Optometry & Vision Science:
Pseudomonas aeruginosa Infection and Inflammation During Contact Lens Wear: A Review
WILLCOX, MARK D. P. PhD
Institute for Eye Research, Vision CRC and School of Optometry and Vision Science, University of New South Wales, Australia
Received August 16, 2006; revision accepted October 10, 2006.
Infection and inflammation during contact lens wear is often associated with microbial contamination of lenses. Several different types of microbes that colonize lenses can lead to infection and inflammation, but the most common cause of infection (microbial keratitis; MK) remains the Gram-negative bacterium Pseudomonas aeruginosa. P. aeruginosa has a battery of cell-associated and extracellular virulence factors it can use to initiate and maintain infection. Its ability to produce proteases, to either invade or kill corneal cells, and to coordinate expression of virulence factors via quorum-sensing have been shown to be important during MK. Another important factor that contributes to the destruction of the cornea during MK is excessive activation of the host defense system. P. aeruginosa can activate several pathways of the immune system during MK, and activation often involves receptors on the corneal epithelial cells called toll-like receptors (TLRs). These TLRs recognize e.g., lipopolysaccharide or flagella from P. aeruginosa and activate the epithelial cells to produce inflammatory mediators such as cytokines and chemokines. These cytokines or chemokines recruit white blood cells, predominantly polymorphonuclear leukocytes, to the infection in order that they can phagocytose and kill the P. aeruginosa. However, continued recruitment and presence of these polymorphonuclear neutrophils and other white blood cells in the corneal tissue leads to destruction of corneal cells and tissue components. This can ultimately lead to scarring and vision loss.
Infection and inflammation during contact lens wear is often associated with microbial contamination of lenses. Several different types of microbes that colonize lenses can lead to infection and inflammation, but the most common cause of infection (microbial keratitis; MK) remains the Gram-negative bacterium Pseudomonas aeruginosa. P. aeruginosa has a battery of cell-associated and extracellular virulence factors it can use to initiate and maintain infection. Its ability to produce proteases, to either invade or kill corneal cells, and to coordinate expression of virulence factors via quorum-sensing have been shown to be important during MK. Another important factor that contributes to the destruction of the cornea during MK is excessive activation of the host defense system. P. aeruginosa can activate several pathways of the immune system during MK, and activation often involves receptors on the corneal epithelial cells called toll-like receptors (TLRs). These TLRs recognize e.g., lipopolysaccharide or flagella from P. aeruginosa and activate the epithelial cells to produce inflammatory mediators such as cytokines and chemokines. These cytokines or chemokines recruit white blood cells, predominantly polymorphonuclear leukocytes, to the infection in order that they can phagocytose and kill the P. aeruginosa. However, continued recruitment and presence of these polymorphonuclear neutrophils (PMNs) and other white blood cells in the corneal tissue leads to destruction of corneal cells and tissue components. This can ultimately lead to scarring and vision loss. Bacterial colonization of contact lens surfaces causes many adverse responses encountered during contact lens wear.1–8 The most devastating of these is microbial keratitis (MK) which, if not treated promptly or with the proper antibiotics, can lead to scarring and blindness. Other adverse responses associated with microbial colonization of contact lenses include contact lens-induced acute red eye (CLARE), contact lens-induced peripheral ulceration, infiltrative keratitis (IK), and asymptomatic infiltrative keratitis (AIK). For a detailed clinical description of these conditions the reader is referred to the article by Holden et al.9
Nonbacterial microbial colonization of contact lenses is associated with MK, especially colonization of lenses by Acanthamoeba10 or fungi.11,12 However, MK is most commonly caused by colonization of contact lenses with the bacterium Pseudomonas aeruginosa,13–15 a Gram-negative bacterium that is commonly found in many environments, including water. CLARE is associated with colonization of contact lenses with Gram-negative bacteria (in particular Haemophilus influenzae)3 or the Gram-positive bacterium Streptococcus pneumoniae.4 Contact Lens Induced Peripheral Ulceration is produced by Gram-positive colonization of contact lenses, with the bacterium Staphylococcus aureus being the most commonly associated bacterium.7 Causes of IK and AIK are many, but include colonization by large numbers of Gram-negative bacteria for IK and large numbers of Gram-positive bacteria for AIK (Table 1).
