Kevin S. McIver, Ph.D.

Bacterial Pathogenesis; Host-Pathogen Interactions
Molecular Microbiology; Gene Regulation

GRAM-POSITIVE BACTERIAL PATHOGENESIS:

My laboratory is interested in the molecular mechanisms by which pathogenic Streptococci as well as other G+ pathogens (e.g., MRSA, Enterococcus) regulate their virulence repertoire in response to host signals. The group A streptococcus (Streptococcus pyogenes, GAS) is an important 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 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 to survive in that particular environment.
A main focus in our lab is on 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, Bacillus anthracis 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. We have uncovered a direct link between the metabolic state of the pathogen (carbon utilization) and activation of the Mga pathway. This has led us to look into the influence of sugar metabolism on virulence during infection by 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 mutated 12 of the 13 S. pyogenes two-component response regulators (TCS) in several serotypes of GAS and are investigating their role in pathogenesis. 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.

BIODEFENSE-RELATED PATHOGENS:

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. Our lab is looking into factors produced by Ft during tularemia that may be important for disease as well as investigating novel methods to detect and identify Ft in the environment. Through these endeavors, we hope to identify potential targets for therapies to diminish acute symptoms or for early detection to allow proper treatments.

Vahling, C.M. and K. S. McIver (2006) Domains required for transcriptional activation show conservation in the Mga family of virulence gene regulators. Journal of Bacteriology 188(3):863-873.

Almengor, A.C. and K. S. McIver (2006) Mga is sufficient to activate transcription in vitro of sof-sfbX and other Mga-regulated virulence genes in the group A streptococcus. Journal of Bacteriology 188(6):2038-2047.

Ribardo, D.A. 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, Molecular Microbiology 62:491-508.

Almengor, A.C., T.L Kinkel, S.J. Day, and K. S. McIver (2007) The catabolite control protein CcpA binds to Pmga and influences the expression of the virulence regulator Mga in the group A streptococcus. Journal of Bacteriology 189(23):8405-8416.

Hondorp, E.R. and K. S. McIver (2007) The Mga virulence regulon: Infection where the grass is greener. Molecular Microbiology 66(5): 1056-1065.
Kinkel, T.L. and K.S. McIver (2008) CcpA-mediated repression of streptolysin S expression and virulence in the group A streptococcus. Infection & Immunity, 76(8):3451-3463.

Leday, T.V.*, K.M. Gold*, T.L. Kinkel, K, S.A. Roberts, J.R. Scott, and K.S. McIver (2008) TrxR, a new CovR-repressed response regulator that activates the Mga virulence regulon in the group A streptococcus, Infection & Immunity, 76(10):4569-4668.

M. Fisher, Y. Huang, X. Li, K.S. McIver, and Z. Eichenbaum (2008) Shr is a broad-spectrum surface receptor that contributes to adherence and virulence in the group A streptococcus. Infection & Immunity, 76(11):5006-5015.

M. Nakata, T. Koller, K. Moritz, D. Ribardo, L. Jonas, K.S. McIver, T. Sumitomo, Y Terao, S. Kawabata, A. Podbielski, and B. Kreikemeyer (2009) Mode of Expression and functional characterization of FCT-3 Pilus region-encoded proteins in S. pyogenes serotype M49. Infection & Immunity, 77(1):32-44.
K.S. McIver (2009) Stand-alone response regulators controlling global virulence networks in Streptococcus pyogenes. Contributions to Microbiology, 16:103-119.

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