Human Ocular Microbiome: Bacteria, Fungi and Viruses in the Human Eye

Foreword
Preface
	The Beginning of Microbiome Research
	The Human Ocular Microbiome
	Contents of the Book Human Ocular Microbiome: Bacteria, Fungi and Viruses in the Human Eye
	Target Audience and Importance
Acknowledgements
Contents
About the Author
Abbreviations
Chapter 1: Introduction: From the Gut Microbiome to the Ocular Surface Microbiome-Are They Associated?
	1.1 Introduction
	1.2 Gut Microbiome Functions
	1.3 Core Gut Microbiome and `Dysbiosis´
	1.4 Gut Microbiome Is Associated with Disease
	1.5 Gut Microbiome Dysbiosis and Human Health
		1.5.1 Gut Microbiome Dysbiosis and Intestinal Diseases
		1.5.2 Gut Microbiome Dysbiosis and Extra-intestinal Diseases
		1.5.3 Gut Microbiome Dysbiosis and Ocular Diseases
			1.5.3.1 Gut Microbiome Dysbiosis and Uveitis
			1.5.3.2 Gut Microbiome Dysbiosis and Bacterial Keratitis (BK)
			1.5.3.3 Gut Microbiome Dysbiosis and Fungal Keratitis (FK)
			1.5.3.4 Gut Microbiome Dysbiosis and Ocular Mucosal Disease
			1.5.3.5 Gut Microbiome Dysbiosis and Age-Related Macular Degeneration (AMD)
			1.5.3.6 Gut Microbiome Dysbiosis and Diabetic Retinopathy
	1.6 Modulation of the Gut Microbiome as a Therapy
	1.7 What Needs to Be Done
	References
Chapter 2: The Cultivable Bacteria of the Human Eye
	2.1 Introduction
	2.2 Commensal Microbes of the Ocular Surface
		2.2.1 Bacterial Load on the Ocular Surface
		2.2.2 Viable Community of Bacteria on the Ocular Surface
		2.2.3 Impact of Age on the Ocular Surface Cultivable Microbiome
		2.2.4 Impact of Sex on Ocular Surface Cultivable Microbiome
		2.2.5 Impact of Geographical Location on Ocular Surface Cultivable Microbiome
	2.3 Cultivable Microbiome of Eyelids and Tears
	2.4 Ocular Microbiota Changes in the Diseased Eye
		2.4.1 Keratitis
		2.4.2 Conjunctivitis
		2.4.3 Blepharitis
		2.4.4 Scleritis
		2.4.5 Orbital Cellulitis
		2.4.6 Endophthalmitis
		2.4.7 Uveitis
		2.4.8 Retinitis
		2.4.9 Post-fever Retinitis
		2.4.10 Dacryocystitis
		2.4.11 Meibomian Gland Dysfunction
		2.4.12 Dry Eye Disease
		2.4.13 Stevens-Johnson Syndrome
		2.4.14 Sjogren´s Syndrome
		2.4.15 Lax Eyelid Syndrome
		2.4.16 Ocular Graft vs. Host Disease
		2.4.17 Prior to Cataract Surgery
		2.4.18 Diabetes
		2.4.19 Contact Lens Use
		2.4.20 Alcoholism
		2.4.21 Chronic Limbal Stem Cell Deficiency
		2.4.22 Behçet´s Disease
	2.5 Treatment of Ocular Infectious Diseases
	2.6 Conclusions
	References
Chapter 3: The Microbiome of the Human Eye
	3.1 Introduction
	3.2 What Is a Microbiome?
	3.3 The Microbiome Approach
		3.3.1 Amplicon Sequencing
		3.3.2 Metagenome Sequencing
		3.3.3 Data Analysis
			3.3.3.1 Amplicon Sequencing Reads
			3.3.3.2 Metagenome Sequencing Reads
	3.4 Culture-independent Methods to Identify Ocular Bacteria
		3.4.1 The Ocular Surface Microbiome Using Amplicon Sequencing
		3.4.2 Impact of Age on Ocular Surface Microbiome
		3.4.3 Impact of Sex on Ocular Surface Microbiome
		3.4.4 Impact of Geographical Location on Ocular Surface Cultivable Microbiome
	3.5 Microbiome of Various Microhabitats of the Eye
	3.6 The Effect of Sampling Depth on the Ocular Surface Microbiome
	3.7 Ocular Microbiome Changes in the Diseased Eye
		3.7.1 Ocular Microbiome of Individuals with Fungal Keratitis
		3.7.2 Ocular Microbiome of Individuals with Bacterial Keratitis
		3.7.3 Ocular Surface Microbiome of Individuals with Endophthalmitis
		3.7.4 Ocular Surface Microbiome of Individuals with Conjunctivitis
		3.7.5 Ocular Surface Microbiome of Individuals with Blepharitis
		3.7.6 Ocular Surface Microbiome of Individuals with Retinitis
		3.7.7 Ocular Surface Microbiome of Individuals with Meibomian Gland Dysfunction
