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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.
Nikolai Siemens; Rudolf Lütticken. Streptococcus pyogenes (“Group A Streptococcus”), a Highly Adapted Human Pathogen—Potential Implications of Its Virulence Regulation for Epidemiology and Disease Management. Pathogens 2021, 10, 776 .
AMA StyleNikolai Siemens, Rudolf Lütticken. Streptococcus pyogenes (“Group A Streptococcus”), a Highly Adapted Human Pathogen—Potential Implications of Its Virulence Regulation for Epidemiology and Disease Management. Pathogens. 2021; 10 (6):776.
Chicago/Turabian StyleNikolai Siemens; Rudolf Lütticken. 2021. "Streptococcus pyogenes (“Group A Streptococcus”), a Highly Adapted Human Pathogen—Potential Implications of Its Virulence Regulation for Epidemiology and Disease Management." Pathogens 10, no. 6: 776.
Inflammasomes are innate immune sensors that regulate caspase-1 mediated inflammation in response to environmental, host- and pathogen-derived factors. The NLRP3 inflammasome is highly versatile as it is activated by a diverse range of stimuli. However, excessive or chronic inflammasome activation and subsequent interleukin-1β (IL-1β) release are implicated in the pathogenesis of various autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, and diabetes. Accordingly, inflammasome inhibitor therapy has a therapeutic benefit in these diseases. In contrast, NLRP3 inflammasome is an important defense mechanism against microbial infections. IL-1β antagonizes bacterial invasion and dissemination. Unfortunately, patients receiving IL-1β or inflammasome inhibitors are reported to be at a disproportionate risk to experience invasive bacterial infections including pneumococcal infections. Pneumococci are typical colonizers of immunocompromised individuals and a leading cause of community-acquired pneumonia worldwide. Here, we summarize the current limited knowledge of inflammasome activation in pneumococcal infections of the respiratory tract and how inflammasome inhibition may benefit these infections in immunocompromised patients.
Surabhi Surabhi; Fabian Cuypers; Sven Hammerschmidt; Nikolai Siemens. The Role of NLRP3 Inflammasome in Pneumococcal Infections. Frontiers in Immunology 2020, 11, 1 .
AMA StyleSurabhi Surabhi, Fabian Cuypers, Sven Hammerschmidt, Nikolai Siemens. The Role of NLRP3 Inflammasome in Pneumococcal Infections. Frontiers in Immunology. 2020; 11 ():1.
Chicago/Turabian StyleSurabhi Surabhi; Fabian Cuypers; Sven Hammerschmidt; Nikolai Siemens. 2020. "The Role of NLRP3 Inflammasome in Pneumococcal Infections." Frontiers in Immunology 11, no. : 1.
Necrotizing skin and soft tissue infections (NSTIs) are severe life-threatening and rapidly progressing infections. Beta-hemolytic streptococci, particularly S. pyogenes (group A streptococci (GAS)) but also S. dysgalactiae subsp. equisimilis (SDSE, most group G and C streptococcus), are the main causative agents of monomicrobial NSTIs and certain types, such as emm1 and emm3, are over-represented in NSTI cases. An arsenal of bacterial virulence factors contribute to disease pathogenesis, which is a complex and multifactorial process. In this chapter, we summarize data that have provided mechanistic and immuno-pathologic insight into host-pathogens interactions that contribute to tissue pathology in streptococcal NSTIs. The role of streptococcal surface associated and secreted factors contributing to the hyper-inflammatory state and immune evasion, bacterial load in the tissue and persistence strategies, including intracellular survival and biofilm formation, as well as strategies to mimic NSTIs in vitro are discussed.
Nikolai Siemens; Johanna Snäll; Mattias Svensson; Anna Norrby-Teglund. Pathogenic Mechanisms of Streptococcal Necrotizing Soft Tissue Infections. Advances in Experimental Medicine and Biology 2020, 1294, 127 -150.
