Can we learn from the pathogenetic strategies of group A hemolytic streptococci how tissues are injured and organs fail in post-infectious and inflammatory sequelae?

Abstract

The purpose of this review-hypothesis is to discuss the literature which had proposed the concept that the mechanisms by which infectious and inflammatory processes induce cell and tissue injury, in vivo, might paradoxically involve a deleterious synergistic 'cross-talk', among microbial- and host-derived pro-inflammatory agonists. This argument is based on studies of the mechanisms of tissue damage caused by catalase-negative group A hemolytic streptococci and also on a large body of evidence describing synergistic interactions among a multiplicity of agonists leading to cell and tissue damage in inflammatory and infectious processes. A very rapid cell damage (necrosis), accompanied by the release of large amounts of arachidonic acid and metabolites, could be induced when subtoxic amounts of oxidants (superoxide, oxidants generated by xanthine-xanthine oxidase, HOCl, NO), synergized with subtoxic amounts of a large series of membrane-perforating agents (streptococcal and other bacterial-derived hemolysins, phospholipases A2 and C, lysophosphatides, cationic proteins, fatty acids, xenobiotics, the attack complex of complement and certain cytokines). Subtoxic amounts of proteinases (elastase, cathepsin G, plasmin, trypsin) very dramatically further enhanced cell damage induced by combinations between oxidants and the membrane perforators. Thus, irrespective of the source of agonists, whether derived from microorganisms or from the hosts, a triad comprised of an oxidant, a membrane perforator, and a proteinase constitutes a potent cytolytic cocktail the activity of which may be further enhanced by certain cytokines. The role played by non-biodegradable microbial cell wall components (lipopolysaccharide, lipoteichoic acid, peptidoglycan) released following polycation- and antibiotic-induced bacteriolysis in the activation of macrophages to release oxidants, cytolytic cytokines and NO is also discussed in relation to the pathophysiology of granulomatous inflammation and sepsis. The recent failures to prevent septic shock by the administration of only single antagonists is disconcerting. It suggests, however, that since tissue damage in post-infectious syndromes is caused by synergistic interactions among a multiplicity of agents, only cocktails of appropriate antagonists, if administered at the early phase of infection and to patients at high risk, might prevent the development of post-infectious syndromes.

The role of bacteriolysis in the pathophysiology of inflammation, infection and post‐infectious sequelae

“…However, the significance of the biochemical degradation of microbes as related to tissue injury in inflammation and in post‐infectious sequelae has emerged mainly from a large series of investigations which had focused on: 1) the structure and function of the bacterial cell wall (29–30), 2) the role of muramidases (autolytic wall enzymes) in normal bacterial multiplication (31, 32), 3) the role played by lysozyme (33), leukocyte‐derived polycations, cationic enzymes (20, 21), and antibiotics (mostly beta‐lactams) in bacteriolysis (13, 16–19), 4) the role of muramidase‐deficient strains and of tolerance to antibiotics in microbial killing and degradation (18), 5) the role of the cell‐wall components: LPS, LTA and PPG in the activation of leukocytes and in the generation of oxidants, proteinases and cytotoxic cytokines (1–15, 23, 34, 35), and 6) the role of microbial cell‐wall components in the pathogenesis of granulomatous inflammation (36–39) and in the potentiation of innate immunity to infections and of tumor‐cell proliferation (40, 41).…”

“…How then can the synergism among microbial and host‐derived agonists be controlled at the bedside? (1–3, 13–55, 23, 105).…”

“…An effective control of bacteriolysis and its aftermath in humans probably necessitates the use of ulti‐drug strategies (3, 14, 15) to cope with the multiple synergistic interactions among microbial and host‐derived agonists. The could include combinations of a large assortment of non‐bacteriolytic antibiotics, cocktails of anti‐oxidants, NO synthase inhibitors, antiproteases, anti‐cytokines, coagulation (mainly anti‐thrombin III) protein c to enhance bacteriolysis, complement inhibitors, NSAID, steroids and amino steroids, tetracyclines, PLA2 inhibitors, hemofiltration procedures to remove circulating cytokines, LPS, LTA and additional cytotoxic agents, pentoxyphilline, the non metabolizable sugars lactulose to alter microbial translocation from the gut, tyrosine kinase inhibitors, cannabinoids, and bacterial permeability increasing cationic peptides (BPI) (77) (see also 144–170).…”

The Role of CRISPR-Cas Systems in Virulence of Pathogenic Bacteria

“…These pathogens are able to cause acute or chronic damage to the host (95,96) or are linked to (postinfectious) complications (97)(98)(99)(100)(101)(102)(103)(104)(105)(106)(107).…”

Role of Streptolysin O in a Mouse Model of Invasive Group A Streptococcal Disease

“…The production of active Slo in the bloodstream and its activity on various cells and tissues throughout the host may elicit overstimulation of the host immune system. In support of this idea, Slo has been implicated in the host-mediated inflammation and destruction of tissues through synergy with other streptococcal proteins and host immune cells and molecules (12). If Slo is important as a general activator of the immune system, it is likely to be important for the establishment of other types of streptococcal disease in addition to invasive disease.…”