Authors: Isaac Ginsburg, Erez Koren
Catalase-negative penicillin-sensitive group A hemolytic streptococci (GAS) are multifactorial microorganisms, which do not produce a unique damage-associated molecular patterns which if effectively neutralized might effectively stop their pathogenicity. GAS is involved in the pathogenicity of pharangitis, tonsillitis, rheumatic fever, arthritis, necrotizing fasciitis (NF), toxic shock syndrome and also in sepsis. GAS-induced NF is quite a rare but dangerous and deadly infection, which most commonly occurs in the arms, legs and abdominal wall and is fatal in 30%-40% of cases. GAS, which possess surface capsular polysaccharide and antigenic M and T proteins, arrive at the inflammatory areas by generating spreading factors such as hyaluronidase, DNase and streptokinaseactivated plasmin. GAS can spread in tissues and avidly adhere to membranes of target cells to deliver a nonimmunogenic cell bound hemolysin (CBH) upon cells’ membrane phospholipids to induce a penetrating membrane damage (“a kiss of Death”). Two additional potent extracellular hemolysins, Streptolysin O (SLO) and a nonimmunogenic streptolysin S (SLS) produced can injure neutrophils (PMNs), which are recruited to the infected sites in large numbers. However, PMNs can engage in phagocytosis and also undergo activation to release various proinflammatory agents including NADPH-generated superoxide which dismutates to H2 O2 and with myeloperoxidase (MPO) which forms toxic HOCl upon interaction with halides. Activated PMNs also deliver highly cationic peptides such as LL37, cationic elastase, cathepsins and nuclear histone, which interact electrostatically with egatively-charged membrane sites forming membrane lesions. PMNs also secrete many acid hydrolases, several Th1 cytokines and chemokines, which recruit more PMNs. Similarly, to beta-lactams antibiotics, cationic peptides can also activate bacteriolysis and trigger the release of the pro-inflammatory agents lipoteichoic acid (LTA) and peptidoglycan (PPG).
We hereby propose that in infectious and inflammatory sites GAS and PMNs exo-products and also microbial cellwall structures might all act synergistically to cause cell and tissue damage. Cell damage might be ameliorated by appropriate cocktails of anti-inflammatory agents. also, containing highly negatively charged heparin 23.
View/Download pdf