Contact lens-related corneal infection: Intrinsic resistance and its compromise

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Highlights

  • Corneal barrier function against microbes during health is complex and robust.

  • Pseudomonas aeruginosa is capable of a vast array of virulence strategies.

  • Contact lens-wear enables P. aeruginosa to traverse the corneal epithelium.

  • Contact lens wear impacts the biology of both the cornea and the microbe.

  • The relative contribution of microbial versus host effects is to be determined.

Abstract

Contact lenses represent a widely utilized form of vision correction with more than 140 million wearers worldwide. Although generally well-tolerated, contact lenses can cause corneal infection (microbial keratitis), with an approximate annualized incidence ranging from ~2 to ~20 cases per 10,000 wearers, and sometimes resulting in permanent vision loss. Research suggests that the pathogenesis of contact lens-associated microbial keratitis is complex and multifactorial, likely requiring multiple conspiring factors that compromise the intrinsic resistance of a healthy cornea to infection. Here, we outline our perspective of the mechanisms by which contact lens wear sometimes renders the cornea susceptible to infection, focusing primarily on our own research efforts during the past three decades. This has included studies of host factors underlying the constitutive barrier function of the healthy cornea, its response to bacterial challenge when intrinsic resistance is not compromised, pathogen virulence mechanisms, and the effects of contact lens wear that alter the outcome of host-microbe interactions. For almost all of this work, we have utilized the bacterium Pseudomonas aeruginosa because it is the leading cause of lens-related microbial keratitis. While not yet common among corneal isolates, clinical isolates of P. aeruginosa have emerged that are resistant to virtually all currently available antibiotics, leading the United States CDC (Centers for Disease Control) to add P. aeruginosa to its list of most serious threats. Compounding this concern, the development of advanced contact lenses for biosensing and augmented reality, together with the escalating incidence of myopia, could portent an epidemic of vision-threatening corneal infections in the future. Thankfully, technological advances in genomics, proteomics, metabolomics and imaging combined with emerging models of contact lens-associated P. aeruginosa infection hold promise for solving the problem - and possibly life-threatening infections impacting other tissues.

Introduction

The contact lens was first conceptualized by Leonardo DaVinci in 1508, and the first glass contact lenses brought into use for vision correction, albeit for very brief (hours) periods of wear, in the 19th century. Soft contact lens wear, as we know it today, was initiated by the pivotal invention of biocompatible and transparent hydrophilic hydrogel polymers (Wichterle and Lím, 1960). However, it soon became evident to clinicians that while contact lenses could be of therapeutic value by promoting corneal epithelial healing (Lawrence et al., 1969; Leibowitz and Rosenthal, 1971), contact lens wear had also become an important risk factor for microbial infection of the cornea (microbial keratitis or infectious keratitis) with significant potential for permanent vision loss (Dixon et al., 1966; Galentine et al., 1984; Golden et al., 1971). Importantly, Pseudomonas spp. (invariably Pseudomonas aeruginosa) were at that time, and continue to be, identified as a leading cause of contact lens-associated microbial keratitis: e.g. 23% of isolates in one study (Galentine et al., 1984), and more than 50% in another (Green et al., 2008) (see also Cheng et al., 1999; Cho and Lee, 2018; Golden et al., 1971; Lim et al., 2016; Schein et al., 1989a, 1989b; Stapleton et al., 2008; Stapleton and Carnt, 2012). Multiple epidemiological studies have consistently shown that the annualized incidence of contact lens-related microbial keratitis significantly increases with overnight and/or extended wear versus daily wear (e.g. ~5 to 10-fold or more), that other risk factors can also participate (e.g. patient compliance and hand hygiene, type of lens care solution used, microbial contamination of the lens storage case), and that the introduction of silicone hydrogel lenses with greatly increased oxygen transmissibility has not reduced disease incidence (Cheng et al., 1999; Dart et al., 2008; Robertson, 2013; Schein et al., 1989a; Stapleton et al., 2013, 2008). These patient-based studies have provided important clues as to how lens wear leads to infection pathogenesis, and suggest it is complex and multifactorial.

