Biofilms in Infections of the Eye

Pathogens 2015, 4, 111-136; doi:10.3390/pathogens4010111 OPEN ACCESS pathogens ISSN 2076-0817 www.mdpi.com/journal/pathogens Review Biofilms in Infections of the Eye Paulo J. M. Bispo, Wolfgang Haas and Michael S. Gilmore * Departments of Ophthalmology, Microbiology and Immunology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, 02114 USA * Author to whom correspondence should be addressed; E-Mail: ; Tel.: +1-617-573-3845. Academic Editor: Gianfranco Donelli Received: 21 January 2015 / Accepted: 13 March 2015 / Published: 23 March 2015 Abstract: The ability to form biofilms in a variety of environments is a common trait of bacteria, and may represent one of the earliest defenses against predation. Biofilms are multicellular communities usually held together by a polymeric matrix, ranging from capsular material to cell lysate. In a structure that imposes diffusion limits, environmental microgradients arise to which individual bacteria adapt their physiologies, resulting in the gamut of physiological diversity. Additionally, the proximity of cells within the biofilm creates the opportunity for coordinated behaviors through cell–cell communication using diffusible signals, the most well documented being quorum sensing. Biofilms form on abiotic or biotic surfaces, and because of that are associated with a large proportion of human infections. Biofilm formation imposes a limitation on the uses and design of ocular devices, such as intraocular lenses, posterior contact lenses, scleral buckles, conjunctival plugs, lacrimal intubation devices and orbital implants. In the absence of abiotic materials, biofilms have been observed on the capsule, and in the corneal stroma. As the evidence for the involvement of microbial biofilms in many ocular infections has become compelling, developing new strategies to prevent their formation or to eradicate them at the site of infection, has become a priority. Keywords: biofilm; eye; ocular infections, postoperative ocular infections; device-related ocular infections Pathogens 2015, 4 112 1. Introduction Ever since Robert Koch and Louis Pasteur in the 1860’s established the modern field of bacteriology, studies employing pure bacterial cultures, often grown in liquid media (planktonic growth), have shaped our understanding of bacterial physiology and behavior. Pure cultures were required to establish microbial causes of disease, and growth in liquid media ensured that all cells were exposed to similar conditions and behaved in the same manner. As a result, most of the measures to control pathogenic bacteria (e.g., vaccines and antimicrobial agents) have been developed based on knowledge of bacteria grown as planktonic cells. An appreciation for the fact that in nature, bacteria adhere to many abiotic or biotic surfaces and form communities of differentiated, interacting communities known as “biofilms”, emerged over the past few decades [1], and this concept was enthusiastically promoted by William (Bill) Costerton among others. Evidence of biofilm formation has been found in the analysis of microbial fossils including those from deep-sea hydrothermal sediments. This suggests that the ability to form biofilm is an ancient adaptation that dates back more than 3 billion years [2,3]. Biofilm formation conferred to individual bacteria the ability to collaborate and to adapt to a range of harsh environmental conditions, perhaps most of all, to evade predation by phagocytic microbes. The formation of a biofilm provides a microbe with a small measure of control over the local environment, including fluctuations in temperatures, pH, ultraviolet light, starvation, and exposure to toxic agents [4,5]. The ubiquity of biofilm formation in natural ecosystems, industrial systems, and medical settings has accelerated the pace of biofilm research. Advances in medical biofilm research have led to an understanding that biofilms represent the prevalent form of bacterial life during tissue colonization, and may occur in over 80% of microbial infections in the body [6]. Biofilms play important roles in human infections including native valve endocarditis, otitis media, chronic bacterial prostatitis, lung infections in patients with cystic fibrosis and periodontitis [7,8]. In addition, biofilms form on indwelling devices including prosthetic heart valves, coronary stents, intravascular catheters, urinary catheters, intrauterine devices, ventricular assist devices, neurosurgical ventricular shunts, prosthetic joint, cochlear implants, intraocular and contact lenses [7,8]. Due to their medical importance, development of anti-biofilm compounds for clinical use are of vital interest [9]. 2. Microbial Biofilms The very first description of a biofilm dates back to the 17th century when Anthony van Leeuwenhoek examined his own teeth scrapings with one of the first microscopes and found a large amount of small living “animalcules” in his dental plaque matter. He concluded in his report to the Royal Society of London in 1684 that the thick white material found between his teeth protected the bacteria embedded in this substance against the action of the vinegar that he used to wash his mouth [10]. At the time, miasmatic and humoral theories of disease were dominant, and it took an additional 200 years until the germ theory of disease was advanced by Robert Koch before a connection between microbes and disease was made. Today, biofilms are generally defined as a community of sessile microbes held together by a polymeric extracellular matrix, adherent to a surface, interface or to other cells that are phenotypically Pathogens 2015, 4 113 distinct from their planktonic counterparts [8]. This definition, although reflective of many biofilms, is in our view restrictive, as there is no particular requirement that microbes be held together by an extracellular matrix as opposed to any other adherence principle (surface charge, a network of surface attached proteins, etc.), or that they even adhere to a surface (as a raft consisting of only microbes could achieve all of the behaviors usually ascribed to a biofilm, e.g., microbes transiting the lumen of the colon). Members of a biofilm community, which can be of the same or multiple species, show varying stages of differentiation and exchange information, metabolites, and genes with each other. As a result, members of the biofilm community are in a diversity of physiologies influenced by the unequal sharing of nutrients and metabolic byproducts, which results in subpopulations with increased tolerance to antimicrobials and environmental stresses, the host immune system, and predatory microorganisms [8,11–14]. Canonically, biofilm development has been grouped into five stages that are reflective of conditions in many, but not all biofilms: (1) reversible aggregation of planktonic cells on a surface; (2) irreversible adhesion; (3) formation of microcolonies; (4) biofilm maturation; and (5) detachmen (...truncated)