Hiding within the Human Host - Persistence and Resistance Strategies by Gram-positive Bacteria in Severe Necrotizing Skin and Soft Tissue Infections

• Applicant: Professor Dr. Nikolai Siemens
• Subject Area: Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 407176682

• Final Report Year: 2023

Final Report Abstract

Necrotizing soft tissue infections (NSTIs) are rapidly progressing infections of any layer of the skin or soft tissue. The infections are associated with significant morbidity and mortality. Streptococcus pyogenes (group A streptococci [GAS]) is the major causative pathogen of NSTIs. Furthermore, group B and G streptococcal (GBS, GGS) NSTIs were increasingly reported in recent years. Streptococcal NSTIs are more frequent among younger individuals without comorbidities and often complicated by streptococcal toxic shock syndrome (STSS). Several studies have reported that the tissue passage selects for covR/S mutations in streptococcal species. In GBS, such mutations result in pigmentation of the bacteria. Our studies showed that, irrespective if the pigmentation appears through such mutations or not, pigmented strains and pigment toxin itself induce the release of proinflammatory mediators by a wide range of human immune cells. In addition, they induce blood clotting and factor XII activity on their surface. Furthermore, plasma clotting was noted in response to the pigment toxin, suggesting an interference with coagulation cascade. A follow-up study revealed that GBS resist platelet mediated killing. Moreover, pigment toxin initially activates human platelets, followed by a rapid induction of necrotic cell death. Our study on GAS NSTIs is the first to show that in addition to the genetically induced loss of SpeB expression through covR/S mutations, GAS transiently abrogate SpeB secretion. Neutrophils were identified as major human cells driving this hyper-infective phenotype. Subsequent analyses showed that neutrophil-derived H2O2 and HOCl are mainly responsible for transient SpeB-negative phenotype of GAS. SpeB-negative clones resisted phagocytic killing resulting in enhanced neutrophil degranulation, which was linked to pronounced tissue inflammation and pathology in patients. In summary, our findings provide further insight how streptococcal persistence arises in the tissue setting through heterogeneity of bacteria during infections. Future studies will aim to identify targets, which will improve clearance of the hyper-virulent streptococcal clones.

Publications

• Prothrombotic and Proinflammatory Activities of the β-Hemolytic Group B Streptococcal Pigment. Journal of Innate Immunity, 12(4), 291-303.
  Siemens, Nikolai; Oehmcke-Hecht, Sonja; Hoßmann, Jörn; Skorka, Sebastian B.; Nijhuis, Roel H.T.; Ruppen, Corinne; Skrede, Steinar; Rohde, Manfred; Schultz, Daniel; Lalk, Michael; Itzek, Andreas; Pieper, Dietmar H.; van den Bout, Christiaan, J.; Claas, Eric C.J.; Kuijper, Ed J.; Mauritz, Robert; Sendi, Parham; Wunderink, Herman F. & Norrby-Teglund, Anna
  
• The Role of Streptococcal and Staphylococcal Exotoxins and Proteases in Human Necrotizing Soft Tissue Infections. Toxins, 11(6), 332.
  Shumba, Patience; Mairpady, Shambat Srikanth & Siemens, Nikolai
  
• Pathogenic Mechanisms of Streptococcal Necrotizing Soft Tissue Infections. Advances in Experimental Medicine and Biology, 127-150. Springer International Publishing.
  Siemens, Nikolai; Snäll, Johanna; Svensson, Mattias & Norrby-Teglund, Anna
  
• Streptococcus pyogenes (“Group A Streptococcus”), a Highly Adapted Human Pathogen—Potential Implications of Its Virulence Regulation for Epidemiology and Disease Management. Pathogens, 10(6), 776.
  Siemens, Nikolai & Lütticken, Rudolf
  
• Group B Streptococcal Hemolytic Pigment Impairs Platelet Function in a Two-Step Process. Cells, 11(10), 1637.
  Jahn, Kristin; Shumba, Patience; Quach, Phoenicia; Müsken, Mathias; Wesche, Jan; Greinacher, Andreas; Rajagopal, Lakshmi; Hammerschmidt, Sven & Siemens, Nikolai
  
• Neutrophil-derived reactive agents induce a transient SpeB negative phenotype in Streptococcus pyogenes. Journal of Biomedical Science, 30(1).
  Shumba, Patience; Sura, Thomas; Moll, Kirsten; Chakrakodi, Bhavya; Tölken, Lea A.; Hoßmann, Jörn; Hoff, Katharina J.; Hyldegaard, Ole; Nekludov, Michael; Svensson, Mattias; Arnell, Per; Skrede, Steinar; Hedetoft, Morten; Bruun, Trond; Oppegaard, Oddvar; Nedrebø, Torbjørn; Rath, Eivind; Madsen, Martin Bruun ... & Siemens, Nikolai