Pathogenesis Mechanisms Of Cell Invasion Epithelial Barrier Disruption Biology Essay

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Staphylococci are responsible for the numerous medical problems like surgical site infections, endocarditis and various skin and soft tissue infections (SSTIs). Staphylococcal infections are developed as a result of various medical advancements such as use of catheters and immunosuppressants. Staphylococcal infections are mainly because of two types of species: Staphylococcal aureus and (Coagulase +ve staphylococci) and coagulase -ve staphylococci species.

Staphylococcal Aureus

Many hospital and community infections are mainly caused by staphylococcal aureus. As a major cause of community-acquired infections resistance of staphylococcal aureus to antimicrobial agents is increasing rapidly. Staphylococcal aureus infections are carried out by a wide range of population because it can colonise the anterior nares and skin of individuals. Staphylococcal aureus posses various types of virulence factors and is responsible for the infections at many anatomical sites. Staphylococcal aureus causes wide range of infections but most common are skin and soft tissue infections such as: impetigo, cellulas and soft tissue abscesses. Between 1997 and 2005 Staphylococcal aureus was the most common cause of surgical site infections in 53% of patients. Acute and vertebral asteomyelitis infections of bone and joint are also common cause of Staphylococcal aureus microorganisms. Closed and open trauma sometimes may cause the development of brain abscesses.

In England, 26% causes of hospital-acquired bacteraemia between 1997 and 2002 were because of Staphylococcal aureus. Haemodialysis related bacteraemia is the most common infection by Staphylococcal aureus. Staphylococcal aureus and coagulase -ve staphylococci species together causes native and prosthetic valve endocarditis. Staphylococcal aureus is also responsible for other infections like pyelonephritis, peritonitis and pulmonary abscesses. In all, Staphylococcal aureus is responsible for wide range of serious infections. Depending on the site and susceptibility of the particular strain Staphylococcal aureus has 64% mortality and morbidity rates. These all infections explain the ability of Staphylococcal aureus to produce variety of toxins. Staphylococcal aureus also has a strong ability to acquire resistance towards antimicrobials.

Coagulase -ve Staphylococci

There are 32 species of coagulase -ve staphylococci are known and out of which Staphylococcal hominis and Staphylococcal epidermidis are the main. In clinical microbiology laboratory coagulase -ve staphylococci are the most widely isolated as contaminants but not as agents of infections. Infections associated with coagulase -ve staphylococci are characterised by non-specific clinical manifestations which oppose the fact of infections caused by these microorganisms. But, by using the improved methods of testing infections linked to these microorganisms are clearly investigated. The number of cases for the presence of coagulase -ve staphylococci in patients' blood is increasing rapidly. Rise in these infections are mainly because of the advancements in the medical field. Since 1980s often use of medical devices like prosthetic joints, prosthetic heart valves, vascular and peritoneal catheters is one of the reason in the increase in coagulase -ve staphylococci infections. Most of the coagulase -ve staphylococci species, is resistant to Methicillin antimicrobial agent. A wide increase in the use of broad-spectrum antibiotics leads in the rise of the resistance against these species.

Types of infections

Staphylococcal aureus causes various types of infections:

Boils: In this infection red watery bumps formed due to the infected hair follicles.

Infection causing skin disorders: These infections occurs when the bacteria enters into the host's skin.

Impetigo: These are of 2 types:

Bollous Impetigo: Large watery blisters formation takes place in bollus impetigo.

Non-Bollous Impetigo: It this infection the formation of sores which later when ruptured develops yellowish brown crush.

Food poisoning: Staphylococcal aureus sometimes leads to the contamination of food which may cause food poisoning.

Arthritis: Arthritis is an infection takes place in joints by staphylococcal aureus. The symptoms include swelling of joints, tenderness around the joints.

Cellulitis: Cellulitis occurs in the deep layer of the skin and subcutaneous tissue. This infection results in the rashes on the skin and other symptoms include shivering and high body temperature.