AMA StyleNikolai Siemens, Johanna Snäll, Mattias Svensson, Anna Norrby-Teglund. Pathogenic Mechanisms of Streptococcal Necrotizing Soft Tissue Infections. Advances in Experimental Medicine and Biology. 2020; 1294 ():127-150.
Chicago/Turabian StyleNikolai Siemens; Johanna Snäll; Mattias Svensson; Anna Norrby-Teglund. 2020. "Pathogenic Mechanisms of Streptococcal Necrotizing Soft Tissue Infections." Advances in Experimental Medicine and Biology 1294, no. : 127-150.
Background In tissue infections, adenosine triphosphate (ATP) is released into extracellular space and contributes to purinergic chemotaxis. Neutrophils are important players in bacterial clearance and are recruited to the site of tissue infections. Pneumococcal infections can lead to uncontrolled hyperinflammation of the tissue along with substantial tissue damage through excessive neutrophil activation and uncontrolled granule release. We aimed to investigate the role of ATP in neutrophil response to pneumococcal infections. Methods Primary human neutrophils were exposed to the pneumococcal strain TIGR4 and its pneumolysin-deficient mutant or directly to different concentrations of recombinant pneumolysin. Neutrophil activation was assessed by measurement of secreted azurophilic granule protein resistin and profiling of the secretome, using mass spectrometry. Results Pneumococci are potent inducers of neutrophil degranulation. Pneumolysin was identified as a major trigger of neutrophil activation. This process is partially lysis independent and inhibited by ATP. Pneumolysin and ATP interact with each other in the extracellular space leading to reduced neutrophil activation. Proteome analyses of the neutrophil secretome confirmed that ATP inhibits pneumolysin-dependent neutrophil activation. Conclusions Our findings suggest that despite its cytolytic activity, pneumolysin serves as a potent neutrophil activating factor. Extracellular ATP mitigates pneumolysin-induced neutrophil activation.
Fabian Cuypers; Björn Klabunde; Manuela Gesell Salazar; Surabhi Surabhi; Sebastian B Skorka; Gerhard Burchhardt; Stephan Michalik; Thomas Thiele; Manfred Rohde; Uwe Völker; Sven Hammerschmidt; Nikolai Siemens. Adenosine Triphosphate Neutralizes Pneumolysin-Induced Neutrophil Activation. Journal of Infectious Diseases 2020, 222, 1702 -1712.
AMA StyleFabian Cuypers, Björn Klabunde, Manuela Gesell Salazar, Surabhi Surabhi, Sebastian B Skorka, Gerhard Burchhardt, Stephan Michalik, Thomas Thiele, Manfred Rohde, Uwe Völker, Sven Hammerschmidt, Nikolai Siemens. Adenosine Triphosphate Neutralizes Pneumolysin-Induced Neutrophil Activation. Journal of Infectious Diseases. 2020; 222 (10):1702-1712.
Chicago/Turabian StyleFabian Cuypers; Björn Klabunde; Manuela Gesell Salazar; Surabhi Surabhi; Sebastian B Skorka; Gerhard Burchhardt; Stephan Michalik; Thomas Thiele; Manfred Rohde; Uwe Völker; Sven Hammerschmidt; Nikolai Siemens. 2020. "Adenosine Triphosphate Neutralizes Pneumolysin-Induced Neutrophil Activation." Journal of Infectious Diseases 222, no. 10: 1702-1712.
Respiratory tract infections are a global health problem. The main causative agents of these infections are influenza A virus (IAV), Staphylococcus aureus (S. aureus), and Streptococcus pneumoniae (S. pneumoniae). Major research focuses on genetics and immune responses in these infections. Eicosanoids and other oxylipins are host-derived lipid mediators that play an important role in the activation and resolution of inflammation. In this study, we assess, for the first time, the different intracellular profiles of these bioactive lipid mediators during S. aureus LUG2012, S. pneumoniae TIGR4, IAV, and corresponding viral and bacterial co-infections of 16HBE cells. We observed a multitude of altered lipid mediators. Changes in the amount of 5-hydroxyeicosatetraenoic acid (5-HETE) were prominent for all bacterial infections. The infection with S. pneumoniae showed the strongest impact on bioactive lipid production and led to alterations in the amount of PPARγ ligands and precursors of pro-resolving lipid mediators.
