Pathogenic Mechanisms of Streptococcal Necrotizing Soft Tissue Infections

Siemens, Nikolai; Snäll, Johanna; Svensson, Mattias; Norrby‐Teglund, Anna

doi:10.1007/978-3-030-57616-5_9

Cited by 13 publications

(26 citation statements)

References 167 publications

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“…The human-specific pathogen GAS has co-evolved with the human immune system, and therefore has multiple mechanisms for survival within the host (1,11). Although GAS is an extracellular bacterial pathogen, phagocytic cells such as macrophages can readily engulf bacteria (13,15,31).…”

Section: Discussionmentioning

confidence: 99%

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Group AStreptococcusInduces Lysosomal Dysfunction in THP-1 Macrophages

Nishioka

Snipper

Lee

et al. 2022

Preprint

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The human-specific bacterial pathogen Group A Streptococcus (GAS) is a significant cause of morbidity and mortality. Macrophages are important to control GAS upon infection, but previous data indicate that GAS can persist in macrophages. In this study, we detail the molecular mechanisms by which GAS survives in THP-1 macrophages. Our fluorescence microscopy studies demonstrate that GAS are readily phagocytosed by macrophages, but persist within phagolysosomes. These phagolysosomes are not acidified, which is in agreement with the inability of the GAS to survive in low pH environments. We find that the secreted pore-forming toxin Streptolysin O (SLO) perforates the phagolysosomal membrane, allowing leakage of not only protons, but large proteins including the lysosomal protease cathepsin B. Additionally, GAS blocks the activity of vacuolar ATPase (v-ATPase) to prevent acidification of the phagolysosome. Thus, while GAS does not inhibit fusion of the lysosome with the phagosome, it has multiple mechanisms to prevent proper phagolysosome function, allowing for persistence of the bacteria within the macrophage. This has important implications for not only the initial response, but the overall function of the macrophages and resulting pathology in GAS infection and suggests that therapies aimed at improving macrophage function may improve outcomes in GAS infection.

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Section: Discussionmentioning

confidence: 99%

“…GAS is a human-specific pathogen and therefore has evolved mechanisms to survive the immune response (11). Previous data have indicated that phagocytosed GAS can prevent fusion with destructive organelles such as azurophilic granules and lysosomes (12,13).…”

Section: Introductionmentioning

confidence: 99%

Group AStreptococcusInduces Lysosomal Dysfunction in THP-1 Macrophages

Nishioka

Snipper

Lee

et al. 2022

Preprint

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“…There are many more secreted virulence factors, including DNases, streptococcal inhibitor of complement (SIC), and SAgs [ 67 ]. All of them contribute to colonization, immune evasion, immunomodulation, bacterial spread, and other crucial infection relevant functions [ 85 ]. To ensure that the right factor is expressed at the precise time point of the infection stage, the expression is tightly controlled by two component systems (TCS) and stand-alone transcriptional regulators.…”

Section: Major Gas Virulence Factorsmentioning

confidence: 99%

Streptococcus pyogenes (“Group A Streptococcus”), a Highly Adapted Human Pathogen—Potential Implications of Its Virulence Regulation for Epidemiology and Disease Management

Siemens

Lütticken²

2021

Pathogens

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Streptococcus pyogenes (group A streptococci; GAS) is an exclusively human pathogen. It causes a variety of suppurative and non-suppurative diseases in people of all ages worldwide. Not all can be successfully treated with antibiotics. A licensed vaccine, in spite of its global importance, is not yet available. GAS express an arsenal of virulence factors responsible for pathological immune reactions. The transcription of all these virulence factors is under the control of three types of virulence-related regulators: (i) two-component systems (TCS), (ii) stand-alone regulators, and (iii) non-coding RNAs. This review summarizes major TCS and stand-alone transcriptional regulatory systems, which are directly associated with virulence control. It is suggested that this treasure of knowledge on the genetics of virulence regulation should be better harnessed for new therapies and prevention methods for GAS infections, thereby changing its global epidemiology for the better.

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“…However, these bacterial species also cause highly invasive diseases. These include but are not limited to necrotizing skin and soft tissue infections (NSTIs; S. pyogenes ) (Siemens et al, 2020 ), pneumonia, sepsis, and meningitis ( S. pneumoniae, S. suis ) (Votsch et al, 2018 ; Steinert et al, 2020 ; Palmer and Kimmey, 2022 ), neonatal sepsis ( S. agalactiae ) (Armistead et al, 2019 ), and endocarditis ( S. anginosus ) (Reissmann et al, 2010 ). The invasiveness is linked to a plethora of bacterial as well as host factors.…”

mentioning

confidence: 99%

“…The invasiveness is linked to a plethora of bacterial as well as host factors. Virulence factors help pathogens to escape the host immune response while uncontrolled and excessive activation of host factors can aggravate the disease progression (Doran et al, 2016 ; Siemens et al, 2020 ; Steinert et al, 2020 ). Consequently, all these actions can result in substantial host tissue damage, bacterial dissemination, and subsequent death of the host.…”

mentioning

confidence: 99%