365-2591.2009.01550.x	journal	June 2009
Molecular complexity of successive bacterial epidemics deconvoluted by comparative pathogenomics Beres, S. B.; Carroll, R. K.; Shea, P. R. Proceedings of the National Academy of Sciences, Vol. 107, Issue 9 https://doi.org/10.1073/pnas.0911295107	journal	February 2010
A role for Trigger Factor and an Rgg-like regulator in the transcription, secretion and processing of the cysteine proteinase of Streptococcus pyogenes Lyon, William R.; Gibson, Carmela M.; Caparon, Michael G. The EMBO Journal, Vol. 17, Issue 21 https://doi.org/10.1093/emboj/17.21.6263	journal	November 1998
MolProbity: all-atom contacts and structure validation for proteins and nucleic acids Davis, I. W.; Leaver-Fay, A.; Chen, V. B. Nucleic Acids Research, Vol. 35, Issue Web Server https://doi.org/10.1093/nar/gkm216	journal	May 2007
Evolutionary pathway to increased virulence and epidemic group A Streptococcus disease derived from 3,615 genome sequences Nasser, W.; Beres, S. B.; Olsen, R. J. Proceedings of the National Academy of Sciences, Vol. 111, Issue 17 https://doi.org/10.1073/pnas.1403138111	journal	April 2014
Establishment of an experimental model of a Staphylococcus aureus abscess in mice by use of dextran and gelatin microcarriers Ford, C. W.; Hamel, J. C.; Stapert, D. Journal of Medical Microbiology, Vol. 28, Issue 4 https://doi.org/10.1099/00222615-28-4-259	journal	April 1989
The CCP4 suite programs for protein crystallography Acta Crystallographica Section D Biological Crystallography, Vol. 50, Issue 5, p. 760-763 https://doi.org/10.1107/S0907444994003112	journal	September 1994
Structural Insights into Streptococcal Competence Regulation by the Cell-to-Cell Communication System ComRS Talagas, Antoine; Fontaine, Laetitia; Ledesma-Garca, Laura PLOS Pathogens, Vol. 12, Issue 12 https://doi.org/10.1371/journal.ppat.1005980	journal	December 2016
Effect of the abscess environment on the antimicrobial activity of ciprofloxacin Bryant, Richard E.; Mazza, Joyce A. The American Journal of Medicine, Vol. 87, Issue 5 https://doi.org/10.1016/0002-9343(89)90014-4	journal	November 1989
Dynamics of speB mRNA Transcripts in Streptococcus pyogenes Chen, Z.; Itzek, A.; Malke, H. Journal of Bacteriology, Vol. 194, Issue 6 https://doi.org/10.1128/jb.06612-11	journal	January 2012
Histidine Residue 94 Is Involved in pH Sensing by Histidine Kinase ArsS of Helicobacter pylori Müller, Stefanie; Götz, Monika; Beier, Dagmar PLoS ONE, Vol. 4, Issue 9 https://doi.org/10.1371/journal.pone.0006930	journal	September 2009
Effects of Organic Acid Anions on Growth, Glycolysis, and Intracellular pH of Oral Streptococci Dashper, S. G.; Reynolds, E. C. Journal of Dental Research, Vol. 79, Issue 1 https://doi.org/10.1177/00220345000790011601	journal	January 2000
Nutritional immunity: transition metals at the pathogen–host interface Hood, M. Indriati; Skaar, Eric P. Nature Reviews Microbiology, Vol. 10, Issue 8 https://doi.org/10.1038/nrmicro2836	journal	July 2012
Author Correction: Structure of the yeast Swi/Snf complex in a nucleosome free state Wang, Chengcheng; Guo, Zhouyan; Zhan, Xiechao Nature Communications, Vol. 11, Issue 1 https://doi.org/10.1038/s41467-020-19707-8	journal	November 2020
Alkaline pH decreases expression of the accessory gene regulator (agr) in Staphylococcus aureus. Regassa, L. B.; Betley, M. J. Journal of Bacteriology, Vol. 174, Issue 15 https://doi.org/10.1128/jb.174.15.5095-5100.1992	journal	January 1992
Effects of Organic Acid Anions on Growth, Glycolysis, and Intracellular pH of Oral Streptococci Dashper, S. G.; Reynolds, E. C. Journal of Dental Research, Vol. 79, Issue 1 https://doi.org/10.1177/00220345000790011601	journal	January 2000
