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Potential Approaches to Limiting Group A Streptococcus Virulence

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abstract
Group A Streptococcus (GAS) is an obligate human pathogen capable of causing a wide array of diseases ranging in both severity and site of infection. The current forms of treatment are limited, consisting of antibiotic regimens and in severe cases surgical debridement to remove infected tissue. Treatment failure has been reported in approximately 35% of GAS pharyngitis patients. It is hypothesized that a major contributing factor to this treatment failure is the increase in antibiotic resistance among GAS strains. To address the need for alternative methods of GAS treatment, this study focused on two potential approaches to limiting GAS virulence. First, we investigated GAS mechanisms of copper tolerance. Copper plays an important role in the development and maintenance of the human immune system. Macrophages utilize copper as an additional stressor to aid in bacterial killing. In GAS, we identified a highly conserved set of copper-responsive genes among a range of clinical isolates. Evaluation of the effect of copper stress on S. pyogenes in a planktonic or biofilm state revealed that biofilms may aid in protection during initial exposure to copper. However, copper stress appears to prevent the shift from planktonic to the biofilm state. Therefore, our results indicate that GAS may use several virulence mechanisms including altered gene expression and a transition to and from planktonic and biofilm states to promote survival during copper stress. The GAS virulence mechanisms utilized to combat copper stress could serve as potential therapeutic targets to reduce GAS survival during infection. In our second approach, we investigated a novel nanotechnology therapy for its effectiveness in eradicating GAS. Certain nanoparticles can generate heat when exposed to near infrared light that reach high temperatures sufficient for bacterial killing. In this study, we found that multi-wall carbon nanotubes (MWNTs) when exposed to infrared light were capable of generating sufficient heat to kill GAS in planktonic culture and within a biofilm. Furthermore, antibody labeled nanotubes had enhanced killing of GAS in planktonic culture and within a biofilm when used in conjunction with infrared light compared to unlabeled nanotubes. Analysis of GAS photothermally ablated in direct contact with ex vivo porcine skin showed that heat sufficient for killing GAS remained local and did not cause collateral damage in tissue adjacent to the treated area. The results of this study support the use of nanoparticles as highly localized photothermal agents with vast potential for translation into the clinical treatment of GAS soft tissue infections. Overall, the findings from this two-part study provide a platform that will be useful for developing novel treatments to GAS in the future.
subject
biofilms
copper-responsive operon
copper tolerance
Group A Streptococcus
multi-wall carbon nanotubes
Streptococcus pyogenes
contributor
Young, Christie Ann (author)
Reid, Sean D (committee chair)
Levi-Polyachenko, Nicole H (committee member)
Deora, Rajendar (committee member)
Haas, Karen M (committee member)
date
2015-06-23T08:36:00Z (accessioned)
2016-06-22T08:30:10Z (available)
2015 (issued)
degree
Microbiology & Immunology (discipline)
embargo
2016-06-22 (terms)
identifier
http://hdl.handle.net/10339/57187 (uri)
language
en (iso)
publisher
Wake Forest University
title
Potential Approaches to Limiting Group A Streptococcus Virulence
type
Dissertation

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