• Molecular & Cellular Biology (MOCB) concentration, Biological Sciences (BISI)
• Computational Biology, Bioinformatics, & Genomics (CBBG) concentration, BISI
• Co-Program Director; NIH T32 Graduate Training in 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 the National Institutes of Health (NIH) in the National Institute of Allergy and Infectious Diseases (NIAID).

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-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, heme and iron stress, biofilm formation, and during colonization of mucosal surfaces.  Validation and investigation of these datasets has led to the discovery of novel virulence factors and metabolic transport pathways important in different host niches (see below).  We have also begun to assemble genetic interaction maps using global virulence regulators (see below) under these same host-relevant environments. In collaboration, we are investigating metal stress, biofilm formation, mucosal colonization in Group B Streptococcus (Kelly Doran at U. Colorado), and Gram-positive bacterial cell wall biosynthesis (Nina van Sorge, Netherlands; Natalia Korotkova, U. Kentucky).

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 (e.g., RofA) and homologs in other pathogenic streptococci.  We have shown PTS phosphorylation of Mga and RofA by PTS, which in the case of Mga can impact is activity.  Overall, this suggests a link to sugars as an in vivo signal for GAS virulence.  By RNA-seq, we found that glucose availability impacts the Mga regulon and are now investigating the RofA regulon.  Finally, we are using genetic interactions mapping using Tn-seq in mutant backgrounds to identify the novel pathways in GAS. 

Role of Carbohydrate and Amino Acid uptake on pathophysiology of GAS:  Due to the discovery of Mga as a PCVR, we have characterized 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 for PCVRs.  Ongoing work is focused on how glucose and mannose impact on the pathogen during infection.

From our Tn-seq studies, we have also identified a number of putative transporters of amino acids and other metabolites that play a critical role for fitness in soft tissue and survival from innate immunity. These include ScfCDE (tryptophan), MetQNP (methionine), ScfAB (unknown substrate), and PdxRKU (pyridoxal).  We are currently asking how these and other transporters are contributing to the pathophysiology of GAS.

Heme stress adaptation and regulation :  Heme is a highly important nutrient for GAS fitness during infection that in excess can be toxic to the bacterial cell.  In collaboration with Zehava Eichenbaum at Georgia State University, we have established the heme stress transcriptome in GAS under heme stress and have begun to identify key components needed for responding to this environment, including known and predicated regulatory systems as well as efflux complexes. We are now employing Tn-seq and RNA-seq to reveal the genes important for responding to heme stress to drive future studies to learn the molecular mechanisms involved.

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

Assistant Professor - UT Southwestern Medical Center, 1999-2006

Associate Professor – University of Maryland, College Park, 2006-2012

Professor – University of Maryland, College Park, 2012-present

Chair – University of Maryland, College Park, 2022-present