Alkaline pH decreases expression of the accessory gene regulator (agr) in Staphylococcus aureus. Regassa, L. B.; Betley, M. J. Journal of Bacteriology, Vol. 174, Issue 15 https://doi.org/10.1128/jb.174.15.5095-5100.1992	journal	January 1992
A Novel Method for Continuous Determination of the Intracellular pH in Bacteria with the Internally Conjugated Fluorescent Probe 5 (and 6-)-Carboxyfluorescein Succinimidyl Ester. Breeuwer, P.; Drocourt, J.; Rombouts, F. M. Applied and environmental microbiology, Vol. 62, Issue 1 https://doi.org/10.1128/aem.62.1.178-183.1996	journal	January 1996
Cathelicidin LL-37 in Severe Streptococcus pyogenes Soft Tissue Infections in Humans Johansson, Linda; Thulin, Pontus; Sendi, Parham Infection and Immunity, Vol. 76, Issue 8 https://doi.org/10.1128/IAI.01392-07	journal	May 2008
MolProbity : all-atom structure validation for macromolecular crystallography Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1 https://doi.org/10.1107/S0907444909042073	journal	December 2009
Coot model-building tools for molecular graphics Emsley, Paul; Cowtan, Kevin Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132 https://doi.org/10.1107/S0907444904019158	journal	November 2004
Thermofluor-based high-throughput stability optimization of proteins for structural studies Ericsson, Ulrika B.; Hallberg, B. Martin; DeTitta, George T. Analytical Biochemistry, Vol. 357, Issue 2 https://doi.org/10.1016/j.ab.2006.07.027	journal	October 2006
An amino-terminal signal peptide of Vfr protein negatively influences RopB-dependent SpeB expression and attenuates virulence in Streptococcus pyogenes: Regulation of speB expression by Vfr signal peptide Shelburne III, Samuel A.; Olsen, Randall J.; Makthal, Nishanth Molecular Microbiology, Vol. 82, Issue 6 https://doi.org/10.1111/j.1365-2958.2011.07902.x	journal	November 2011
Crystal Structure of Peroxide Stress Regulator from Streptococcus pyogenes Provides Functional Insights into the Mechanism of Oxidative Stress Sensing Makthal, Nishanth; Rastegari, Sheila; Sanson, Misu Journal of Biological Chemistry, Vol. 288, Issue 25 https://doi.org/10.1074/jbc.m113.456590	journal	May 2013
PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
Adhesin competence repressor (AdcR) from Streptococcus pyogenes controls adaptive responses to zinc limitation and contributes to virulence Sanson, Misu; Makthal, Nishanth; Flores, Anthony R. Nucleic Acids Research, Vol. 43, Issue 1 https://doi.org/10.1093/nar/gku1304	journal	December 2014
Rgg protein structure–function and inhibition by cyclic peptide compounds Parashar, Vijay; Aggarwal, Chaitanya; Federle, Michael J. Proceedings of the National Academy of Sciences, Vol. 112, Issue 16 https://doi.org/10.1073/pnas.1500357112	journal	April 2015
Molecular aspects of bacterial pH sensing and homeostasis Krulwich, Terry A.; Sachs, George; Padan, Etana Nature Reviews Microbiology, Vol. 9, Issue 5 https://doi.org/10.1038/nrmicro2549	journal	April 2011
Metabolic dependent and independent pH-drop shuts down VirSR quorum sensing in Clostridium perfringens Adachi, Keika; Ohtani, Kaori; Kawano, Michio Journal of Bioscience and Bioengineering, Vol. 125, Issue 5 https://doi.org/10.1016/j.jbiosc.2017.12.019	journal	May 2018
Dynamic Changes of Intracellular pH in Individual Lactic Acid Bacterium Cells in Response to a Rapid Drop in Extracellular pH Siegumfeldt, Henrik; Björn Rechinger, K.; Jakobsen, Mogens Applied and Environmental Microbiology, Vol. 66, Issue 6 https://doi.org/10.1128/aem.66.6.2330-2335.2000	journal	June 2000
In Situ Determination of the Intracellular pH of Lactococcus lactis and Lactobacillus plantarum during Pressure Treatment Molina-Gutierrez, Adriana; Stippl, Volker; Delgado, Antonio Applied and Environmental Microbiology, Vol. 68, Issue 9 https://doi.org/10.1128/aem.68.9.4399-4406.2002	journal	September 2002
