Proinflammatory mechanisms of streptococcal pyrogenic exotoxins Restricted; Files Only
Johnson, Anders (Spring 2023)
Published
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
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