Abstract

Hemolytic Streptococcus pyogenes, commonly referred as Group A Streptococcus (GAS), is an important human pathogen causing pharyngitis, cellulitis, scarlet fever, necrotizing fasciitis, toxic shock syndrome, acute rheumatic fever, rheumatic heart disease, and glomerulonephritis. The pathogenesis of GAS infection is mediated by an abundance of virulence factors which make effective immunotherapeutic control of GAS diseases extremely difficult. Iron acquisition systems of many bacterial pathogens are key virulence factors. Their role in virulence, conserved antigenicity, and surface exposure make them attractive vaccine candidates. GAS can sequester iron from hemoglobin and heme is thought to be the primary iron source for GAS in vivo. However, little is known about the machinery for heme acquisition in GAS. Recently, we identified a novel heme-associated cell-surface protein (designated Shp1) made by GAS. The shp 1 gene is co-transcribed with 8 contiguous downstream genes, including spy1795, spy1794, and spy1793 encoding homologues of the components of ABC transporters involved in iron uptake in Gramnegative bacteria. My preliminary results suggest that the lipoprotein component (Spy1795, designated Shp2) of the GAS putative transporter also binds heme. The proposed studies will investigate whether the sht locus (containing shp1 and shp2) encodes the machinery for heme acquisition in GAS and if sht is required for GAS virulence. I plan to achieve the following specific aims using biochemical and genetic approaches and infection models to define the role of heme acquisition in GAS pathogenesis. ? ? Aim 1. Determine whether recombinant Shp2 binds heme ? Aim 2. Elucidate if the sht locus encodes a transporter system for heme acquisition ? Aim 3. Investigate whether the disruption of shp1 and/or shp2 attenuates GAS virulence ? ? The study will advance our understanding of the mechanism of heme acquisition in GAS and may identify new potential GAS vaccine candidate(s). ? ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Career Transition Award (K22)
Project #
5K22AI057347-02
Application #
6871949
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID)
Program Officer
Rubin, Fran A
Project Start
2004-03-01
Project End
2006-02-28
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
2
Fiscal Year
2005
Total Cost
$108,000
Indirect Cost

  Institution

Name
Montana State University - Bozeman
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
625447982
City
Bozeman
State
MT
Country
United States
Zip Code
59717

  Publications

Ran, Yanchao; Malmirchegini, G Reza; Clubb, Robert T et al. (2013) Axial ligand replacement mechanism in heme transfer from streptococcal heme-binding protein Shp to HtsA of the HtsABC transporter. Biochemistry 52:6537-47
Lei, Benfang (2010) Benfang Lei's research on heme acquisition in Gram-positive pathogens and bacterial pathogenesis. World J Biol Chem 1:286-90
Zhu, Hui; Liu, Mengyao; Lei, Benfang (2008) The surface protein Shr of Streptococcus pyogenes binds heme and transfers it to the streptococcal heme-binding protein Shp. BMC Microbiol 8:15
Aranda 4th, Roman; Worley, Chad E; Liu, Mengyao et al. (2007) Bis-methionyl coordination in the crystal structure of the heme-binding domain of the streptococcal cell surface protein Shp. J Mol Biol 374:374-83
Ran, Yanchao; Zhu, Hui; Liu, Mengyao et al. (2007) Bis-methionine ligation to heme iron in the streptococcal cell surface protein Shp facilitates rapid hemin transfer to HtsA of the HtsABC transporter. J Biol Chem 282:31380-8
Liu, Mengyao; Zhu, Hui; Zhang, Jinlian et al. (2007) Active and passive immunizations with the streptococcal esterase Sse protect mice against subcutaneous infection with group A streptococci. Infect Immun 75:3651-7
Hanks, Tracey S; Liu, Mengyao; McClure, Michael J et al. (2006) Differential regulation of iron- and manganese-specific MtsABC and heme-specific HtsABC transporters by the metalloregulator MtsR of group A Streptococcus. Infect Immun 74:5132-9
Liu, Mengyao; Hanks, Tracey S; Zhang, Jinlian et al. (2006) Defects in ex vivo and in vivo growth and sensitivity to osmotic stress of group A Streptococcus caused by interruption of response regulator gene vicR. Microbiology 152:967-78
Nygaard, Tyler K; Blouin, George C; Liu, Mengyao et al. (2006) The mechanism of direct heme transfer from the streptococcal cell surface protein Shp to HtsA of the HtsABC transporter. J Biol Chem 281:20761-71
Nygaard, Tyler K; Liu, Mengyao; McClure, Michael J et al. (2006) Identification and characterization of the heme-binding proteins SeShp and SeHtsA of Streptococcus equi subspecies equi. BMC Microbiol 6:82

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