Structure of peptide sex pheromone receptor PrgX and PrgX/pheromone complexes and regulation of conjugation in Enterococcus faecalis Shi, K.; Brown, C. K.; Gu, Z. -Y. Proceedings of the National Academy of Sciences, Vol. 102, Issue 51 https://doi.org/10.1073/pnas.0506163102	journal	December 2005
Bioenergetics of lactic acid bacteria: cytoplasmic pH and osmotolerance Kashket, Eva R. FEMS Microbiology Letters, Vol. 46, Issue 3 https://doi.org/10.1111/j.1574-6968.1987.tb02463.x	journal	September 1987
Evolutionary pathway to increased virulence and epidemic group A Streptococcus disease derived from 3,615 genome sequences Nasser, W.; Beres, S. B.; Olsen, R. J. Proceedings of the National Academy of Sciences, Vol. 111, Issue 17 https://doi.org/10.1073/pnas.1403138111	journal	April 2014
Longitudinal analysis of the group A Streptococcus transcriptome in experimental pharyngitis in cynomolgus macaques Virtaneva, K.; Porcella, S. F.; Graham, M. R. Proceedings of the National Academy of Sciences, Vol. 102, Issue 25 https://doi.org/10.1073/pnas.0503671102	journal	June 2005
Genetic Inactivation of an Extracellular Cysteine Protease (SpeB) Expressed by Streptococcus pyogenes Decreases Resistance to Phagocytosis and Dissemination to Organs Lukomski, Slawomir; Burns, Eugene H.; Wyde, Philip R. Infection and Immunity, Vol. 66, Issue 2 https://doi.org/10.1128/IAI.66.2.771-776.1998	journal	February 1998
The acid tolerance response of Bacillus cereus ATCC14579 is dependent on culture pH, growth rate and intracellular pH Thomassin, Séverine; Jobin, Michel P.; Schmitt, Philippe Archives of Microbiology, Vol. 186, Issue 3 https://doi.org/10.1007/s00203-006-0137-1	journal	August 2006
A cell-cell communication signal integrates quorum sensing and stress response Lee, Jasmine; Wu, Jien; Deng, Yinyue Nature Chemical Biology, Vol. 9, Issue 5 https://doi.org/10.1038/nchembio.1225	journal	March 2013
Expression and Characterization of Group AStreptococcus Extracellular Cysteine Protease Recombinant Mutant Proteins and Documentation of Seroconversion during Human Invasive Disease Episodes Gubba, Siddeswar; Low, Donald E.; Musser, James M. Infection and Immunity, Vol. 66, Issue 2 https://doi.org/10.1128/IAI.66.2.765-770.1998	journal	February 1998
A pH-gated conformational switch regulates the phosphatase activity of bifunctional HisKA-family histidine kinases Liu, Yixiang; Rose, Joshua; Huang, Shaojia Nature Communications, Vol. 8, Issue 1 https://doi.org/10.1038/s41467-017-02310-9	journal	December 2017
Effect of Culture Medium Composition and pH on the Production of M Protein and Proteinase by Group A Streptococci Cohen, Jay O. Journal of Bacteriology, Vol. 99, Issue 3 https://doi.org/10.1128/jb.99.3.737-744.1969	journal	January 1969
Inactivation of the C protein antigen gene, bca, by a novel shuttle/suicide vector results in attenuation of virulence and immunity in group B Streptococcus Li, J.; Kasper, D. L.; Ausubel, F. M. Proceedings of the National Academy of Sciences, Vol. 94, Issue 24 https://doi.org/10.1073/pnas.94.24.13251	journal	November 1997
Structure and Proposed Mechanism for the pH-Sensing Helicobacter pylori Chemoreceptor TlpB Goers Sweeney, Emily; Henderson, J. Nathan; Goers, John Structure, Vol. 20, Issue 7 https://doi.org/10.1016/j.str.2012.04.021	journal	July 2012
Nutritional immunity: transition metals at the pathogen–host interface Hood, M. Indriati; Skaar, Eric P. Nature Reviews Microbiology, Vol. 10, Issue 8 https://doi.org/10.1038/nrmicro2836	journal	July 2012