Pseudomonas aeruginosa Virulence Factors
As P. aeruginosa is a major causative agent of MK, CLARE, CPU and AIK, this review will focus on aspects of this bacterium that contribute to infection, and the host response to this bacterium in the cornea. A major part of the virulence of P. aeruginosa is attributed to its ability to produce several destructive proteins, and to induce an excessive host immune response in the ocular tissues.16 The P. aeruginosa virulence factors most associated with ocular damage are exoenzymes S (gene called exoS), and U (exoU),17 elastase (lasB),18 alkaline protease (aprA)19 and protease IV (prpL).20 Another important pathogenic mechanism is a cell-to-cell communication system called quorum sensing.21
P. aeruginosa strains can usually be distinguished by the presence of either genes to exoS or exoU, which encode the toxins exoenzyme S and exotoxin U respectively. Cells possessing the exoS gene tend to invade the interior of the cell, but do not secrete ExoU. Conversely, cells possessing exoU tend to remain outside the host cell but secrete ExoU directly into the cells interior.22 ExoS protein is both a GTPase-activating protein and an ADP-ribosyltransferase and both these activities lead to rearrangement of the cytoskeleton protein actin and ultimately cell death,23,24 whereas ExoU is an intracellular phospholipase and causes rapid cell death.25
Elastase (LasB) breaks down elastin, fibrin, and collagen, which are critical for the mechanical properties of connective tissue. It has also shown to degrade host immunological factors IgG, IgA, IFNγ, TNFα.26 Alkaline protease is known to degrade fibrin, complement molecules C1q, and C3, and in conjunction with LasB, cytokines IFNγ and TNFα.26 It was shown to enhance bacterial binding to corneal epithelium by exposure of lipase sensitive receptors,27 but subsequently determined not to be of major importance in virulence in the eye. Protease IV degrades important host immunological proteins such as complement and IgG.28 Protease IV also compromises the integrity of structural proteins such as elastin,29 therefore causing tissue damage and facilitating bacterial infection. Protease IV degrades the iron binding proteins lactoferrin and transferrin which enables P. aeruginosa to scavenge iron from the host.29 Protease IV has been shown to be a key virulence factor for P. aeruginosa in ocular infections.30
Controlled expression of several key P. aeruginosa virulence factors including the gene for elastase, lasB31 and ExoS production32 are mediated via population density biosensor mechanisms, known as quorum-sensing. Quorum sensing activates genes only when a quorum, i.e., a certain density of bacteria, is present. Once the density of bacteria reaches a certain threshold, the bacteria respond as a population, switching on the production of genes, especially those associated with pathogenicity. This control of the expression of virulence or pathogenicity factors might help the bacterium be “invisible” to the host (i.e., eye) until such a time when the levels of the bacteria are sufficient to allow the bacteria to overcome host defense systems.
Inflammatory Response in the Cornea During Pseudomonas aeruginosa Keratitis
Pseudomonas aeruginosa infection of the cornea triggers an intense inflammatory response, which persists and can result in severe corneal damage, including perforation.33 Corneal infection with P. aeruginosa is characterized by the extensive recruitment of inflammatory cells with PMNs being the most predominant cell type seen in the cornea. PMNs are believed to be essential for the elimination of bacteria and to promote wound healing; however, persistence of these cells may contribute to corneal damage. A reduction in PMN recruitment is accompanied by a significant reduction in tissue damage during bacterial infection of the cornea in mice.34
The initial inflammatory cascade is most likely mediated by the innate immune system, i.e., the immune system not dependent on antibody production. The characteristics of the innate immune response are a broad-spectrum relatively nonspecific response, no memory or lasting protective immunity, a limited repertoire of recognition molecules and the fact that the responses are phylogenetically ancient. Innate immunity includes anatomic barriers such as the lids, lashes and an intact epithelial surface. A large number of diverse chemical compounds are involved in innate immunity. These include factors present all the time in tears such as lactoferrin (binds iron which is an essential nutrient for microbes), lysozyme (an enzyme which cleaves the cell wall peptidoglycan of bacteria), secretory phospholipase A2 (which cleaves membrane lipids of certain bacteria) and components of the complement cascade (which helps recruit white blood cells to sites of bacterial colonization and aids in killing of bacteria). Other factors are produced by resident ocular cells, such as epithelial cells, upon stimulation by bacteria. These factors include defensins (which help kill bacteria by boring holes in their membranes) and arachidonic acid metabolites (which help recruit white blood cells).
