Paul Sumby, Ph.D.
Postdoctoral Fellow, Infectious Disease, Tufts University, Boston, MA
Dr. Sumby completed his postdoctoral fellowship in infectious disease in 2007 and became an assistant member of HMRI that same year. He has published numerous articles in peer-reviewed journals on the genetic virulence determinants of group A Streptococcus (GAS), the causative agent of strep throat and the “flesh-eating” disease.
Research in the Sumby lab is aimed towards advancing our understanding of the global regulatory mechanisms controlling virulence gene expression in bacterial pathogens, and illuminating currently unknown mediators of pathogenesis. Newly identified virulence-related regulatory mechanisms represent attractive targets for manipulation by new antimicrobial agents, translational research which is an integral component of the laboratory’s long term goals. The lab is focused on regulatory systems employing small regulatory RNAs (sRNAs). sRNAs are small RNA molecules that primarily function through repression of mRNA translation following sRNA:mRNA duplex formation. As a model organism we use the human bacterial pathogen group A Streptococcus (GAS) which causes a broad spectrum of diseases including pharyngitis, necrotizing fasciitis, a toxic-shock-like syndrome, and the post-infection sequel acute rheumatic fever. A highly integrated signal transduction network is key to the ability of GAS to cause such disease diversity, processing microenvironment-dependent stimuli into an optimized transcriptional response. Through use of bioinformatic and Affymetrix tiling microarray approaches we have identified candidate sRNAs in the GAS genome. Candidate sRNAs are currently being characterized and their regulatory pathways delineated through use of genome-wide technologies, affinity chromatography, and in vivo models of disease.
The human bacterial pathogen group A Streptococcus (GAS) causes a broad spectrum of diseases including pharyngitis, necrotizing fasciitis, a toxic-shock-like syndrome, and the post-infection sequel acute rheumatic fever. The ability of GAS to cause such a wide diversity of diseases is in part due to the coordinate expression of specific subsets of virulence factors in response to microenvironment-dependent stimuli.
As with other bacterial pathogens, the regulation of GAS gene expression has been well studied with regard to protein transcription factors. However, an emerging theme in infectious diseases research is the regulation of bacterial virulence by small regulatory RNAs (sRNAs). Commonly, sRNAs regulate post-transcriptionally by blocking ribosome access to target mRNA transcripts, by blocking ribosome access to the AUG start codon, and/or by targeting mRNAs for degradation by double-stranded RNA cleaving ribonucleases. All 3 of these mechanisms are achieved via complementary base-pairing between the sRNA and mRNA transcripts, creating an sRNA : mRNA duplex. Despite the importance of sRNAs in regulating the virulence of other bacterial pathogens, no comprehensive genome-wide assessment of GAS sRNAs has been performed. However, three putative sRNAs have been described in GAS, the pleiotropic effect locus (pel), the RofA-like protein 4 regulator X (rivX), and the fibronectin/fibrinogen binding/hemolytic activity/streptokinase regulator X (fasX).
Our laboratory is focused on identifying the contribution of sRNAs in the regulation of GAS gene expression, particularly during the transition of GAS from distinct infection types (e.g. from a pharyngeal infection to an invasive infection). Through use of genome-wide technologies, such as Affymetrix tiling microarrays and bioinformatics, we have identified >40 new candidate sRNAs within the GAS genome. Candidate sRNAs are currently being characterized and their regulatory pathways delineated through use of expression microarrays, affinity chromatography, and in vivo models of disease. Our ability to monitor GAS gene expression on a genome-wide scale from samples of in vitro, ex vivo, and in vivo origin will be critical to our success in delineating the complex interplay between temporally and spatially transcribed sRNAs and GAS transcriptional alterations.
An integral component of the laboratory’s goals is to develop clinical applications from basic research advances. As sRNA mediators of GAS virulence would be attractive targets for manipulation by novel antimicrobial agents, we move forward with our research with the mindset of pursuing translational research opportunities.