Neutrophil-generated oxidative stress and protein damage in Staphylococcus aureus Beavers, William N.; Skaar, Eric P. Pathogens and Disease, Vol. 74, Issue 6 https://doi.org/10.1093/femspd/ftw060	journal	June 2016
Spores hit the spot Zhong, Chao Nature Chemical Biology, Vol. 16, Issue 2 https://doi.org/10.1038/s41589-019-0451-y	journal	January 2020
pH of pus collected from periapical abscesses Nekoofar, M. H.; Namazikhah, M. S.; Sheykhrezae, M. S. International Endodontic Journal, Vol. 42, Issue 6 https://doi.org/10.1111/j.1365-2591.2009.01550.x	journal	June 2009
PHENIX: a comprehensive Python-based system for macromolecular structure solution. Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.45787	text	January 2010
Histidine Residue 94 Is Involved in pH Sensing by Histidine Kinase ArsS of Helicobacter pylori Müller, Stefanie; Götz, Monika; Beier, Dagmar PLoS ONE, Vol. 4, Issue 9 https://doi.org/10.1371/journal.pone.0006930	journal	September 2009
Sharply Tuned pH Response of Genetic Competence Regulation in Streptococcus mutans: a Microfluidic Study of the Environmental Sensitivity of comX Son, Minjun; Ghoreishi, Delaram; Ahn, Sang-Joon Applied and Environmental Microbiology, Vol. 81, Issue 16 https://doi.org/10.1128/aem.01421-15	journal	June 2015
Growth Phase and pH Influence Peptide Signaling for Competence Development in Streptococcus mutans Guo, Q.; Ahn, S. -J.; Kaspar, J. Journal of Bacteriology, Vol. 196, Issue 2 https://doi.org/10.1128/jb.00995-13	journal	October 2013
Structural basis for the activation mechanism of the PlcR virulence regulator by the quorum-sensing signal peptide PapR Grenha, R.; Slamti, L.; Nicaise, M. Proceedings of the National Academy of Sciences, Vol. 110, Issue 3 https://doi.org/10.1073/pnas.1213770110	journal	December 2012
Substitution of cysteine 192 in a highly conserved Streptococcus pyogenes extracellular cysteine protease (interleukin 1beta convertase) alters proteolytic activity and ablates zymogen processing. Musser, J. M.; Stockbauer, K.; Kapur, V. Infection and immunity, Vol. 64, Issue 6 https://doi.org/10.1128/iai.64.6.1913-1917.1996	journal	January 1996
Inactivation of Streptococcus pyogenes extracellular cysteine protease significantly decreases mouse lethality of serotype M3 and M49 strains. Lukomski, S.; Sreevatsan, S.; Amberg, C. Journal of Clinical Investigation, Vol. 99, Issue 11 https://doi.org/10.1172/jci119445	journal	June 1997
Exploring the gas access routes in a [NiFeSe] hydrogenase using crystals pressurized with krypton and oxygen Zacarias, Sónia; Temporão, Adriana; Carpentier, Philippe JBIC Journal of Biological Inorganic Chemistry, Vol. 25, Issue 6 https://doi.org/10.1007/s00775-020-01814-y	journal	August 2020
Decreased necrotizing fasciitis capacity caused by a single nucleotide mutation that alters a multiple gene virulence axis Olsen, R. J.; Sitkiewicz, I.; Ayeras, A. A. Proceedings of the National Academy of Sciences, Vol. 107, Issue 2 https://doi.org/10.1073/pnas.0911811107	journal	January 2010
Bioenergetics of lactic acid bacteria: cytoplasmic pH and osmotolerance Kashket, Eva R. FEMS Microbiology Letters, Vol. 46, Issue 3 https://doi.org/10.1111/j.1574-6968.1987.tb02463.x	journal	September 1987
Metabolic dependent and independent pH-drop shuts down VirSR quorum sensing in Clostridium perfringens Adachi, Keika; Ohtani, Kaori; Kawano, Michio Journal of Bioscience and Bioengineering, Vol. 125, Issue 5 https://doi.org/10.1016/j.jbiosc.2017.12.019	journal	May 2018
Rgg protein structure–function and inhibition by cyclic peptide compounds Parashar, Vijay; Aggarwal, Chaitanya; Federle, Michael J. Proceedings of the National Academy of Sciences, Vol. 112, Issue 16 https://doi.org/10.1073/pnas.1500357112	journal	April 2015
