Role of Interleukin-6 during restriction of acapsulated group A Streptococcus Público
Wilde, Shyra (Summer 2022)
Abstract
Streptococcus pyogenes (group A Streptococcus; GAS) is an exclusively human pathogen that causes roughly 600 million infections annually. Infection can be relatively mild in the form of ‘strep throat’ or pharyngitis, or manifest as an invasive infection such as bacteremia, streptococcal toxic shock syndrome, or necrotizing fasciitis. GAS infection can also result in post-infectious immune sequelae like rheumatic fever and rheumatic heart disease. GAS causes an estimated 18 million invasive infections and 600,000 annual deaths due to these diseases.
Invasive GAS in immunocompetent individuals is largely linked to hypervirulent strains, such as strain 5448, that have developed strategies to overcome host immune defenses. Congenital immunodeficiencies and those acquired from chronic disease or immunosuppressant drugs also increase risk of severe illness, specifically, drugs inhibiting Interleukin-1 or -6 (IL-1/6) signaling. We recovered a non-hypervirulent strain of GAS, M4C20, from the blood of a patient receiving a biologic inhibitor of IL-6. Survival of this strain and 5448 were markedly different in both in vitro and in vivo infection models. M4C20 was only virulent in the presence of IL-1 or IL-6 inhibitors, but 5448 was broadly virulent and resisted IL-6-mediated killing. These findings introduced IL-6 signaling deficiencies as a risk factor for invasive GAS infection, but the mechanism by which IL-6 contributes to GAS killing remained unclear.
Our work was later able to demonstrate that IL-6 acts against GAS by inducing the production of antimicrobial reactive oxygen species (ROS). GAS lacks catalase, a virulence factor used by many diverse species for detoxifying ROS, yet some strains of GAS can withstand ROS and cause severe disease. Through analysis of clinical isolates, we found that the capsule of GAS, composed of hyaluronic acid, also confers protection against ROS. We also showed that hyaluronic acid can act as a direct antioxidant against ROS in vitro. Nonetheless, we find that in vivo ROS is not essential for killing of GAS in an intradermal infection model. However, lesion size was significantly impacted by both the absence of ROS in host cells and production of capsule by GAS, supporting a model in which ROS and hyaluronic acid regulate pathology during invasive GAS skin infections.
Table of Contents
Abstract
Acknowledgements
Table of Contents
List of Tables and Figures
Chapter 1: Introduction………………………………………………………………………… 1
Chapter 1 References.........................................................................................................21
Chapter 1 Tables and Figures………………………………………………………...….38
Chapter 2: Opportunistic invasive infection by group a Streptococcus during anti-interleukin-6 immunotherapy………………………………………………………………………………..…42
Chapter 2 References.........................................................................................................54
Chapter 2 Tables and Figures…………………………………………………………....56
Chapter 3: Reactive oxygen species and hyaluronic acid capsule drive pathology during group A Streptococcal skin infections………………………………………………..……………..…59
Chapter 3 References.........................................................................................................80
Chapter 3 Tables and Figures…………………………………………………………....85
Chapter 4: Concluding Remarks and Future Directions……………………………………......94
Chapter 4 References…………………………………………………………..…...…..104
Chapter 4 Figures……………………...………………………………………………..109
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