Gene regulation, infectious disease, pathogenesis, genomics
Trevino J, Liu Z, Cao TN, Ramirez-Pena E, Sumby P. RivR is a negative regulator of virulence factor expression in group A Streptococcus. Infect Immun. 2013 Jan;81(1):364-72.
Liu Z, Treviño J, Ramirez-Peña E, Sumby P. The small regulatory RNA FasX controls pilus expression and adherence in the human bacterial pathogen group A Streptococcus. Mol Microbiol. 2012 Oct;86(1):140-54.
Carroll RK, Beres SB, Sitkiewicz I, Peterson L, Matsunami RK, Engler DA, Flores AR, Sumby P, Musser JM. Evolution of diversity in epidemics revealed by analysis of the human bacterial pathogen group A Streptococcus. Epidemics. 2011 Sep;3(3-4):159-70.
Pflughoeft KJ, Sumby P, Koehler TM. Bacillus anthracis sin locus and regulation of secreted proteases. J Bacteriol. 2011 Feb;193(3):631-9.
Ramirez-Peña E, Treviño J, Liu Z, Perez N, Sumby P. The group A Streptococcus small regulatory RNA FasX enhances streptokinase activity by increasing the stability of the ska mRNA transcript. Mol Microbiol. 2010 Dec;78(6):1332-47.
Shelburne SA, Olsen RJ, Suber B, Sahasrabhojane P, Sumby P, Brennan RG, Musser JM. A combination of independent transcriptional regulators shapes bacterial virulence gene expression during infection. PLoS Pathog. 2010 Mar 19;6(3):e1000817.
Treviño J, Perez N, Sumby P. The 4.5S RNA component of the signal recognition particle is required for group A Streptococcus virulence. Microbiology. 2010 May;156(Pt 5):1342-50.
Perez N, Treviño J, Liu Z, Ho SC, Babitzke P, Sumby P. A genome-wide analysis of small regulatory RNAs in the human pathogen group A Streptococcus. PLoS One. 2009 Nov 2;4(11):e7668.
Zhu H, Liu M, Sumby P, Lei B. The secreted esterase of group A Streptococcus is important for invasive skin infection and dissemination in mice. Infect Immun. 2009 Dec;77(12):5225-32.
Treviño J, Perez N, Ramirez-Peña E, Liu Z, Shelburne SA 3rd, Musser JM, Sumby P. CovS simultaneously activates and inhibits the CovR-mediated repression of distinct subsets of group A Streptococcus virulence factor-encoding genes. Infect Immun. 2009 Aug;77(8):3141-9.
Sumby P, Tart AH, Musser JM. A non-human primate model of acute group A Streptococcus pharyngitis. Methods Mol Biol. 2008;431:255-67.
Shelburne SA 3rd, Keith D, Horstmann N, Sumby P, Davenport MT, Graviss EA, Brennan RG, Musser JM. A direct link between carbohydrate utilization and virulence in the major human pathogen group A Streptococcus. Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1698-703.
Sumby P, Zhang S, Whitney AR, Falugi F, Grandi G, Graviss EA, Deleo FR, Musser JM. A chemokine-degrading extracellular protease made by group A Streptococcus alters pathogenesis by enhancing evasion of the innate immune response. Infect Immun. 2008 Mar;76(3):978-85.
Shelburne SA 3rd, Okorafor N, Sitkiewicz I, Sumby P, Keith D, Patel P, Austin C, Graviss EA, Musser JM. Regulation of polysaccharide utilization contributes to the persistence of group A Streptococcus in the oropharynx. Infect Immun. 2007 Jun;75(6):2981-90.
Shelburne SA 3rd, Fang H, Okorafor N, Sumby P, Sitkiewicz I, Keith D, Patel P, Austin C, Graviss EA, Musser JM, Chow DC. MalE of group A Streptococcus participates in the rapid transport of maltotriose and longer maltodextrins. J Bacteriol. 2007 Apr;189(7):2610-7.