Molecular aspects of bacterial pH sensing and homeostasis Krulwich, Terry A.; Sachs, George; Padan, Etana Nature Reviews Microbiology, Vol. 9, Issue 5 https://doi.org/10.1038/nrmicro2549	journal	April 2011
Quorum sensing integrates environmental cues, cell density and cell history to control bacterial competence Moreno-Gámez, Stefany; Sorg, Robin A.; Domenech, Arnau Nature Communications, Vol. 8, Issue 1 https://doi.org/10.1038/s41467-017-00903-y	journal	October 2017
Activation of the Bacterial Sensor Kinase PhoQ by Acidic pH Prost, Lynne R.; Daley, Margaret E.; Le Sage, Valerie Molecular Cell, Vol. 26, Issue 2 https://doi.org/10.1016/j.molcel.2007.03.008	journal	April 2007
Bacillus subtilis RapA Phosphatase Domain Interaction with Its Substrate, Phosphorylated Spo0F, and Its Inhibitor, the PhrA Peptide Diaz, A. R.; Core, L. J.; Jiang, M. Journal of Bacteriology, Vol. 194, Issue 6 https://doi.org/10.1128/JB.06747-11	journal	January 2012
Role for a secreted cysteine proteinase in the establishment of host tissue tropism by group A streptococci Svensson, Mikael D.; Scaramuzzino, Dominick A.; Sjobring, Ulf Molecular Microbiology, Vol. 38, Issue 2 https://doi.org/10.1046/j.1365-2958.2000.02144.x	journal	October 2000
Longitudinal analysis of the group A Streptococcus transcriptome in experimental pharyngitis in cynomolgus macaques Virtaneva, K.; Porcella, S. F.; Graham, M. R. Proceedings of the National Academy of Sciences, Vol. 102, Issue 25 https://doi.org/10.1073/pnas.0503671102	journal	June 2005
A cell-cell communication signal integrates quorum sensing and stress response Lee, Jasmine; Wu, Jien; Deng, Yinyue Nature Chemical Biology, Vol. 9, Issue 5 https://doi.org/10.1038/nchembio.1225	journal	March 2013
Extracellular Cysteine Protease Produced by Streptococcus pyogenes Participates in the Pathogenesis of Invasive Skin Infection and Dissemination in Mice Lukomski, Slawomir; Montgomery, Charles A.; Rurangirwa, Jacqueline Infection and Immunity, Vol. 67, Issue 4 https://doi.org/10.1128/IAI.67.4.1779-1788.1999	journal	April 1999
The Crystallization and Serological Differentiation of a Streptococcal Proteinase and its Precursor Elliott, S. D. The Journal of Experimental Medicine, Vol. 92, Issue 3 https://doi.org/10.1084/jem.92.3.201	journal	September 1950
Bacterial Stress Responses during Host Infection Fang, Ferric C.; Frawley, Elaine R.; Tapscott, Timothy Cell Host & Microbe, Vol. 20, Issue 2 https://doi.org/10.1016/j.chom.2016.07.009	journal	August 2016
Molecular Pathogenesis of Necrotizing Fasciitis Olsen, Randall J.; Musser, James M. Annual Review of Pathology: Mechanisms of Disease, Vol. 5, Issue 1 https://doi.org/10.1146/annurev-pathol-121808-102135	journal	January 2010
N-Acylhomoserine Lactones Undergo Lactonolysis in a pH-, Temperature-, and Acyl Chain Length-Dependent Manner during Growth of Yersinia pseudotuberculosis and Pseudomonas aeruginosa Yates, Edwin A.; Philipp, Bodo; Buckley, Catherine Infection and Immunity, Vol. 70, Issue 10 https://doi.org/10.1128/IAI.70.10.5635-5646.2002	journal	October 2002
Leaderless secreted peptide signaling molecule alters global gene expression and increases virulence of a human bacterial pathogen Do, Hackwon; Makthal, Nishanth; VanderWal, Arica R. Proceedings of the National Academy of Sciences, Vol. 114, Issue 40 https://doi.org/10.1073/pnas.1705972114	journal	September 2017
Structural Mechanisms of Peptide Recognition and Allosteric Modulation of Gene Regulation by the RRNPP Family of Quorum-Sensing Regulators Do, Hackwon; Kumaraswami, Muthiah Journal of Molecular Biology, Vol. 428, Issue 14 https://doi.org/10.1016/j.jmb.2016.05.026	journal	July 2016
