• BISI - Molecular & Cellular Biology (MOCB)
• BISI - Computational Biology, Bioinformatics, & Genomics (CBBG) 
• Co-Director; NIH T32 Training Grant on Host-Pathogen Interactions

Bacterial Pathogenesis; Host-Pathogen Interactions

Molecular Microbiology; Gene Regulation 

In vivo Fitness and Pathophysiology of the Group A Streptococcus

GRAM-POSITIVE BACTERIAL PATHOGENESIS:

The McIver laboratory is interested in the molecular mechanisms by which pathogenic Streptococci as well as other G+ pathogens adapt to host tissues and regulate their virulence repertoire. The group A streptococcus (GAS) or Streptococcus pyogenes is an important pathogen strictly limited to infections of humans, eliciting primarily self-limiting purulent infections such as ‘strep throat’ and impetigo. However, GAS may also invade normally sterile sites in the body to cause severe and often fatal invasive disorders, including necrotizing fasciitis (‘flesh-eating disease’) and streptococcal toxic shock syndrome (STSS). In addition, some GAS infections can lead to the serious immune sequelae acute rheumatic fever (ARF) and glomerulonephritis, as well as possibly triggering neurological tic disorders. Since GAS has the capacity to persist within various host niches, it strongly suggests that they are able to sense their changing surroundings and coordinately express those factors needed for fitness and survival in that particular environment.  Our overall goal is to increase knowledge of GAS and Gram-positive bacterial pathogenesis that may lead to new treatment strategies.  Our research is supported by NIH/National Institutes of Allergy and Infectious Diseases (NIAID) and the American Heart Association.

Genetic Determinants of In Vivo Fitness and Essentiality: We have been employing high throughput genetic screens, using a mariner transposon system developed in the lab for GAS to apply transposon site hybridization (TraSH) and transposon-sequencing (Tn-seq).  The McIver lab has successfully assayed genes required for fitness in rich media (THY), whole human blood and in murine soft tissue.  We have also used Tn-seq to determine the essential core genes found in all GAS and pathogenic streptococci for use as potential antimicrobial targets.  Ongoing Tn-seq studies are focusing on genes required for fitness during PMN interactions, biofilm formation, and during colonization of mucosal surfaces.  Validation and investigation of these datasets has led to the discovery of novel virulence factors and pathways important in different host niches.  We have also begun to assemble genetic interaction maps using global virulence regulators (see below) under these same host-relevant environments. Through collaboration, we are looking at metal stress, biofilm formation, mucosal colonization in Group B Streptococcus, and Gram-positive cell wall biosynthesis, among others.

Global Regulation of Virulence Genes:  The McIver lab has long been interested in exploring global regulatory circuits for their involvement in GAS pathogenesis. One such pathway is controlled by the stand-alone regulator Mga, which activates a number of important surface virulence factors in response to positive growth signals, (e.g., M protein, C5a peptidase, streptococcal collagen-like protein SclA, serum opacity factor Sof, and others).  Our group discovered that Mga represents a new family of PRD-containing Virulence Regulators (PCVRs) found in Gram-positive pathogens that directly communicate with the PEP Phosphotransferase System (PTS) involved in carbohydrate uptake.  Along with the AtxA toxin regulator from Bacillus anthracis, they are the paradigm of this family with paralogs in GAS and homologs in other pathogenic streptococci.  Phosphorylation of Mga by PTS impacts is activity and suggests a link to sugars as an in vivo signal.  By RNA-seq, we found that glucose availability impacts the Mga regulon and are now investigating other PCVRs.  Finally, we are using genetic interactions mapping by Tn-seq to identify the overall pathway in GAS. 

In addition to Mga, the McIver lab has interests in two-component signal transduction systems. We have looked at the TCS TrxSR with Emanuel Hanski’s group in Israel and identified the TrxR regulon in the context of host cell contact as well its involvement in pathogenesis. In collaboration with Zehava Eichenbaum’s group at Georgia State University, we have looked at the iron-responsive regulator MtsR and used RNA-seq to determine the heme stress transcriptome in GAS.   

Role of Carbohydrate Uptake and Metabolism on Virulence:  Due to the discovery of Mga as a PCVR, we have begun to characterize the PTS system in GAS by inactivating each of the 14 sugar-specific EIIC transporters found in the genome and determining their impact on growth and virulence.  Loss of the entire PTS pathway (∆EI) leads to an exacerbated expression of Streptolysin S across growth and hyper-virulent lesion formation during soft tissue infection.  We are using the EIIC mutant library to be reveal which transporters (and sugars) lead to this phenotype and to better understand in vivo signals.  Ongoing work is to determine how glucose is imported by GAS and the impact on the pathogen during infection.  

M. Baruch, I. Belotserkovsky, B. Hertzog, M. Ravins, E. Dov, K.S. McIver, Y. LeBreton, Y. Zhou, C. Youting, and E. Hanski  (2014) An Extracellular Bacterial Pathogen Modulates Host Metabolism to Regulate Its Own Sensing and Proliferation, Cell 156:97-108. DOI:  10.1016/j.cell.2013.12.007.  PMID: 24439371. 

