Pathogenesis of Staphylococci

Antigenic structure

Staphylococci comprise antigenic polysaccharides and proteins as well as different substances essential in cell wall structure. Peptidoglycan, a polysaccharide polymer containing related subunits, presents the rigid exoskeleton of the cell wall. Peptidoglycan is destroyed by way of strong acid or exposure to lysozyme. It's miles critical inside the pathogenesis of contamination: It elicits manufacturing of interleukin-1 (endogenous pyrogen) and opsonic antibodies by means of monocytes, and it is able to be a chemoattractant for polymorphonuclear leukocytes, have endotoxin-like the hobby, and activate supplement. Teichoic acids, that are polymers of polyribitol–phosphate, are move linked to the peptidoglycan and can be antigenic. Antiteichoic acid antibodies detectable by using gel diffusion may be found in sufferers with energetic endocarditis caused by S aureus. Protein A is a cellular wall component of S aureus traces and is a bacterial surface protein that has been characterized by a group of adhesins called microbial surface additives recognizing adhesive matrix molecules (MSCRAMMS). Bacterial attachment to host cells is mediated by means of MSCRAMMS, and these are important virulence factors. Protein A binds to the Fc part of IgG molecules except for IgG3. The Fab part of the IgG bound to protein A is unfastened to combine with a selected antigen. Protein A has emerged as a critical reagent in immunology and diagnostic laboratory generation; as an example, protein A with attached IgG molecules directed against a specific bacterial antigen agglutinates bacteria that have that antigen (“coagglutination”). Any other vital MSCRAMM is clumping issue at the mobile wall surface; clumping issue binds nonenzymatically to fibrinogen and platelets, yielding aggregation of the bacteria. The final MSCRAMMs, too numerous to mention right here, play vital roles in establishing S aureus colonization and invasion. Maximum S aureus traces of medical importance have polysaccharide pills, which inhibit phagocytosis via polymorphonuclear leukocytes except precise antibodies are present. at the least eleven serotypes had been diagnosed, with kinds five and eight liable for the general public of infections. those pill types are targets for a conjugate vaccine. Serologic exams have constrained usefulness in identifying staphylococci.

Enzymes and toxins

Staphylococci can produce sickness both through their capability to multiply and unfold extensively in tissues and through their production of many extracellular substances. A number of these materials are enzymes; others are taken into consideration to be toxins, even though they may function as enzymes. A number of the pollutants are under the genetic manipulate of plasmids; a few can be beneath both chromosomal and extrachromosomal control; and for others, the mechanism of genetic control is not nicely defined.

Catalase

Staphylococci produce catalase, which converts hydrogen peroxide into water and oxygen. The catalase takes a look at differentiates the staphylococci, which are superb, from the streptococci, which can be bad.

Coagulase and Clumping element

S aureus produces coagulase, an enzyme-like protein that clots oxalate or citrated plasma. Coagulase binds to prothrombin; together they end up enzymatically lively and initiate fibrin polymerization. Coagulase may additionally deposit fibrin at the surface of staphylococci, possibly altering their ingestion by phagocytic cells or their destruction inside such cells. Coagulase manufacturing is taken into consideration synonymous with invasive pathogenic capacity. The clumping component is any other instance of an MSCRAMM this is answerable for adherence of the organisms to fibrinogen and fibrin. when combined with plasma, S aureus forms clumps. The clumping issue is wonderful from coagulase. because clumping thing induces a strong immunogenic reaction inside the host, it has been the focal point of vaccine efforts. but, no human vaccines towards this element are to be had to this point.

Other Enzymes

other enzymes produced with the aid of staphylococci include a hyaluronidase, or spreading element; a staphylokinase ensuing in fibrinolysis, however, appearing an awful lot extra slowly than streptokinase; proteinases; lipases; and -lactamase.

Hemolysins

Hemolysin is a heterogeneous protein that acts on an extensive spectrum of eukaryotic cellular membranes. The -toxin degrades sphingomyelin and consequently is poisonous for lots styles of cells, along with human purple blood cells. The -toxin is heterogeneous and dissociates into subunits in nonionic detergents. It disrupts biologic membranes and can have a function in S aureus diarrheal illnesses. The ïƒ£ï€ hemolysin is a leukocidin that lyses white blood cells and consists of proteins targeted S and F. -Hemolysin can have interaction with the two proteins comprising the Panton-Valentine leukocidin to form six capability two component pollutants. All six of that protein pollution are able to successfully lysing white blood cells via inflicting pore formation within the cell membranes that increase cation permeability. This ends in the massive release of inflammatory mediators such as IL-8, leukotriene, and histamine, which can be answerable for necrosis and intense infection.

Panton-Valentine Leukocidin

This toxin of S aureus has components, and unlike the chromosomally encoded hemolysins above, PVL is encoded on a mobile phage. it is able to kill white blood cells of people and rabbits. the 2 components designated as S and F act synergistically at the white blood cellular membrane as defined for ïƒ£ï€ the antoxin. This toxin is a crucial virulence aspect in CA-MRSA infections. each organizations of hemolysins are regulated with the aid of agr.

Exfoliative pollutants

These epidermolytic pollutants of S aureus are distinct proteins of the same molecular weight. Exfoliative toxin A is encoded with the aid of eta placed on a phage and is heat stable (resists boiling for 20 minutes). Exfoliative toxin B is plasmid mediated and warmth labile. those epidermolytic pollution yield the generalized desquamation of the staphylococcal scalded skin syndrome via dissolving the mucopolysaccharide matrix of the dermis. The pollutants are superantigens.