Toxic Shock Syndrome: Toxic shock syndrome is caused by staphylococcal aureus and occurs when the strains enter the blood stream and start releasing toxins. This can be characterized by decrease in the blood pressure of individuals.

Systemic infections: Skin infections caused by staphylococcal aureus may develop other systemic complications due to lack of immunity. Use of medical equipment such as catheters, prosthetic joints etc., may also develops the infection.

Sepsis: This infection of staphylococcal aureus includes elevated body temperature, diarrhea, fast breathing, tachycardia and hypotension.


Mechanisms of cell invasion

Epithelial barrier disruption

Staphylococcal aureus microorganisms secrete a group of exotoxins and enzymes. Staphylococcal aureus also secretes nucleases, lipases, collagenase, hyaluronidase and four hemolysins (α, β, γ and δ - toxins). Some Staphylococcal aureus targets the specific molecules which constitute the host immune system and cell adhesion. Staphylococcal aureus sticks to the surfaces of the epithelial cells through surface proteins and wall TA. After adhesion Staphylococcal aureus releases α - toxin, which makes the pores in the cell wall. α - toxins is capable of causing wide range of events in the both infected and non-infected cells. The Staphylococcal aureus cellular events cause the activation of phosphatidylinositol hydrolysis, nitric oxide production, thromboxane and prostaglandins. Staphylococcal aureus leads to up regulation of inflammatory cytotoxins. The activation of these components leads to systemic inflammatory response syndrome (SIRS).

Acantholytic infections

SSSS and bullous impetigo are acantholytic infections caused by Staphylococcal aureus. Generalised form of SSSS mainly affects infants, children and newborns. The diagnosis of SSSS is usually characterised using cutaneous manifestations, because infected strain can be easily recovered from intact bullae. Due to the less developed immunity and less efficient renal clearance of the toxin makes children highly susceptible for the SSSS. Localised form of SSSS is known as bullous impetigo. In localised SSSS infected strains can be recovered from bullae. There are basically three types of ETs for staphylococcal microorganisms: ETA, ETB and ETD. ETs have a property that they are capable for the cleavage of human Dsg1. In human SSSS ETA and ETB are more responsible but ETB is usually isolated more frequently than ETA in children. The etd gene-positive strain sometimes responsible for infections like cutaneous abscesses, furuncles and also finger-pulp infection.

Host immunity evasion

Chemotaxis and opsonisation interference

A family of proteins known as compliment is capable of recruiting effector cells against pathogens by chemotactic molecules such as C5a and C3a, releasing cytolytic peptides and promoting phagocytosis with the help of neutrophils. Chemoattractant molecules like formylated peptides are also produced by the proliferating bacteria. Chemotaxis inhibitory protein of staphylococci (CHIP) is secreted by the Staphylococcal aureus strains which have a capability to binds with the receptors of formyl peptides and C5a. There is another inhibitory protein, major histocapability class II (Map) which inhibits the neutrophil chemotaxis. 'Map' on neutrophil surfaces also interferes with the action of LFA-1 by blocking the endothelial cells expressed ICAM-1 molecules. Individuals has antibodies present in their body because of Staphylococcal aureus infections which can fight against bacterial cell surface antigens like peptidoglycan and TA. But, because of the wide range of evasion mechanisms these antibodies are unable to fight against infections.

Formation of Biofilm

Bacteria may produce a polysaccharide-containing material known as bacterial glycocalyx. This bacterium adheres to implanted medical devices or damaged tissue. Bacterial glycocalyx can be the cause of many infections. A biofilm is a slimy layer that is formed by these bacteria encasing themselves in a hydrated matrix of polysaccharides and proteins. An interested thing to note about these particular bacteria is that antimicrobial agents might not eradicate S. aureus without the help of neutrophils. This S. aureus glycocalyx can play a critical role in the colonization and adherence to damaged skin tissue.

