Proinflammatory mechanisms of streptococcal pyrogenic exotoxins Restricted; Files Only

Abstract

Group A Streptococcus (GAS) is an obligate human pathogen responsible for the severe

infections scarlet fever and streptococcal toxic shock syndrome (STSS). The toxins behind scarlet

fever and STSS are streptococcal pyrogenic exotoxins, most of which are superantigens that

interact with the immune system to cause a cytokine storm. The exception to this toxin family is

the cysteine protease SpeB, which degrades and activates many host and pathogenic factors. Prior

work has shown that SpeB acts as a bacterial caspase and activates proinflammatory host factors

IL-1β and GSDMA. We present data showing that SpeB activates IL-18 secreted by keratinocytes

independent of infection. This activation is exclusive to strains of GAS producing SpeB and is not

found in commensal microbes of the skin. This active cytokine goes on to be recognized by the

immune system to generate an inflammatory response to bacterial infection. These data suggest

keratinocyte-secreted IL-18 is acting as a sensor and sounds an early alarm to skin pathogens.

Streptococcal superantigens have also been shown as targets of SpeB. Prior literature has shown

the superantigen SpeA is resistant to degradation, while SmeZ is susceptible to degradation.

However, the interaction of SpeB with the other streptococcal superantigens had not been

characterized. Here we present data showing the variety of degradation tendencies of SpeB on

streptococcal superantigens. We show that there is a range of susceptibility to SpeB, that is

independent of superantigen grouping and species of origin. We also present data showing that

SpeB synergizes with superantigens to enhance their proinflammatory capabilities, instead of

strictly antagonizing and degrading them. Altogether, SpeB is shown to be a tool of GAS to

activate the host proinflammatory immune response, which when overactivated, is a major cause

of morbidity and mortality during infection.

Table of Contents

Abstract

Acknowledgments

Table of Contents

List of Figures and Tables

Chapter 1. Introduction ………………………………………………………………… 1

Introduction……………………………………………………………………….. 2

GAS Infections……………………………………………………………………. 3

Streptococcal pyrogenic exotoxin B………………………………………………. 4

Targets of SpeB…………………………………………………………………… 6

Superantigens……………………………………………………………………... 8

Antibiotic Treatment of GAS Infections………………………………………….. 11

Antibiotic Resistance……………………………………………………………… 12

β-lactam Resistance Concerns…………………………………………………….. 13

Additional Considerations with Antibiotic Treatment……………………………. 15

Mechanisms for Treatment Failure……………………………………………….. 15

Antivirulence Treatment…………………………………………………………... 18

Vaccines for GAS…………………………………………………………………. 19

Closing Comments………………………………………………………………... 20

References………………………………………………………………………… 23

Figures…………………………………………………………………………….. 45

Chapter 2. Constitutive secretion of pro-IL-18 allows keratinocytes to initiate

inflammation during bacterial infection ……………………………………………….

47

Abstract……………………………………………………………………………. 48

Introduction……………………………………………………………………….. 49

Results…………………………………………………………………………….. 51

Discussion…………………………………………………………………………. 57

Materials and Methods……………………………………………………………. 59

Acknowledgements……………………………………………………………….. 63

References………………………………………………………………………… 65

Figures…………………………………………………………………………….. 72

Supplementary Figures……………………………………………………………. 78

Chapter 3 The synergy of SpeB with streptococcal superantigens…………………… 79

Abstract……………………………………………………………………………. 80

Introduction……………………………………………………………………….. 80

Results…………………………………………………………………………….. 82

Discussion…………………………………………………………………………. 85

Materials and Methods……………………………………………………………. 86

Acknowledgements……………………………………………………………….. 89

References………………………………………………………………………… 90

Figures…………………………………………………………………………….. 93

Chapter 4. Discussion …………………………………………………………………… 99

Conclusion………………………………………………………………………… 100

References………………………………………………………………………… 105

Figures…………………………………………………………………………….. 107

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Microbiology & Molecular Genetics
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Health Sciences, Immunology Biology, Microbiology
Keyword	Pathogenesis Interleukin-18 Keratinocytes Streptococcus pyogenes Streptococcal pyrogenic exotoxins Superantigen Group A Streptococcus
Committee Chair / Thesis Advisor	Christopher LaRock, Emory University
Committee Members	Timothy Read, Emory University Shonna McBride, Emory University David Weiss, Emory University Luisa Cervantes-Barragan, Emory University

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