For almost three decades, this laboratory has focused exclusively on understanding why contact lens wear predisposes the cornea to infection by P. aeruginosa, from the perspective of both host defense and bacterial virulence. This effort has necessitated delving into an array of topics and disciplines, some not previously studied in the same context, and has led to development of models and methods not previously available.

Our general approach has been to ask the following inter-related questions: 1) how does the intact healthy cornea intrinsically resist infection in vivo? 2) how are key components of this resistance impacted by contact lens wear to trigger infection risk? 3) how do bacteria take advantage of these conditions to cause infection? After this brief introduction (Section 1), this perspective paper provides a comprehensive review of our own work, including only relevant research done by colleagues in the field. We begin with studies aimed at understanding the constitutive defenses of the healthy cornea that usually prevent microbes from traversing through the surface epithelium and associated basement membrane (basal lamina) to reach the vulnerable underlying stroma (Section 2). This is followed by examination of bacterial virulence factors and mechanisms involved in P. aeruginosa interactions with non-lens wearing corneas (Section 3), and studies of how contact lens wear compromises those defenses and/or renders microbes able to overcome them (Section 4). After a summative discussion (Section 5), we have outlined future directions that we believe will eventually help solve the problem of contact lens-associated P. aeruginosa keratitis (Section 6), which is followed by a short conclusion (Section 7).

It is our hope that this line of research will lead to strategies for completely avoiding infection and therefore infection-related pathology. There may also be applications beyond the lens-wearing eye, given the numerous sites that this versatile and life-threatening human pathogen can infect.

Before moving forward, we would like to emphasize that our interest in corneal defense relates only to the barriers that usually prevent microbes from accessing the vulnerable corneal stroma. We believe this knowledge is foundational to understanding how lens wear compromises those barriers. Our research focus has generally not extended to host immune responses occurring after bacteria have already arrived at corneal stroma, a separate important topic elegantly investigated and reviewed by others (e.g. Foldenauer et al., 2013; Hazlett, 2004; Sun et al., 2010; Sun et al., 2012; Thanabalasuriar et al., 2019; Willcox, 2007). Also important to note, our studies have almost exclusively utilized P. aeruginosa, the most common cause of contact lens-related infection.

We are cognizant that there are many other important topics that relate to infection and contact lens wear, and that there are other lens-related adverse events. These include: the efficacy of contact lens disinfection, the role of storage case contamination, patient compliance and hygiene, the impact of lens wear on corneal and tear film physiology, and the epidemiology of multiple contact lens-related phenomena including infection. Further, infections can involve microbes other than P. aeruginosa, they can be associated with therapeutic contact lenses used for other corneal epithelial pathologies, and microbes can instead cause inflammatory events such as CLARE (Contact Lens-induced Acute Red Eye). While some of these topics are discussed in this review, many excellent articles have thoroughly reviewed those topics, to which we direct the reader (Carnt et al., 2007; Carnt and Stapleton, 2016; Dartt and Willcox, 2013; Efron et al., 2013; Foulks, 2006; Jones and Powell, 2013; Muntz et al., 2015; Stapleton et al., 2007; Stapleton and Carnt, 2012).

Section snippets

How do intact healthy corneas intrinsically resist infection?

Knowing how lens wear alters corneal resistance to infection necessitates first knowing how infection resistance is maintained without lens wear. Indeed, the cornea is constantly exposed to the outside environment and is barraged with particulate matter and allergens, not only microbes and their antigens. At the same time, the cornea needs to maintain clarity critical for vision, which depends on barrier function and proper regulation of ion and fluid transport by cells in both the endothelium

How does P. aeruginosa interact with the non-lens wearing cornea?

Another topic foundational to knowing how contact lens wear enables corneal infection is understanding bacterial virulence capacity in the context of the tear film, corneal epithelium, and basal lamina. Our efforts in this area have focused almost exclusively on P. aeruginosa, because it continues to be the most common cause of contact lens-related corneal infections after five decades of soft contact lens wear. This focus has also enabled us to delve more deeply into mechanisms.

