Kevin S. McIver

Associate Professor

Research Interests: Host-Bacterial Pathogen Interactions, Molecular Mechanisms of pathogenesis for Streptococcus pyogenes and Francisella tularensis, Gene regulation

The group A streptococcus (Streptococcus pyogenes, GAS) is an important Gram-positive bacterial pathogen strictly limited to infections of humans, eliciting primarily self-limiting purulent infections such as pharyngitis (‘strep throat’) and impetigo.  However, GAS may also invade normally sterile sites in the body to elicit severe and often fatal invasive disorders, including necrotizing fasciitis (‘flesh-eating disease’) and a streptococcal toxic shock syndrome (STSS). In addition, some group A streptococcal 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 to survive in that particular environment. 

Our laboratory is interested in the molecular mechanisms by which GAS regulates its virulence repertoire in response to host signals.  A main focus is the multiple virulence gene regulator of GAS (Mga), a DNA-binding protein that regulates expression of key virulence factors essential for colonization of the host and immune evasion in response to changing stimuli.  Orthologs of Mga can be found in other Gram-positive pathogens such as Streptococcus pneumonia and Enterococcus faecalis.  Ongoing studies include a structure/function analysis of Mga, exploring the mechanism of activation at the different Mga regulon promoters, and the role of other regulatory elements at the mga promoter.  We have identified and are further characterizing novel genes that are required for Mga regulon expression and environmental sensing.  GAS DNA microarrays are being used to provide a more global view of virulence involving global changes in gene expression under various conditions relevant to disease. Finally, mouse models of GAS infection are being utilized to assess the role of Mga in GAS disease.

We are also exploring the role of other regulatory circuits for their involvement in GAS pathogenesis.  Two-component signal transduction systems are used by bacteria to coordinately regulate large sets of genes for a particular function (e.g., virulence) in response to a specific environmental cue.   We have constructed a series of mutagenic plasmids that allow the inactivation of 12 of the 13 S. pyogenes two-component response regulators (SptR) in most serotypes of GAS.  These mutant strains are being assayed for virulence in various mouse models to identify those regulatory pathways necessary for different types of streptococcal disease.   The overall goal is to increase our knowledge of GAS and Gram-positive bacterial pathogenesis that may lead to new treatment strategies.

Francisella tularensis (Ft) is the etiologic agent of tularemia, a severe and often fatal disease of humans.  More recently, its role as a potential biothreat agent (category A) has increased the need to better understand the pathogenesis of this organism in order to develop new diagnostic, vaccine, and intervention strategies.  To date, there have been no secreted proteins of Ft identified or implicated in the pathogenesis of this pathogen.  As part of a multi-component program project grant to investigate the molecular biology of F. tularensis virulence, our lab is conducting a comprehensive analysis of the Ft extracellular proteome produced in different environments.  These studies are combining proteomic and genomic approaches as well as in situ and in vivo murine infection models to characterize the role such exoproteins during tularemia.  Through these endeavors, we hope to identify potential targets for therapies to diminish acute symptoms during early stages of F. tularensis infection.

Selected Publications:

D.A. Ribardo and K.S. McIver (2006) Defining the Mga virulence regulon: Comparative transcriptome analysis reveals both direct and indirect regulation by Mga in the group A streptococcus, In press: Mol. Microbiol.
A.C. Almengor, M. Walters and K.S. McIver (2006) Mga is sufficient to activate transcription in vitro of sof-sfbX and other Mga-regulated virulence gene in the Group A streptococcus, J. Bacteriol. 188(6): 2038-2047.
C.M. Vahling and K.S. McIver (2006) Domains required for transcriptional activation show conservation in the Mga family of virulence gene regulators. J. Bacteriol. 188(3):863-873.
C.M. Vahling and K.S. McIver (2005) Identification of residues responsible for the defective virulence gene regulator Mga produced by a natural mutant of Streptococcus pyogenes. J. Bacteriol. 187(17): 5955-5966.
A.C. Almengor and K.S. McIver (2004) Transcriptional activation of sclA by Mga requires a distal binding site in Streptococcus pyogenes, J. Bacteriol. 186(23): 7847-7857.
K.S. McIver, E. Kessler, and D.E. Ohman (2004) Identification of residues in the Pseudomonas aeruginosa elastase propeptide required for chaperone and secretion activities, Microbiol. 150(12): 3969-3977.
D.A. Ribardo, T.J. Lambert, and K.S. McIver (2004) Role of Streptococcus pyogenes 2-component response regulators in the temporal control of Mga-regulated virulence genes emm and mga. Infect. Immun. 72(6):3668-3673.
D.A. Ribardo and K.S. McIver (2003) amrA encodes a putative membrane protein necessary for maximal exponential phase expression of the Mga virulence regulon in Streptococcus pyogenes Mol. Microbiol. 50(2),673-685.
B. Kreikemeyer, K.S. McIver, and A. Podbielski (2003) The missing links-virulence factor regulation and regulatory networks in Streptococcus pyogenes and their impact on bacteria-host interactions. Trends in Microbiol. 11(5):1-10.
K.S. McIver and R..L. Myles (2002) Two DNA-binding domains of Mga are required for virulence gene activation in the group A streptocococcus Mol. Microbiol. 43:1591-1602.
 

Graduate Research Assistantships: My lab provides an excellent environment for graduate students development, including outstanding individual research projects.  Please contact me for possible lab rotations.