The adaptive antibody-associated immune system probably plays a smaller role in the initial inflammatory response during keratitis, but is likely to increase in importance as the infection develops. (It should be noted that in the case of Acanthamoeba keratitis, it is believed that the adaptive immune response is of major importance).35 During the course of the inflammatory response, migrating and resident white blood cells, including polymorphonuclear leukocytes, macrophages, dentritic cells, and T cells, take over as the major mediators of the inflammatory response. It seems that the activation of TLRs of dentritic cells is a major influence on the progression from an innate to adaptive immune response. For recent reviews of the role of the innate immune response during Pseudomonas aeruginosa keratitis see several publications arising from the Hazlett laboratory.16,36,37,38
Figure 1 outlines the stages involved in the production of the inflammatory response to Pseudomonas aeruginosa during MK. Epithelial cells respond to P. aeruginosa and other bacteria through several systems, including the use of TLRs. This host receptor–bacteria interaction has been described as occurring between pattern-recognition receptors (such as TLRs) on host cells and pathogen-associated molecular patterns (PAMPs) of microorganisms.39 The cornea or conjunctiva have been shown to possess TLR 2, TLR 4, TLR 5, and TLR 9. These receptors recognize distinct PAMPs; TLR 2 recognizes components from both Gram-positives (i.e., Staphylococcus aureus) and Gram-negatives (i.e., Pseudomonas aeruginosa), including ExoS of P. aeruginosa40; TLR 4 recognizes lipopolysaccharide which is only produced by Gram-negatives and ExoS of P. aeruginosa40; TLR 5 recognizes flagellin, the major protein component of flagella of many different bacteria; TLR 9 recognizes DNA and RNA from bacteria and viruses (see review by Yu and Hazlett36). Interestingly, it seems that the cornea may “hide” its TLRs, thus reducing the propensity for corneal inflammation. TLR 4 is only expressed at low levels until stimulated by inflammatory cytokines such as IL-1β41 and TLR 5 is only expressed in basal or wing cells of the corneal epithelium, not on the superficial cells42 and is therefore hidden until the cornea epithelial surface is disrupted. TLR 9 seems to be involved in P. aeruginosa keratitis, probably helping to stimulate bacterial killing in the cornea,43 and TLR 5 on corneal epithelial cells can recognize P. aeruginosa flagellin.42 Intracellular signaling cascades in corneal epithelial cells after PAMP recognition stimulate the production of cytokines and chemokines involved in the inflammatory response. TLRs can also mediate expression of proteins that are directly antimicrobial, e.g., the defensins. Several defensins can be produced by corneal epithelial cells directly as the result of TLR stimulation.41,44,45 Defensins can also be produced from the products of TLR activation, e.g., IL-1β.46
The recruitment of leukocytes from the blood vessels to the site of infection or inflammation is a highly orchestrated process, involving a cascade of chemoattractant signals and adhesion molecules. Chemokines are a superfamily of structurally related proteins whose principal function seems to be regulation of leukocyte recruitment.47 The family is divided into four groups (CXC, CC, C, and CX3C) based on the position of the first two cysteine amino acids.48–51 Based on in vitro experimentation and corroborative in vivo studies, members of the CXC chemokines that contain a tripeptide motif Glu-Leu-Arg (ELR+),52 such as interleukin (IL)-8,53 have been shown to promote the migration of PMNs, but not of mononuclear cells, whereas those that do not contain the motif (ELR−) are potent chemoattractants for mononuclear cells. By contrast, members of the CC chemokine subfamily, such as MIP-1α (CCL5) and the monocyte chemoattractant protein-1 (MCP-1; CCL2) usually only promote the migration of monocytes and T lymphocytes, but not of PMNs.54,55
Apart from the chemokines directly associated with recruitment of PMNs, several other cytokines or chemokines have been shown to play major roles in the inflammatory response associated with Pseudomonas aeruginosa keratitis, and these include IL-1β, IL-6, IL-10, IL-18 and interferon (IFN)γ. IL-1β may be the master mediator of the inflammatory response; after its appearance other mediators are generated. Certainly, IL-1β appears very early in the infection in animal models56,57 and human corneal epithelial cells exposed to P. aeruginosa in tissue culture.58 Blocking IL-1β reduces corneal inflammation during keratitis.56,59–61 IL-6, on the other hand, may be involved in down-regulating corneal inflammation and the resolution of disease.62 Mice that have been constructed without the IL-6 gene (IL-6 gene knockouts) show more severe disease63 and if IL-6 is given to mice by injection during P. aeruginosa infection, the animals show better disease progression,64 whereas IL-1β and IL-6 are initially produced by the corneal epithelial cells, and IL-10 is predominantly produced by a subset of infiltrating white blood cells65 and as such mediates its effects later in the infection and inflammation. IL-10 may be involved in preventing excessive angiogenesis during corneal infection,65 thereby controlling vision loss during infection. IL-18 is involved in the regulation of IFNγ production, and it seems that IL-18 has a role in preventing growth of P. aeruginosa during infection through IFNγ.66 IL-18 is produced mainly by resident macrophages or dentritic cells of the cornea and stimulates T, NK, and NKT cells to produce IFNγ. IL-18 driven IFNγ production, in the absence of IL-12 is associated with increased bacterial killing and less corneal destruction.37
