Management of bacterial keratitis: Beyond exorcism towards consideration of organism and host factors

Abstract

In summary, the pathogenesis of bacterial keratitis initially requires the adherence of bacteria to disrupted or normal corneal epithelium. Adhesins are microbial proteins that direct the high-affinity binding to specific cell-surface components. These adhesins are able to promote bacterial entry into the host cell, derange leucocyte migration, activate plasmin, and induce cytokine production. In addition, they may act as toxins directly. Adhesins recognize carbohydrate and protein moieties on the host cell surface. Most bacteria can display a number of adhesins. Although the cognate oligosaccharides for bacterial adhesins are known, the molecules bearing these determinants are not well characterized. Integrins are a family of glycoproteins mediating cell-cell and cell-extracellular matrix recognition. Many bacterial pathogens have co-opted the existing integrin-based system masking ancillary ligand recognition in a form of mimicry. Once the bacterial pathogen has adhered to the corneal epithelial surface, the next step in establishing infection is invasion into the corneal stroma. Bacterial invasion is facilitated by proteinases that degrade basement membrane and extracellular matrix and cause cell lysis. Proteinases may be derived from bacteria, corneal cells, and migrating leucocytes. Corneal matrix metalloproteinases are excreted in an inactive form, but are activated during infection by bacterial proteinase. Corneal proteinase production may also be induced during the course of infection. The invasion of bacteria into the cornea is facilitated by a number of exotoxins, including P. aeruginosa phospholipase, heat-stable haemolysin, and exotoxin-A, which leads to stromal necrosis. Once the bacterial invasion into the cornea has ensued, infection is further facilitated by a complex sequence leading to interruption of the host immune response. Exopolysaccharide formation by both Gram-positive and Gram-negative bacteria results in local immunosuppressive effects. Certain bacteria with capsular polysaccharide also have immunosuppressive properties, including interference with phagocytosis. Proteases degrade complement components, immunoglobulins, and cytokines and may inhibit leucocyte chemotaxis and lymphocyte function. Toxin-A inhibits protein synthesis much as diphtheria toxin by catalysing the transfer of ADPR portion of nicotinamide dinucleotide to mammalian elongation factor-II. Exoenzyme-S is another ADP-ribosyl transferase that may act as an adhesin and also contribute to dissemination of the organism. Two specific bacterial proteases, elastase and alkaline protease, cause marked destruction of the cornea when injected intrastromally. Intrastromal injection of purified elastase alone also results in severe corneal damage. Inhibition of elastase activity with 2-mercaptoacetyl-L-phenylalanine-L-leucine prevents keratolysis. The proteases contribute to the pathogenesis of keratitis by degrading basement membrane, laminin, proteoglycans, extracellular matrix, and collagen. In addition, the bacterial proteases inhibit host defense systems by degrading immunoglobulins, interferon, complement, IL-I, IL-II, and TNF. Such interference results in decreased neutrophil chemotaxis, T-lymphocyte function, and NK cell function. Mutants deficient for alkaline protease do not establish corneal infection, suggesting that this protease is an important initiating factor. A bacterial heat-labile phospholipase C has been shown in antibody/substrate specificity studies to be produced in mouse ocular infections suggesting its role as a potential virulence factor. Bacterial lipopolysaccharide (LPS) stimulates neutrophil migration and infiltration into the cornea with subsequent corneal scarring and opacification. Bacterial exotoxins are released by actively replicating organisms and some endotoxins are released only after the death of the organism. These enzymes and toxins have been shown to persist in the cornea for a protracted period and continue to cause stromal destruction after the death of the pathogen. Most of the bacterial exotoxins are thermal labile and have antigenic properties. Gram-positive bacteria elaborate a variety of biologically active and immunologically distinct toxins. Coagulase-positive strains of Staphylococci are the most pathogenic and elaborate other extracellular enzymes, such as staphylokinase, lipase, hyaluronidase, DNase, coagulase, and lysozyme. Coagulase-negative Staphylococci, including S. epidermidis also produce potentially destructive toxin. Streptococcal toxins include Streptolysin O and S, erythrogenic toxin and the enzymes hyaluronidase, streptodornase, and streptokinase. The invasiveness of S. pneumoniae is aided by collagenase activity, although the organism may be inherently invasive without toxin production.