Daniel Schultz; Surabhi Surabhi; Nicolas Stelling; Michael Rothe; KoInfekt Study Group; Karen Methling; Sven Hammerschmidt; Nikolai Siemens; Michael Lalk. 16HBE Cell Lipid Mediator Responses to Mono and Co-Infections with Respiratory Pathogens. Metabolites 2020, 10, 113 .
AMA StyleDaniel Schultz, Surabhi Surabhi, Nicolas Stelling, Michael Rothe, KoInfekt Study Group, Karen Methling, Sven Hammerschmidt, Nikolai Siemens, Michael Lalk. 16HBE Cell Lipid Mediator Responses to Mono and Co-Infections with Respiratory Pathogens. Metabolites. 2020; 10 (3):113.
Chicago/Turabian StyleDaniel Schultz; Surabhi Surabhi; Nicolas Stelling; Michael Rothe; KoInfekt Study Group; Karen Methling; Sven Hammerschmidt; Nikolai Siemens; Michael Lalk. 2020. "16HBE Cell Lipid Mediator Responses to Mono and Co-Infections with Respiratory Pathogens." Metabolites 10, no. 3: 113.
A prominent feature of severe streptococcal infections is the profound inflammatory response that contributes to systemic toxicity. In sepsis the dysregulated host response involves both immunological and nonimmunological pathways. Here, we report a fatal case of an immunocompetent healthy female presenting with toxic shock and purpura fulminans caused by group B streptococcus (GBS; serotype III, CC19). The strain (LUMC16) was pigmented and hyperhemolytic. Stimulation of human primary cells with hyperhemolytic LUMC16 and STSS/NF-HH strains and pigment toxin resulted in a release of proinflammatory mediators, including tumor necrosis factor, interleukin (IL)-1β, and IL-6. In addition, LUMC16 induced blood clotting and showed factor XII activity on its surface, which was linked to the presence of the pigment. The expression of pigment was not linked to a mutation within the CovR/S region. In conclusion, our study shows that the hemolytic lipid toxin contributes to the ability of GBS to cause systemic hyperinflammation and interferes with the coagulation system.
Nikolai Siemens; Sonja Oehmcke-Hecht; Jörn Hoßmann; Sebastian B. Skorka; Roel H.T. Nijhuis; Corinne Ruppen; Steinar Skrede; Manfred Rohde; Daniel Schultz; Michael Lalk; Andreas Itzek; Dietmar H. Pieper; Christiaan J. Van Den Bout; Eric C.J. Claas; Ed J. Kuijper; Robert Mauritz; Parham Sendi; Herman F. Wunderink; Anna Norrby-Teglund. Prothrombotic and Proinflammatory Activities of the β-Hemolytic Group B Streptococcal Pigment. Journal of Innate Immunity 2019, 12, 291 -303.
AMA StyleNikolai Siemens, Sonja Oehmcke-Hecht, Jörn Hoßmann, Sebastian B. Skorka, Roel H.T. Nijhuis, Corinne Ruppen, Steinar Skrede, Manfred Rohde, Daniel Schultz, Michael Lalk, Andreas Itzek, Dietmar H. Pieper, Christiaan J. Van Den Bout, Eric C.J. Claas, Ed J. Kuijper, Robert Mauritz, Parham Sendi, Herman F. Wunderink, Anna Norrby-Teglund. Prothrombotic and Proinflammatory Activities of the β-Hemolytic Group B Streptococcal Pigment. Journal of Innate Immunity. 2019; 12 (4):291-303.