T-cells are specialized white blood cells that play a central role in cell-mediated immunity. CD4+ T-cells (also known as helper T cells) are involved in activating and directing other immune cells, and are particularly important in the acquired immune system. They are essential in determining B cell antibody class switching, in the activation and growth of cytotoxic T cells, and in promoting bactericidal activity of phagocytes such as macrophages. In corneal infection, CD4+ T cells seem to promote corneal perforation and susceptibility during infection with P. aeruginosa.67 There are two distinct types of helper T cells, Th1, and Th2. Th1 cells produce for example IFN-γ, whereas Th2 cells produce IL-4, IL-5 and IL-13, among numerous other cytokines. Cytokines produced by Th1 cells maximize the killing efficacy of the macrophages and the proliferation of cytotoxic CD8+ T cells. The cytokines produced by Th2 cells stimulate B cells into proliferation, to undergo antibody class switching, and to increase antibody production. It has become clear that, in mouse strains, the Th1 response is associated with susceptibility of the cornea to perforation following infection with P. aeruginosa, whereas the Th2 response is associated with resistance to perforation.68 The Th1 response seems to assist in the continued recruitment of PMNs to the cornea, and it is these PMNs that mediate perforation.
In summary, microbial keratitis during contact lens wear is most often caused by P. aeruginosa. This bacterium can produce a variety of virulence factors, including toxins and proteases that help it to initiate and maintain the infection. Aspects of the innate immune system help control the bacterial infection and during infection, the host mounts an inflammatory response to try to overcome the bacteria. This inflammatory response is mediated, at least initially, through the innate immune system via pathogen-associated recognition receptors on corneal epithelial cells. Subsequent to this recognition of infection, epithelial cells and resident lymphocytes stimulate the recruitment of predominately PMNs. It is the recruitment of large numbers of PMNs that helps contain the infection, but may ultimately lead to corneal destruction and vision loss.
Institute for Eye Research
Rupert Myers Building
University of New South Wales
NSW 2052, Australia
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Infection and ImmunityPseudomonas aeruginosa induces membrane blebs in epithelial cells, which are utilized as a niche for intracellular replication and motilityInfection and Immunity
Investigative Ophthalmology & Visual ScienceThe Impact of Inoculation Parameters on the Pathogenesis of Contact Lens-Related Infectious KeratitisInvestigative Ophthalmology & Visual Science
Fems Immunology and Medical MicrobiologyExpression of surfactant protein D in human corneal epithelial cells is upregulated by Pseudomonas aeruginosaFems Immunology and Medical Microbiology
Clinical and Experimental OptometryBest practice contact lens care: A review of the Asia Pacific Contact Lens Care SummitClinical and Experimental Optometry
Investigative Ophthalmology & Visual ScienceRole of Neutrophils, MyD88-Mediated Neutrophil Recruitment, and Complement in Antibody-Mediated Defense against Pseudomonas aeruginosa KeratitisInvestigative Ophthalmology & Visual Science
Journal of Medical MicrobiologyComparison of virulence factors in Pseudomonas aeruginosa strains isolated from contact lens- and non-contact lens-related keratitisJournal of Medical Microbiology
Plos OneAn Eye to a Kill: Using Predatory Bacteria to Control Gram-Negative Pathogens Associated with Ocular InfectionsPlos One
American Journal of OphthalmologyWhy Does the Healthy Cornea Resist Pseudomonas aeruginosa Infection?American Journal of Ophthalmology
Plos OneExtracellular Matrix Protein Lumican Promotes Clearance and Resolution of Pseudomonas aeruginosa Keratitis in a Mouse ModelPlos One
Investigative Ophthalmology & Visual ScienceAcanthamoeba-Cytopathic Protein Induces Apoptosis and Proinflammatory Cytokines in Human Corneal Epithelial Cells by cPLA(2 alpha) ActivationInvestigative Ophthalmology & Visual Science
Plos OnePseudomonas aeruginosa PA1006 Is a Persulfide-Modified Protein That Is Critical for Molybdenum HomeostasisPlos One
Expert Opinion on PharmacotherapyPharmacological treatment for infectious corneal ulcersExpert Opinion on Pharmacotherapy
Optometry & Vision SciencePathogenesis of Contact Lens-Associated Microbial KeratitisOptometry & Vision Science
keratitis; Pseudomonas aeruginosa; toll-like receptors; cytokines
© 2007 American Academy of Optometry
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