The acid tolerance response of Bacillus cereus ATCC14579 is dependent on culture pH, growth rate and intracellular pH Thomassin, Séverine; Jobin, Michel P.; Schmitt, Philippe Archives of Microbiology, Vol. 186, Issue 3 https://doi.org/10.1007/s00203-006-0137-1	journal	August 2006
Signaling by a Conserved Quorum Sensing Pathway Contributes to Growth Ex Vivo and Oropharyngeal Colonization of Human Pathogen Group A Streptococcus Makthal, Nishanth; Do, Hackwon; VanderWal, Arica R. Infection and Immunity, Vol. 86, Issue 5 https://doi.org/10.1128/iai.00169-18	journal	March 2018
Cavin1 intrinsically disordered domains are essential for fuzzy electrostatic interactions and caveola formation Tillu, Vikas A.; Rae, James; Gao, Ya Nature Communications, Vol. 12, Issue 1 https://doi.org/10.1038/s41467-021-21035-4	journal	February 2021
An amino-terminal signal peptide of Vfr protein negatively influences RopB-dependent SpeB expression and attenuates virulence in Streptococcus pyogenes: Regulation of speB expression by Vfr signal peptide Shelburne III, Samuel A.; Olsen, Randall J.; Makthal, Nishanth Molecular Microbiology, Vol. 82, Issue 6 https://doi.org/10.1111/j.1365-2958.2011.07902.x	journal	November 2011
Structural Insights into Streptococcal Competence Regulation by the Cell-to-Cell Communication System ComRS Talagas, Antoine; Fontaine, Laetitia; Ledesma-Garca, Laura PLOS Pathogens, Vol. 12, Issue 12 https://doi.org/10.1371/journal.ppat.1005980	journal	December 2016
Extracellular Cysteine Protease Produced by Streptococcus pyogenes Participates in the Pathogenesis of Invasive Skin Infection and Dissemination in Mice Lukomski, Slawomir; Montgomery, Charles A.; Rurangirwa, Jacqueline Infection and Immunity, Vol. 67, Issue 4 https://doi.org/10.1128/.67.4.1779-1788.1999	journal	January 1999
From transcription to activation: how group A streptococcus, the flesh-eating pathogen, regulates SpeB cysteine protease production: Streptococcal cysteine protease Carroll, Ronan K.; Musser, James M. Molecular Microbiology, Vol. 81, Issue 3 https://doi.org/10.1111/j.1365-2958.2011.07709.x	journal	June 2011
Structural and functional analysis of RopB: a major virulence regulator in S treptococcus pyogenes: Crystal structure of RopB Makthal, Nishanth; Gavagan, Maire; Do, Hackwon Molecular Microbiology, Vol. 99, Issue 6 https://doi.org/10.1111/mmi.13294	journal	February 2016
Structural Mechanisms of Peptide Recognition and Allosteric Modulation of Gene Regulation by the RRNPP Family of Quorum-Sensing Regulators Do, Hackwon; Kumaraswami, Muthiah Journal of Molecular Biology, Vol. 428, Issue 14 https://doi.org/10.1016/j.jmb.2016.05.026	journal	July 2016
Molecular complexity of successive bacterial epidemics deconvoluted by comparative pathogenomics Beres, S. B.; Carroll, R. K.; Shea, P. R. Proceedings of the National Academy of Sciences, Vol. 107, Issue 9 https://doi.org/10.1073/pnas.0911295107	journal	February 2010
Pheromone Recognition and Selectivity by ComR Proteins among Streptococcus Species Shanker, Erin; Morrison, Donald A.; Talagas, Antoine PLOS Pathogens, Vol. 12, Issue 12 https://doi.org/10.1371/journal.ppat.1005979	journal	December 2016
The Crystallization and Serological Differentiation of a Streptococcal Proteinase and its Precursor Elliott, S. D. The Journal of Experimental Medicine, Vol. 92, Issue 3 https://doi.org/10.1084/jem.92.3.201	journal	September 1950
Glucose and nonmaintained pH decrease expression of the accessory gene regulator (agr) in Staphylococcus aureus. Regassa, L. B.; Novick, R. P.; Betley, M. J. Infection and Immunity, Vol. 60, Issue 8 https://doi.org/10.1128/IAI.60.8.3381-3388.1992	journal	January 1992
