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Staphylococcus aureus
Published in Peter M. Lydyard, Michael F. Cole, John Holton, William L. Irving, Nino Porakishvili, Pradhib Venkatesan, Katherine N. Ward, Case Studies in Infectious Disease, 2010
Peter M. Lydyard, Michael F. Cole, John Holton, William L. Irving, Nino Porakishvili, Pradhib Venkatesan, Katherine N. Ward
S. aureus targets those with a breach of the skin and/or mucosal barriers (burns, traumatic wounds, surgical incisions, ulceration, viral skin lesions) together with those with reduced host resistance (cystic fibrosis, immunosuppression, diabetes mellitus, drug addiction). Intact barrier epithelia together with innate immune factors such as α-defensins and cathelicidin contribute to preventing invasion of S. aureus. If S. aureus breaches the epithelial barrier then the bacteria are combated by soluble innate antimicrobial proteins in the intercellular spaces and by neutrophils. α-Defensins and cathelicidin are also secreted by epithelial cells and neutrophils as well as being constituents of phagocyte lysosomes. However, staphylokinase and the metalloproteinase, aureolysin, can inactivate these defense factors. S. aureus also is resistant to lysozyme, a muramidase found in external secretions and in lysosomal vacuoles. Neutrophil phagocytosis is critical in defense against S. aureus. S. aureus is able to inhibit chemotaxis of neutrophils and monocytes in response to C5a and formylated bacterial peptides by secreting a chemotactic inhibitory protein (CHIP). In addition, nuclease produced by the bacterium are able to degrade the neutrophil extracellular traps (NETs) that are comprised of chromatin and microbicidal granule proteins. Initially, phagocytosis is aided by the innate pathways of the complement cascade (lectin and alternative pathways) and later by opsonic IgM and IgG antibodies. Consistent with the importance of opsonophagocytosis in host defense against S. aureus, the bacterium has several methods by which to avoid opsonization and phagocytosis and death within the phagolysosome. The bacterial capsule and protein A impair attachment and internalization. Protein A binds IgG antibodies via the Fc region, which prevents their specific binding that would otherwise lead to opsonization and complement activation resulting in further opsonization by C3b. In addition, plasminogen bound on the surface of S. aureus can be cleaved by staphylokinase into plasmin, which can then cleave IgG and C3b. Furthermore, S. aureus is able to inhibit the C3 convertase. S. aureus resists the bactericidal environment of the phagolysosome by the production of catalase and carotenoids. Carotenoids give S. aureus colonies their golden color. Both molecules neutralize singlet oxygen and superoxide produced as a result of the respiratory burst. Furthermore, several of the exotoxins produced by S. aureus kill neutrophils and monocytes/macrophages as well as other types of cells. The pus formed in these infections is a mixture of dead organisms and dead phagocytes and the release of their lysosomal contents contributes to the observed tissue damage. Neutralizing IgG antibodies are important in defense against TSST-1.
An update on the role of chronic rhinosinusitis with nasal polyps as a co-morbidity in severe asthma
Published in Expert Review of Respiratory Medicine, 2020
Riccardo Castagnoli, Amelia Licari, Ilaria Brambilla, Mariangela Tosca, Giorgio Ciprandi, Gian Luigi Marseglia
Besides a broad variety of adhesins, exotoxins and other virulence factors affecting the host, S. aureus produces 10 proteolytic enzymes comprising a metalloproteinase (aureolysin), two related cysteine proteases ScpA and SspB, a serine glutamyl endopeptidase SspA, and six other serine proteases (splA, B, C, D, E, F) [68].
Inhibition of bacterial and human zinc-metalloproteases by bisphosphonate- and catechol-containing compounds
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Fatema Rahman, Tra-Mi Nguyen, Olayiwola A. Adekoya, Cristina Campestre, Paolo Tortorella, Ingebrigt Sylte, Jan-Olof Winberg
TLN from Bacillus thermoproteolyticus is the model enzyme of the M4 family of proteases, which is also termed the thermolysin family50. These enzymes have a zinc ion in the catalytic site, which has tetrahedral coordination. Two histidines of a HEXXH motif and a glutamic acid located 18–72 residues C-terminal to the HEXXH motif are the three ligands that anchor the zinc ion to the enzyme, while the fourth ligand is a water molecule as in the MMPs, which also binds the side chain of the glutamate following the first histidine in the zinc binding segment8,9,50. Inhibitors containing a metal binding group replace the catalytic water molecule on the zinc ion when they bind the catalytic site51. TLN, PLN from Pseudomonas aeruginosa (LasB or elastase of P. aeruginosa) and aureolysin (ALN) from Staphylococcus aureus belong to the subclan MA(E) of the M4 family, also known as the “Glu-zincins”8,9,50. These three proteases have several similarities despite a modest sequence identity (28% between TLN and PLN)52,53. The three dimensional (3D) structures of PLN and TLN have been extensively studied, also in complex with inhibitors, and reveal large similarities in the overall structure. The main structural differences are that PLN consists of a slightly more open substrate binding cleft than TLN, and that PLN has one structural calcium while TLN has three53–55. For ALN only the 3 D-structure of the free enzyme is known56. Although PLN is not as well characterised as TLN, it appears that the slight difference in substrate specificity between the two enzymes is mainly due to the size of the S1′-subpocket and a more open substrate binding cleft in PLN than in TLN. PLN has a broader substrate specificity than most other M4 family members including TLN, although all these enzymes prefer a hydrophobic amino acid at the P1’ position. Furthermore, for substrate degradation four subsites of PLN require to be occupied50,53,55.