Restriction of gene expression to a specific phase of the bacterial growth cycle is known as growth phase regulation. For pathogens, it is generally assumed to reflect spatio-temporal adaptations made in response to a dynamic host milieu. However, establishing this link requires identification of specific regulatory elements, their hierarchical relationships, and whether the regulatory network responds in a similar pattern in vivo. Since regulation of virtually all of its recognized virulence factors involves a growth phase component, this issue has emerged as an important concept for understanding the myriad and diverse diseases caused by the important human pathogen Streptococcus pyogenes. Recent work has implicated carbon catabolite regulation (CCR) as an important component of S. pyogenes growth phase regulation, functioning to couple expression of virulence genes to the presence or absence of specific growth substrates. This suggests that substrate availability is a major cue used to distinguish between specific stages of the infection and/or that variation in nutritional signals between different host tissues may drive transcriptome behavior to promote different disease presentations. However, the specific substrates sensed and how any regulator of CCR functions to the control behavior of the S. pyogenes transcriptome in time- and compartment-specific patterns is not well understood and is the subject of this proposal. A CCR regulator known as Carbon Catabolite Protein A (CcpA) makes an important contribution to the temporal regulation of virulence factor genes in S. pyogenes. A major question is how this this single regulator functions to coordinate diverse patterns of gene expression with respect to time. The CcpA pathway is highly conserved among the low G+C firmicutes and elegant studies have revealed the structural basis of how CcpA activity is modulated by multiple co-factors. However, no comprehensive analysis of modes of global regulation that integrates all these regulatory elements has been conducted in any bacterium. The goal of this proposal is to leverage knowledge of CcpA biochemistry along with possible unique properties of S. pyogenes CcpA (spCcpA), a comprehensive examination of S. pyogenes carbohydrate metabolism during infection of soft tissue and an analysis of the energy-producing pathways used for growth in tissue, in order to probe the relationship between growth substrates, temporal control of virulence factor expression, CCR and pathogenesis

Public Health Relevance

Why the bacterium Streptococcus pyogenes (group A streptococcus) can cause life-threatening disease in certain tissues (e.g. muscle) while causing non-life-threatening diseases at other tissues (e.g. 'strep throat') is not understood. One idea is that the streptococcus grows on different carbon sources in different host tissues and these growth substrates change the patterns in which its virulence genes are regulated. A consequence of these different patterns is that they result in different disease outcomes. Understanding the mechanisms by which growth substrates regulate virulence will be important for understanding which genes are important for causing serious disease so that new therapies can be developed that target the virulence proteins these genes encode.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI070759-07
Application #
8774156
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
GU, Xin-Xing
Project Start
2007-07-01
Project End
2018-11-30
Budget Start
2014-12-01
Budget End
2015-11-30
Support Year
7
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Washington University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Cervantes-Barragan, Luisa; Chai, Jiani N; Tianero, Ma Diarey et al. (2017) Lactobacillus reuteri induces gut intraepithelial CD4+CD8??+ T cells. Science 357:806-810
Port, Gary C; Cusumano, Zachary T; Tumminello, Paul R et al. (2017) SpxA1 and SpxA2 Act Coordinately To Fine-Tune Stress Responses and Virulence in Streptococcus pyogenes. MBio 8:
Cusumano, Zachary T; Caparon, Michael G (2015) Citrulline protects Streptococcus pyogenes from acid stress using the arginine deiminase pathway and the F1Fo-ATPase. J Bacteriol 197:1288-96
Port, Gary C; Paluscio, Elyse; Caparon, Michael G (2015) Complete Genome Sequences of emm6 Streptococcus pyogenes JRS4 and Parental Strain D471. Genome Announc 3:
Paluscio, Elyse; Caparon, Michael G (2015) Streptococcus pyogenes malate degradation pathway links pH regulation and virulence. Infect Immun 83:1162-71
Cusumano, Zachary T; Watson Jr, Michael E; Caparon, Michael G (2014) Streptococcus pyogenes arginine and citrulline catabolism promotes infection and modulates innate immunity. Infect Immun 82:233-42
Cusumano, Zachary; Caparon, Michael (2013) Adaptive evolution of the Streptococcus pyogenes regulatory aldolase LacD.1. J Bacteriol 195:1294-304
Watson Jr, Michael E; Nielsen, Hailyn V; Hultgren, Scott J et al. (2013) Murine vaginal colonization model for investigating asymptomatic mucosal carriage of Streptococcus pyogenes. Infect Immun 81:1606-17
Kietzman, Colin C; Caparon, Michael G (2011) Distinct time-resolved roles for two catabolite-sensing pathways during Streptococcus pyogenes infection. Infect Immun 79:812-21
Kietzman, Colin C; Caparon, Michael G (2010) CcpA and LacD.1 affect temporal regulation of Streptococcus pyogenes virulence genes. Infect Immun 78:241-52

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