Effect of the abscess environment on the antimicrobial activity of ciprofloxacin Bryant, Richard E.; Mazza, Joyce A. The American Journal of Medicine, Vol. 87, Issue 5 https://doi.org/10.1016/0002-9343(89)90014-4	journal	November 1989
Thermofluor-based high-throughput stability optimization of proteins for structural studies Ericsson, Ulrika B.; Hallberg, B. Martin; DeTitta, George T. Analytical Biochemistry, Vol. 357, Issue 2 https://doi.org/10.1016/j.ab.2006.07.027	journal	October 2006
Peptide signaling in Staphylococcus aureus and other Gram-positive bacteria Lyon, Gholson J.; Novick, Richard P. Peptides, Vol. 25, Issue 9 https://doi.org/10.1016/j.peptides.2003.11.026	journal	September 2004
Cellâcell signalling in bacteria: not simply a matter of quorum: Cellâcell signalling in bacteria Boyer, MickaÃ«l; Wisniewski-DyÃ©, Florence FEMS Microbiology Ecology, Vol. 70, Issue 1 https://doi.org/10.1111/j.1574-6941.2009.00745.x	journal	October 2009
Bacterial Quorum Sensing: Its Role in Virulence and Possibilities for Its Control Rutherford, S. T.; Bassler, B. L. Cold Spring Harbor Perspectives in Medicine, Vol. 2, Issue 11 https://doi.org/10.1101/cshperspect.a012427	journal	November 2012
Role for a secreted cysteine proteinase in the establishment of host tissue tropism by group A streptococci Svensson, Mikael D.; Scaramuzzino, Dominick A.; Sjobring, Ulf Molecular Microbiology, Vol. 38, Issue 2 https://doi.org/10.1046/j.1365-2958.2000.02144.x	journal	October 2000
Editorial: The sum of all defenses: tolerance + resistance Napier, Brooke A.; Monack, Denise M. Pathogens and Disease, Vol. 75, Issue 2 https://doi.org/10.1093/femspd/ftx015	journal	February 2017
Isolation and characterization of erythrogenic toxins V. Communication: Identity of erythrogenic toxin type B and Streptococcal proteinase precursor Gerlach, Dieter; Knöll, Heide; Köhler, Werner Zentralblatt für Bakteriologie, Mikrobiologie und Hygiene. 1. Abt. Originale. A, Medizinische Mikrobiologie, Infektionskrankheiten und Parasitologie, Vol. 255, Issue 2-3 https://doi.org/10.1016/s0174-3031(83)80161-9	journal	September 1983
The integration of macromolecular diffraction data Leslie, Andrew G. W. Acta Crystallographica Section D Biological Crystallography, Vol. 62, Issue 1 https://doi.org/10.1107/S0907444905039107	journal	December 2005
Naturally occurring single amino acid replacements in a regulatory protein alter streptococcal gene expression and virulence in mice Carroll, Ronan K.; Shelburne, Samuel A.; Olsen, Randall J. Journal of Clinical Investigation, Vol. 121, Issue 5 https://doi.org/10.1172/JCI45169	journal	May 2011
The pH of the Host Niche Controls Gene Expression in and Virulence of Candida albicans De Bernardis, Flavia; Mühlschlegel, Fritz A.; Cassone, Antonio Infection and Immunity, Vol. 66, Issue 7 https://doi.org/10.1128/iai.66.7.3317-3325.1998	journal	July 1998
Effect of Culture Medium Composition and pH on the Production of M Protein and Proteinase by Group A Streptococci Cohen, Jay O. Journal of Bacteriology, Vol. 99, Issue 3 https://doi.org/10.1128/jb.99.3.737-744.1969	journal	January 1969
Substitution of cysteine 192 in a highly conserved Streptococcus pyogenes extracellular cysteine protease (interleukin 1beta convertase) alters proteolytic activity and ablates zymogen processing. Musser, J. M.; Stockbauer, K.; Kapur, V. Infection and immunity, Vol. 64, Issue 6 https://doi.org/10.1128/iai.64.6.1913-1917.1996	journal	January 1996
A Novel Method for Continuous Determination of the Intracellular pH in Bacteria with the Internally Conjugated Fluorescent Probe 5 (and 6-)-Carboxyfluorescein Succinimidyl Ester. Breeuwer, P.; Drocourt, J.; Rombouts, F. M. Applied and environmental microbiology, Vol. 62, Issue 1 https://doi.org/10.1128/aem.62.1.178-183.1996	journal	January 1996