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The role of secreted virulence factors in disease progression and severity during streptococcal and pneumococcal infections

  • Group A streptococcus (GAS) and Streptococcus pneumoniae are both Gram-positive bacteria that asymptomatically colonise various human body parts. Both microbes cause diseases ranging from mild to severe invasive infections. The later are associated with high mortality. GAS is the major microbial aetiology of type II necrotising skin and soft tissue infections (NSTIs). Type II NSTIs typically affect the lower and upper limbs of healthy young adults and often require debridement as a surgical intervention to prevent the spread of infection. S. pneumoniae is the major cause of respiratory tract infections including community-acquired pneumonia in young children and the elderly. Although most respiratory tract infections are successfully treated with antibiotics, emerging antibiotic resistance is a major cause of concern. Secreted virulence factors of Gram-positive bacteria play a major role in the successful invasion of host tissues causing different diseases. Additionally, they facilitate the spread of infection, contribute to tissue pathology, and potentially act as immune evasion mechanisms. This thesis summarises the consequences of streptococcal pyrogenic exotoxin B (SpeB), a potent cysteine protease secreted by GAS and pneumococci-derived hydrogen peroxide (H2O2) on host responses. GAS have developed genetic or phenotypic ways of adapting to the immune response to escape immune clearance. Analysis of GAS clones recovered from NSTI patient biopsies exhibit a mixed SpeB phenotype, with most clones being SpeB negative. SpeB negative clones have been associated with hyper-virulence. In Paper II, we showed that SpeB negative GAS clones recovered from tissue exhibit reversible impaired SpeB secretion due to environmental factors. In addition, mutations in covS and ropB, the major transcriptional regulators of SpeB expression, were responsible for the irreversible loss of SpeB expression. Immunohistochemistry analysis demonstrated that neutrophil degranulation, necrosis and excessive inflammation observed in NSTIs patient biopsies correlated with bacterial load and SpeB negativity of clones. Proteomic data analysis showed that SpeB negative GAS recovered from neutrophil infection harboured the protease intracellularly suggesting that the bacteria expressed but did not secrete SpeB. We have also shown that neutrophil-derived reactive oxygen species, H2O2 and hypochlorous acid, drive the SpeB negative phenotype. The SpeB negative clones survived neutrophil-mediated antimicrobial killing and induced excessive degranulation when compared with SpeB positive clones. These results provide new insights into GAS fitness induced by host factors in tissue and may be useful for the development of new treatment strategies in NSTIs. Pneumococci produce H2O2 as a by-product of carbohydrate metabolism in a reaction catalysed by pyruvate oxidase SpxB. However, very little is known about the effects of pneumococcal H2O2 as a virulence factor. Our study aimed to investigate the role of H2O2 in initiating epithelial cell death, focusing on apoptosis and pyroptosis. In Paper III, we showed that pneumococci-derived H2O2 caused epithelial cell cytotoxicity by priming and activating the NLRP3 inflammasome resulting in subsequent IL-1β production and release. Additionally, H2O2 caused apoptotic and pyroptotic cell death as evidenced by activation of caspase-3/7 and caspase-1, respectively. However, the release of IL-1β was dependent on apoptosis and not pyroptosis since inactive gasdermin D was detected post-infection. These observations were not detected in the absence of H2O2. Overall, we showed the damaging effects of pneumococci-derived H2O2 on human bronchial epithelial cells.

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Metadaten
Author: Patience Shumba
URN:urn:nbn:de:gbv:9-opus-62378
Title Additional (German):Die Rolle sekretierter Virulenzfaktoren für den Krankheitsverlauf und die Schwere der Erkrankung bei Streptokokken- und Pneumokokken-Infektionen
Referee:Prof. Dr. Nikolai Siemens, Prof. Dr. Maren von Köckritz-Blickwede
Advisor:Prof. Dr. Nikolai Siemens
Document Type:Doctoral Thesis
Language:English
Year of Completion:2022
Granting Institution:Universität Greifswald, Mathematisch-Naturwissenschaftliche Fakultät
Date of final exam:2022/05/24
Release Date:2022/06/14
Tag:pneumococcal infection; secreted virulence factors; streptococcal infection
GND Keyword:secreted virulence factors, streptococci, pneumococci, infection
Page Number:185
Faculties:Mathematisch-Naturwissenschaftliche Fakultät / Interfakultäres Institut für Genetik und Funktionelle Genomforschung
DDC class:500 Naturwissenschaften und Mathematik / 570 Biowissenschaften; Biologie