K. Gera, T. Le, R. Jamin, Z. Eichenbaum, and K.S. McIver (2014) The Phosphoenolpyruvate Phosphotransferase System in group A streptococcus acts to reduce Streptolysin S activity and lesion formation during soft tissue infection, Infection and Immunity 82(3):1192-1204.   DOI: 10.1128/IAI.01271-13. PMID: 24379283.

J.A. Freiberg, K.S. McIver, and M.E. Shirtliff (2014) In Vivo Expression of Streptococcus pyogenes Immunogenic Proteins During Tibial Foreign Body Infection, Infection and Immunity 82(9):3891-9.  DOI: 10.1128/IAI.01831-14.  PMID: 25001603. 

A.J., Sachla, Y. Le Breton, F. Akhter, K.S. McIver and Z. Eichenbaum, (2014) The Crimson Conundrum: Heme Toxicity and Tolerance in GAS. Frontiers in Cellular and Infection Microbiology 4:159. DOI: 10.3389/fcimb.2014.00159.  PMID: 25413836Y. Le Breton, A.T. Belew, K. Valdes, E. Islam, P. Curry, H. Tettelin, M.E. Shirtliff, N.M. El-Sayed, and K.S. McIver (2015) Essential Genes in the Core Genome of the Human Pathogen Streptococcus pyogenes, Scientific Reports, 5:9838; DOI: 10.1038/srep09838 (2015). PMID: 25996237.

S. van der Beek, Y. Le Breton, A. Fernbach, R. Chapman, D. van Aalten, I. Navratilova, G. Boons,  K.S. McIver, N. van Sorge, and H. Dorfmueller (2015) GacA is Essential for Group A Streptococcus and Defines a New Class of Monomeric dTDP-4-dehydrorhamnose Reductases (RmlD), Molecular Microbiology, 1 Oct. 2015, DOI: 10.1111/mmi.13169. PMID: 26278404.  

K.M. Valdes*, G.S. Sundar*, L.A.Vega, A.T. Belew, E. Islam, R. Binet, N.M. El-Sayed, Y. Le Breton, and K.S. McIver (2016) The fruRBA Operon is Necessary for Group A Streptococcal Growth in Fructose and for Resistance to Neutrophil Killing During Growth in Whole Human Blood, Infection and Immunity, 19 Jan. 2016, PMID: 26787724. (* equal contribution)  

J.A. Freiberg, Y. Le Breton, B.Q. Tran, A.J. Scott, J.M. Harro, R.K. Ernst, Y.A. Goo, D.R. Goodlett, K.S. McIver, and M.E. Shirtliff (2016) Global Analysis and Comparison of the Transcriptome and Proteome of Group A Streptococcus Biofilms, mSystems, 1(6):e00149-16.

G.S. Sundar*, E. Islam, K. Gera, Y. Le Breton, and K.S. McIver (2016) A PTS EII Mutant Library Identifies a Promiscuous Man-family Transporter Influencing SLS-Mediated Hemolysis and Virulence, Molecular Microbiology, 2016 Nov 8, DOI: 10.1111/mmi.13573 

L.A. Vega, K.M. Valdes, G.S. Sundar, A.T. Belew, E. Islam, J. Berge, P. Curry, S. Chen, N.M. El-Sayed, Y. Le Breton, and K.S. McIver (2016) The Transcriptional Regulatory CpsY is Important for Innate Immune Evasion in Streptococcus pyogenes, Infection and Immunity, 2016 19 December, DOI: 10.1128/IAI.100925-16.

Y. Le Breton, A.T. Belew, J.A. Freiberg, G.S. Sundar, E. Islam, J. Lieberman, M.E. Shirtliff, H. Tettelin, N.M. El-Sayed, and K.S. McIver (2017) Genome-wide Discovery of Novel M1T1 Group A Streptococcal Determinants Important For Fitness and Virulence During Soft-Tissue Infection, PLoS Pathogens, 13(8):e1006584, DOI:10.1371/ppat.1006584.

S. Brouwer, A.J. Cork, C.Y. Ong, T.C. Barnett, N.P. West, A. G McEwan, K.S. McIver, and M.J. Walker (2018) The Endopeptidase PepO Regulates the SpeB Cysteine Protease and is Essential for the Virulence of Invasive M1T1 Streptococcus pyogenes.  Journal of Bacteriology, 200(8), DOI:10.1128/JB.00654-17, PMID: 29378883.

K.M. Valdes, G.S. Sundar, A.T. Belew, E. Islam, N.M. El-Sayed, Y. Le Breton, and K.S. McIver (2018) Glucose Levels Alter the Mga Virulence Regulon in the Group A Streptococcus, Scientific Reports, 8(1):4971, PMID: 29563558.  

G.S. Sundar, E. Islam, R.D. Braza, A.B. Silver, Y. Le Breton, and K.S. McIver (2018) Route of Glucose Uptake in the Group A Streptococcus Impacts SLS-Mediated Hemolysis and Survival in Human Blood, Frontiers in Cellular and Infection Microbiology, 8:71, DOI: 10.3389/fcimb.2018.00071, PMID: 29594067.  

Ph.D. - University of Tennessee Health Sciences Center, 1994

Postdoc - Emory University School of Medicine, 1994-1999

Asst. Professor - UT Southwestern Medical Center, 1999-2006