Poisonous shock Syndrome Toxin

Most S aureus traces remoted from sufferers with poisonous shock syndrome produce a toxin called toxic surprise syndrome toxin-1 (TSST-1), which is similar to enterotoxin F. TSST-1 is the prototypical superantigen. TSST-1 binds to fundamental histocompatibility class (MHC) class II molecules, yielding T-cellular stimulation, which promotes the protean manifestations of the poisonous surprise syndrome. The toxin is associated with fever, shock, and multisystem involvement, along with a desquamative skin rash. The gene for TSST-1 is discovered in about 20% of S aureus isolates, consisting of MRSA.

Enterotoxins

There are a couple of (A–E, G–J, k–R and U, V) enterotoxins that, much like TSST-1, are superantigens. approximately 50% of S aureus lines can produce one or more of them. The enterotoxins are heat stable and immune to the action of intestine enzymes. essential reasons of meals poisoning, enterotoxins are produced whilst S aureus grows in carbohydrate and protein ingredients. Ingestion of 25 g of enterotoxin B consequences in vomiting and diarrhea. The emetic effect of enterotoxin is probably the end result of crucial anxious gadget stimulation (vomiting middle) after the toxin acts on neural receptors within the intestine. The exfoliative pollutants, TSST-1, and the enterotoxin genes are on a chromosomal element known as a pathogenicity island. It interacts with accent genetic factors—bacteriophages—to produce the toxins.

Pathogenesis

Staphylococci, particularly S epidermidis, are participants of the ordinary microbiota of the human skin and respiratory and gastrointestinal tracts. Nasal carriage of S aureus occurs in 20–50% of people. Staphylococci also are determined frequently on garb, mattress linens, and different fomites in human environments. The pathogenic ability of a given stress of S aureus is the blended impact of extracellular factors and toxins collectively with the invasive homes of the pressure. At one stop of the disorder spectrum is staphylococcal food poisoning, attributable solely to the ingestion of preformed enterotoxin; at the other stop are staphylococcal bacteremia and disseminated abscesses in all organs. Pathogenic, invasive S aureus produces coagulase and has a tendency to provide a yellow pigment and to be hemolytic.

Nonpathogenic, noninvasive staphylococci inclusive of S epidermidis are coagulase negative and tend to be nonhemolytic. Such organisms rarely produce suppuration, however, can also infect orthopedic or cardiovascular prostheses or cause disease in immunosuppressed men and women. they may be refractory to remedy due to the formation of biofilms. S lugdunensis has emerged as a virulent organism causing a sickness spectrum much like S aureus with whom it shares phenotypic traits along with hemolysis and clumping element. S saprophyticus is generally non pigmented, novobiocin resistant, and nonhemolytic; it causes urinary tract infections in young ladies.

Regulation of Virulence Determinants

• The expression of staphylococcal virulence determinants is regulated by using several structures that sense and respond to environmental alerts. the primary of these structures includes
• proteins (two-aspect structures), an instance of that is accented gene regulator (Agr). the opposite two structures consist of DNA-binding proteins (eg, Sar proteins) and small regulatory
• RNAs, respectively (eg, RNAIII). Binding of sensors to precise extracellular ligands or to a receptor effects in a phosphorylation cascade that ends in a binding of the regulator to
• particular DNA sequences. This ultimately results in activation of transcription-regulating functions. There are numerous well described two-thing regulatory systems in S aureus.
• these include agr, the first-class described, sae RS, srrAB, arlSR, and lytRS. A precis of ways these structures have the interaction is in briefly defined underneath.
• The accent gene regulator (agr) is critical in quorum sensing manipulate of gene expression. It controls the preferential expression of surface adhesins (protein A, coagulase, and fibronectin binding protein) and production of exoproteins (pollution which includes TSST-1) depending upon the boom section (and subsequently bacterial density).

At low cellular density, the promoter P2 is off, and transcriptions of the transmembrane protein, AgrB, peptide precursor, AgrD, transmembrane sensor, AgrC, and transcription regulator, Agr A, are at low stages. As mobile density will increase in the course of desk-bound growth section, the AgrC sensor activates the regulator AgrA. AgrA is a DNA-binding protein that activates promoter P2 and promoter P3. Promoter P3 initiates transcription of -hemolysin and an effector called RNAIII, which downregulates the expression of floor adhesins and activates secretion of exoproteins at both the transcriptional and translational stages. Agr is likewise undoubtedly managed by using a DNA-binding protein called SarA (encoded by means of sar) and likely by using different regulatory systems. at least 4 extra -issue regulatory structures had been proven to have an effect on virulence gene expression. these are referred to as sae, S aureus exoproteins; srrAB, staphylococcal respiratory response; arlS, autolysis-associated locus sensor; and lytRS. Sae regulates gene expression on the transcriptional degree and is crucial for manufacturing of -toxin, -hemolysins, and coagulase. Its interest is impartial from that of agr. SsrAB is crucial for regulation of virulence factor expression this is influenced via environmental oxygen. The arlSR locus is essential to the control of autolysis and decreases the activation of the agr locus. The lytRS locus is likewise involved in autolysis.

References:

D greenwood, Slack RCB and J Peutherer.Medical microbiology.2001.

JG College, AG Fraser and BP Marmion.Practical Medical microbiology.Fourteenth Edition. Churchill Livingstone, 1996.

JP Micheal, ECS Chan and NR Krieg.Microbiology.Fifth Edition. Delhi: Mcgraw-hill, 1993.

M Cheesbrugh.Medical laboratory manual for tropical countries.London, 2007.