Chicago/Turabian StyleNikolai Siemens; Sonja Oehmcke-Hecht; Jörn Hoßmann; Sebastian B. Skorka; Roel H.T. Nijhuis; Corinne Ruppen; Steinar Skrede; Manfred Rohde; Daniel Schultz; Michael Lalk; Andreas Itzek; Dietmar H. Pieper; Christiaan J. Van Den Bout; Eric C.J. Claas; Ed J. Kuijper; Robert Mauritz; Parham Sendi; Herman F. Wunderink; Anna Norrby-Teglund. 2019. "Prothrombotic and Proinflammatory Activities of the β-Hemolytic Group B Streptococcal Pigment." Journal of Innate Immunity 12, no. 4: 291-303.
Necrotizing soft tissue infections (NSTIs) are critical clinical conditions characterized by extensive necrosis of any layer of the soft tissue and systemic toxicity. Group A streptococci (GAS) and Staphylococcus aureus are two major pathogens associated with monomicrobial NSTIs. In the tissue environment, both Gram-positive bacteria secrete a variety of molecules, including pore-forming exotoxins, superantigens, and proteases with cytolytic and immunomodulatory functions. The present review summarizes the current knowledge about streptococcal and staphylococcal toxins in NSTIs with a special focus on their contribution to disease progression, tissue pathology, and immune evasion strategies.
Patience Shumba; Srikanth Mairpady Shambat; Nikolai Siemens. The Role of Streptococcal and Staphylococcal Exotoxins and Proteases in Human Necrotizing Soft Tissue Infections. Toxins 2019, 11, 332 .
AMA StylePatience Shumba, Srikanth Mairpady Shambat, Nikolai Siemens. The Role of Streptococcal and Staphylococcal Exotoxins and Proteases in Human Necrotizing Soft Tissue Infections. Toxins. 2019; 11 (6):332.
Chicago/Turabian StylePatience Shumba; Srikanth Mairpady Shambat; Nikolai Siemens. 2019. "The Role of Streptococcal and Staphylococcal Exotoxins and Proteases in Human Necrotizing Soft Tissue Infections." Toxins 11, no. 6: 332.
Bacterial and viral co-infections of the respiratory tract are life-threatening and present a global burden to the global community. Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes are frequent colonizers of the upper respiratory tract. Imbalances through acquisition of seasonal viruses, e.g., Influenza A virus, can lead to bacterial dissemination to the lower respiratory tract, which in turn can result in severe pneumonia. In this review, we summarize the current knowledge about bacterial and viral co-infections of the respiratory tract and focus on potential experimental models suitable for mimicking this disease. Transmission of IAV and pneumonia is mainly modeled by mouse infection. Few studies utilizing ferrets, rats, guinea pigs, rabbits, and non-human primates are also available. The knowledge gained from these studies led to important discoveries and advances in understanding these infectious diseases. Nevertheless, mouse and other infection models have limitations, especially in translation of the discoveries to humans. Here, we suggest the use of human engineered lung tissue, human ex vivo lung tissue, and porcine models to study respiratory co-infections, which might contribute to a greater translation of the results to humans and improve both, animal and human health.
Nikolai Siemens; Sonja Oehmcke-Hecht; Thomas C. Mettenleiter; Bernd Kreikemeyer; Peter Valentin-Weigand; Sven Hammerschmidt. Port d’Entrée for Respiratory Infections – Does the Influenza A Virus Pave the Way for Bacteria? Frontiers in Microbiology 2017, 8, 2602 .
AMA StyleNikolai Siemens, Sonja Oehmcke-Hecht, Thomas C. Mettenleiter, Bernd Kreikemeyer, Peter Valentin-Weigand, Sven Hammerschmidt. Port d’Entrée for Respiratory Infections – Does the Influenza A Virus Pave the Way for Bacteria? Frontiers in Microbiology. 2017; 8 ():2602.
Chicago/Turabian StyleNikolai Siemens; Sonja Oehmcke-Hecht; Thomas C. Mettenleiter; Bernd Kreikemeyer; Peter Valentin-Weigand; Sven Hammerschmidt. 2017. "Port d’Entrée for Respiratory Infections – Does the Influenza A Virus Pave the Way for Bacteria?" Frontiers in Microbiology 8, no. : 2602.