Kevin McIver headshot
Contact Info
Office: 3124 Bioscience Research Bldg
Lab: 3217 Bioscience Research Bldg
Office Phone: 301-405-4136
Lab Phone: 301-314-7514
Kevin McIver
Professor
Department Chair

Teaching

  • General Microbiology (for majors) (BSCI283)
  • Microbial Pathogenesis (CBMG688L)
  • Bacterial Genetics (CBMG688M)

Graduate Program Affiliations

  • BISI-Computational Biology, Bioinformatics, & Genomics (CBBG)
  • BISI-Molecular & Cellular Biology (MOCB)
  • Co-Program Director, NIH T32 Graduate Training in Host-Pathogen Interactions

Research Interests

  • 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.


Education & Positions

  • 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

All Publications

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Latest Publications

Davis SE,Hart MT,Braza RED,Perry AA,Vega LA,Le Breton YS,McIver KS
Microbiol Spectr. 2024 Nov 12;:e0160924. doi: 10.1128/spectrum.01609-24. Epub 2024 Nov 12
Akbari MS,Joyce LR,Spencer BL,Brady A,McIver KS,Doran KS
bioRxiv. 2024 Oct 28;:. pii: 2024.07.30.605887. doi: 10.1101/2024.07.30.605887. Epub 2024 Oct 28
Hart MT,Rom JS,Le Breton Y,Hause LL,Belew AT,El-Sayed NM,McIver KS
Infect Immun. 2024 Jun 11;92(6):e0008324. doi: 10.1128/iai.00083-24. Epub 2024 May 7
Ferretti JJ,Stevens DL,Fischetti VA,Vega LA,Malke H,McIver KS
. 2022 Oct 8;:. . Epub
Rom JS,Le Breton Y,Islam E,Belew AT,El-Sayed NM,McIver KS
Microorganisms. 2022 Aug 22;10(8):. doi: 10.3390/microorganisms10081686. Epub 2022 Aug 22
Burcham LR,Akbari MS,Alhajjar N,Keogh RA,Radin JN,Kehl-Fie TE,Belew AT,El-Sayed NM,McIver KS,Doran KS
mBio. 2022 Jun 28;13(3):e0098522. doi: 10.1128/mbio.00985-22. Epub 2022 Jun 6
Woo JKK,McIver KS,Federle MJ
Mol Microbiol. 2022 Feb;117(2):525-538. doi: 10.1111/mmi.14866. Epub 2022 Jan 3
Rom JS,Hart MT,McIver KS
Front Cell Infect Microbiol. 2021;11:772874. doi: 10.3389/fcimb.2021.772874. Epub 2021 Oct 19
Akhter F,Womack E,Vidal JE,Le Breton Y,McIver KS,Pawar S,Eichenbaum Z
Infect Immun. 2021 Mar 17;89(4):. doi: 10.1128/IAI.00779-20. Epub 2021 Mar 17
Burcham LR,Le Breton Y,Radin JN,Spencer BL,Deng L,Hiron A,Ransom MR,Mendonça JDC,Belew AT,El-Sayed NM,McIver KS,Kehl-Fie TE,Doran KS
mBio. 2020 Nov 10;11(6):. doi: 10.1128/mBio.02302-20. Epub 2020 Nov 10
Braza RE,Silver AB,Sundar GS,Davis SE,Razi A,Islam E,Hart M,Zhu J,Le Breton Y,McIver KS
Infect Immun. 2020 Sep 18;88(10):. doi: 10.1128/IAI.00346-20. Epub 2020 Sep 18
Akhter F,Womack E,Vidal JE,Le Breton Y,McIver KS,Pawar S,Eichenbaum Z
Sci Rep. 2020 Sep 16;10(1):15202. doi: 10.1038/s41598-020-71910-1. Epub 2020 Sep 16
Freiberg JA,Le Breton Y,Harro JM,Allison DL,McIver KS,Shirtliff ME
mBio. 2020 Jul 7;11(4):. doi: 10.1128/mBio.00919-20. Epub 2020 Jul 7
Le Breton Y,Belew AT,McIver KS
Methods Mol Biol. 2020;2136:33-57. doi: 10.1007/978-1-0716-0467-0_4. Epub
Braza RE,Le Breton Y,McIver KS
Infect Immun. 2019 Dec;87(12):. doi: 10.1128/IAI.00613-19. Epub 2019 Nov 18
Edgar RJ,van Hensbergen VP,Ruda A,Turner AG,Deng P,Le Breton Y,El-Sayed NM,Belew AT,McIver KS,McEwan AG,Morris AJ,Lambeau G,Walker MJ,Rush JS,Korotkov KV,Widmalm G,van Sorge NM,Korotkova N
Nat Chem Biol. 2019 May;15(5):463-471. doi: 10.1038/s41589-019-0251-4. Epub 2019 Apr 1
van Hensbergen VP,Movert E,de Maat V,Lüchtenborg C,Le Breton Y,Lambeau G,Payré C,Henningham A,Nizet V,van Strijp JAG,Brügger B,Carlsson F,McIver KS,van Sorge NM
PLoS Pathog. 2018 Oct;14(10):e1007348. doi: 10.1371/journal.ppat.1007348. Epub 2018 Oct 15
Brouwer S,Cork AJ,Ong CY,Barnett TC,West NP,McIver KS,Walker MJ
J Bacteriol. 2018 Apr 15;200(8):. doi: 10.1128/JB.00654-17. Epub 2018 Mar 26
Valdes KM,Sundar GS,Belew AT,Islam E,El-Sayed NM,Le Breton Y,McIver KS
Sci Rep. 2018 Mar 21;8(1):4971. doi: 10.1038/s41598-018-23366-7. Epub 2018 Mar 21
Sundar GS,Islam E,Braza RD,Silver AB,Le Breton Y,McIver KS
Front Cell Infect Microbiol. 2018;8:71. doi: 10.3389/fcimb.2018.00071. Epub 2018 Mar 14