Phagocytosis Evasion

Neutrophils that infiltrate at an infectious site may be damaged by Staphylococcal aureus which has the ability to secrete some leukotoxins. There are six various forms of g-hemolysin/PVL. Three are potential S and two are potential F unit; all of which have the capacity to combine (S+F) to form toxin molecules. When assayed by themselves, each of the subunits lacks haemolytic and leukotoxic activities. However, once added as a pair to a erythrocyte, cytolytic activity can be observable to varying degrees. PVL (LukF-PV/LukS-PV), a pair of leukotoxin, may exhibit specific activity against those neutrophils or monocytes of humans as well as rabbits. This pair may also exhibit specific activity against macrophages as well. Staphylococcal aureus may express an abundant of clumping factor A, or Clfa, during the stationary phase of growth activity. This in turn produces cell-clumping and continues to coat the organism with fibrogen. This may in turn serve to protect the S. aureus further from phagocytosis which may be caused by the formation of the biofilm. The attachment of neutrophils to a cell surface-bound antibodies and compliment are inhibited by capsular-like polysaccharide of Staphylococcal aureus. Neutrophils typically will engulf bacterial cells and kill them by oxygen radicals, lysosomal enzymes, and cationic, antimicrobial peptide, a-defensins (human neutrophil peptide) which belong to the innate immune system. The negative charge of the bacterial wall is neutralized, however, by gained resistance to the cationic peptides by Staphylococcal aureus.

Immunomodulation Induction

Production of Th2 cytokine, IL-40 takes place from platelet-activating factor receptor (PAF-R) because of the immunomodulatory effects of Staphylococcal TA. On mobile genetic elements Staphylococcal aureus posses different antigen genes, like plasmids and pathogenicity islands. Superantigens are responsible for the deletion of Vβ T-Cells by inducing a strong proliferative response. It has been observed that lipopolysaccharide (LPS) and superantigens may leads to symptoms like TSS and SIRS. First stimulation of monocytes takes place by LPS which later leads to the activation of T-cells. Allergic skin inflammation and increased IgE synthesis occurs due to the exposure to superantigens which changes the immune response towards Th2 cells.

Exotoxin production and virulence Mechanisms

Quorum-sensing signalling

A special regulation cascade of bacterial gene expression is Quorum-sensing, in response to an increase in cell density. When Staphylococcal aureus cells multiply, the cells express a signal molecule designated as 'agr' to sense the status of cell density ('quorum'). The agr was first described as "a pleiotropic regulator of staphylococcal exotoxins, proteases and surface proteins". The agr system of Staphylococcal aureus consists of 4 genes (agrA, agrC, agrD, and agrB) that are co transcribed (RNAII). The gene for the effector molecule of the agr system, RNAIII, is also encoded by the gene for a-toxin (hld). Exotoxins via agr quorum-sensing signalling, are produced by Staphylococcal aureus, and at the same time inhibit biofilm formation. Therefore, this pathway permits Staphylococcal aureus cells to impose them and spread from the colonization sites. At these sites, cells are protected by biofilm, but the Staphylococcal aureus cells continue to spread toward other tissues or blood against the host barriers and immune surveillance.

Toxic Shock Syndrome

Toxic Shock Syndrome can be usually classified into two categories: menstrual TSS or nonmenstrual TSS. The former was originally used in association with tampon use. The latter occurs in a variety of clinical settings and has the tendency to recur. TSST-1 which is produced by Staphylococcal aureus is a life-threatening illness.TSS is defined as "an acute and potentially fatal illness characterized by high fever, a diffuse erythematous rash, desquamation of the skin 1-2 weeks after onset, hypotension and involvement of three or more organ systems." An expansion on an extreme scale in the number of TSST-1-reactiveVb2-positive T-cells can be observed in a patient with TSS. T cells activated by TSST-1 produce cytokines and have been implicit in pathogenesis of this disease. TSS occurs infrequently due to the presence of anti-TSST-1 antibodies; however exposure to TSST-1-producing Staphylococcal aureus is a common occurrence in the general population. These TSST-1 antibodies play a role in protecting adults from the development of TSS.