As discussed

Impact of lens wear on the human cornea and tear film

Over the past several decades, research done using human subjects has provided a wealth of information about how lens wear impacts the human ocular surface. Some of these studies have focused on changes visible using equipment readily available in the clinic; e.g. a slit-lamp biomicroscope to detect epithelial microcysts, mucin balls, endothelial blebs, edema, corneal staining etc. Others have developed and used more specialized equipment to study temperature, pH, osmolarity,

Why are certain microbes involved?

Both injury and contact lens-related infections most often involve opportunistic pathogens. By definition, these are the microbes we consider harmless under normal circumstances that can “take advantage” when our defenses are down. While some opportunists have minimal disease-causing capacity, others possess an impressive array of virulence factors. These differ from outright pathogens by being ubiquitous in our environment as a result of their capacity to be adaptive. This has forced us to

Future research

If we are to understand why contact lens wear predisposes to infection, research will need to continue in three inter-related topics: 1) mechanisms by which the cornea resists infection when healthy, 2) how lens wear compromises key components of that resistance, and 3) how microbes take advantage of the situation to cause disease. Specific questions that require further investigation include:

  • 1.

    Which epithelial-associated defenses are compromised by contact lens wear and how? Understanding this

Conclusion

This manuscript illustrates that the pursuit of a seemingly simple question can sometimes occupy an entire career. The quest by us and others to determine how contact lens wear causes infection has driven forays into multiple topics in biology, leading to important information about ocular surface biology in general. It has also provided novel insights about an important human pathogen with relevance beyond the eye.

Things have moved on since the first author of this paper wrote the concluding

Ethics statement

All procedures involving animals described in this manuscript, and our other published work, were carried out in accordance with standards established by the Association for Research in Vision and Ophthalmology, under a protocol approved by the Animal Care and Use Committee, University of California Berkeley, an AAALAC accredited institution. All of our studies involving human subjects were conducted under protocols approved by the Committee for the Protection of Human Subjects, University of

Author contributions

All authors contributed to writing the manuscript. The percentage contributions of each author are as follows; Dr. Fleiszig (40%, overall conceptualization, literature review, writing, editing, illustration concepts, overall coordination), Dr. Evans (33%, overall conceptualization, literature review, writing, editing, illustration concepts, project coordination), Dr. Kroken (10%, section writing, schematic illustrations, editing), Dr. Nieto (5%, section writing, editing), Dr. Grosser (5%,

Declaration of competing interest

Drs. Fleiszig and Evans gratefully acknowledge funding of this research over several decades by the National Eye Institute (currently active EY011221, EY024060, EY030350), and the National Institute for Allergy and Infectious Diseases. Dr. Kroken was supported by the National Eye Institute (EY025069) as is Dr. Nieto (EY029152). Dr. Wan was supported in part by the UC Berkeley Vision Science Training Grant from the National Eye Institute (EY007043). Dr. Grosser was supported by a fellowship from

Acknowledgements

Drs. Fleiszig and Evans gratefully acknowledge funding of this research over several decades by the National Eye Institute (currently active EY011221, EY024060, EY030350), and the National Institute of Allergy and Infectious Diseases (AI079192). Dr. Kroken was supported by the National Eye Institute (EY025069) as is Dr. Nieto (EY029152). Dr. Wan was supported in part by the UC Berkeley Vision Science Training Grant from the National Eye Institute (EY007043). Dr. Grosser was supported by a

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    Present address. Department of Biology, University of North Carolina Asheville, One University Heights, Asheville, NC, USA

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    Percentage of work contributed by each author in the production of the manuscript is as follows: Dr. Fleiszig (40 %, overall conceptualization, literature review, writing, editing, illustration concepts, overall coordination), Dr. Evans (35 %, overall conceptualization, literature review, writing, editing, illustration concepts, project coordination), Dr. Kroken (10 %, section writing, schematic illustrations, editing), Dr. Nieto (5 %, section writing, editing), Dr. Grosser (4 %, section writing), Dr. Wan (4 %, section writing), Dr. Metruccio (2 %, imaging, editing).

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