Activity of the Antimicrobial Agents against Staphylococcal aureus

Activity of any agent acting as antimicrobial against infection should have the power of interfering with the bacterial functioning of the infection at cellular level. Successful treatment of any infection is possible with the knowledge of antimicrobial resistance of the infection. There are different processes of acquiring resistance in Staphylococcal aureus:

Chromosomal Mutation

Chromosomal Transduction

Chromosomal Transformation

Out of above three processes chromosomal mutation is most preferred process which results in the alteration of the target of the action. This also causes hindrance in the permeability of the antimicrobial agent through the bacterial membrane.

The antimicrobial agents acting against Staphylococcal aureus can be classified with respect to their site of action:

Agents acting on the cell wall: These agents target the cell wall by interfering the metabolic and synthesis pathway of the cell wall. The agents are usually bactericidal in nature.

Β - Lactam's: This is the most commonly used group of cell wall inhibitory against Staphylococcal aureus. It is responsible for the cross linking of the cell wall by inactivating the transpeptidase which causes the collapse of the cell wall synthesis resulting in the cell death. This process occurs due to autolysis. Resistance mechanism develops when an altered autolysis process is present. In that case the bactericidal activity of the agent is changed to bacteriostatic activity. The true cause of the resistance development is the opening of the penicillin's β - lactam ring due to class A β - lactamases resulting in the inactivation of the ring. To overcome the problem β - lactamase inhibitor such as clavulonic acid are used.

Penicillin: Penicillin resistance against Staphylococcal aureus has been clinically proven. Hence it is no longer used for the treatment of Staphylococcal aureus infection. Although the agents like oxacillin are used in certain cases e.g. Methicillin resistance Staphylococcal aureus (MRSA).

Methicillin: Methicillin resistance is due to the altered penicillin binding protein (PBP) which is present on the chromosome. It also causes the cross resistance to all other β - lactams including cephalosporins.

Cephalosporins: It is a semisynthetic antimicrobial agent which used for the Staphylococcal aureus infection but is less potent. The resistance against this agent also develops due to the altered PBP similar to Methicillin.

Fosfomycin: It is cell wall inhibitor which acts at an early stage as compared to β - lactams. Inhibition of glucose -6- phosphate transport results in the development of the resistance of the agent. It is always used in the combination with other antimicrobials for the treatment of Staphylococcal aureus.

Agents not acting on the cell wall: These agents are not commonly used because they are not as potent as the cell wall inhibitors. Even though these are used in combination in certain cases where the infection is highly resistance to other agents. These agents are classified as:

Inhibitors of protein synthesis: These agents have the bacteriostatic activity. These are used in combination when resistance develop in any of the agent, it results in depletion of bacteriostaction activity of the combination because they cannot act alone.

Aminoglycosides: These agents act by inhibiting the initiation phase of the protein synthesis and are transported across the cell wall activity in normal mechanism and can be induced by decreased oxygen supply. These are used against Staphylococcal aureus in combination and the action is synergised. The resistance is developed when there is impaired transport across the membrane.

Chloramphenicol: It has bacteriostatic activity by acting on the 50S ribosome subunit. Resistance is developed when there is hindrance in the binding to the ribosome.

Fusidic acid: Fusidic acid is used against Staphylococcal aureus and acts by inhibiting the 50S ribosomal subunits in the elongation step of protein synthesis. The resistance developed results in its activity especially when used as a monotherapy.

Agents acting as nucleic acid and anti-metabolite inhibitors: These agents are classified as:

Flouroquinolones: The resistance of the agent develop due to the acquired chromosomal mutation.

Trimethoprin- Sulfamethoxazole: This is a complex combination which is used against Staphylococcal aureus infections. The resistance to this combination occurs due to abnormal production of amino acids, purines and thymidine.