		3.7.8 Ocular Surface Microbiome of Individuals with Dry Eye Disease
		3.7.9 Ocular Surface Microbiome of Individuals with Stevens-Johnson Syndrome
		3.7.10 Ocular Surface Microbiome of Individuals with Sjogren´s Syndrome
		3.7.11 Ocular Surface Microbiome of Individuals with Ocular Graft Versus Host Disease
		3.7.12 Ocular Surface Microbiome of Individuals with Diabetes Mellitus
		3.7.13 Ocular Surface Microbiome of Individuals with Contact Lens Use
		3.7.14 Ocular Surface Microbiome of Individuals with Floppy Eyelid Syndrome
		3.7.15 Ocular Surface Microbiome of Individuals with Trachoma
	3.8 Conclusions
	References
Chapter 4: Antimicrobial Resistance in Ocular Bacteria
	4.1 Introduction
	4.2 AMR in Ocular Bacteria
	4.3 Factors Driving Antibiotic Resistance in Ocular Bacteria
	4.4 What Is a Biofilm?
		4.4.1 Adhesion
		4.4.2 Microcolony Formation
		4.4.3 Maturation
		4.4.4 Dispersal
	4.5 Biofilm Formation in Ocular Bacteria
	4.6 AMR in Ocular Bacteria Is Associated with Biofilm Formation
	4.7 Biofilm in the Diseased Eye
		4.7.1 Biofilms in Endophthalmitis
			4.7.1.1 Genes Associated with Biofilm Formation in Endophthalmitis
		4.7.2 Biofilms in Keratitis
			4.7.2.1 Factors Associated with Contact Lens Keratitis
		4.7.3 Biofilms in Infectious Crystalline Keratopathy
	4.8 Biofilms Associated with Ocular Implants
		4.8.1 Biofilms Associated with Scleral Buckles
		4.8.2 Biofilms Associated with Conjunctival Plug
		4.8.3 Biofilms Associated with Lacrimal Intubation Devices and Orbital Implants
	4.9 Quorum Sensing and Biofilm Formation in Ocular Bacteria
	4.10 Candidate Genes Involved in Biofilm Formation in Ocular Bacteria
	4.11 Comparison of Candidate Genes Involved in Biofilm Formation in Non-ocular Bacteria
	4.12 Hacking Biofilms to Overcome AMR
		4.12.1 Using Inhibitors of Quorum Sensing
		4.12.2 CRISPRi Technology to Mitigate Quorum Sensing
		4.12.3 Use of Biocides to Inhibit Adhesion
		4.12.4 Use of Antimicrobial Compounds Including Peptides to Inhibit Adhesion
		4.12.5 Modifying the Surface Structure of Ocular Devices to Inhibit Adhesion
		4.12.6 d-amino Acids to Disperse Biofilms
		4.12.7 Antibiotics to Disperse Biofilms
		4.12.8 Enzymatic Degradation of the Biofilm Matrix to Disperse Biofilms
		4.12.9 Use of Natural Products to Disperse Biofilms
		4.12.10 Use of Signalling Molecules to Disperse Biofilms
		4.12.11 Suppression of Enzymes and Inhibition of Biofilm Formation
		4.12.12 Use of Photodynamic Therapy to Eliminate Biofilms
		4.12.13 Phage Therapy to Inhibit Biofilm Formation
		4.12.14 Other Strategies to Inhibit Biofilm Formation
		4.12.15 Limitations in Hacking Strategies
	4.13 The Gap Areas
	4.14 Conclusions
	References
Chapter 5: The Cultivable Fungi of the Human Eye
	5.1 Introduction
	5.2 Collection and Processing of Clinical Samples for Ocular Fungi
	5.3 Direct Microscopy Examination of Clinical Samples
	5.4 Molecular Methods in the Diagnosis of Ocular Infections
	5.5 Confocal Microscopy in the Diagnosis of Ocular Infections
	5.6 Experimental In Vivo Models for Ocular Infections
		5.6.1 Mouse Models
		5.6.2 Rabbit Models
		5.6.3 Rat Models
		5.6.4 Other Models
	5.7 Cultivable Fungi of the Normal Human Eye
	5.8 Cultivable Fungi of the Diseased Human Eye
		5.8.1 Fungi Associated with Fungal Keratitis
		5.8.2 Fungi Associated with Blepharitis
		5.8.3 Fungi Associated with Conjunctivitis
		5.8.4 Fungi Associated with Scleritis
		5.8.5 Fungi Associated with Endophthalmitis
			5.8.5.1 Exogenous Endophthalmitis
			5.8.5.2 Endogenous Endophthalmitis
		5.8.6 Fungi Associated with Retinitis
		5.8.7 Fungi Associated with Chorioretinitis
		5.8.8 Fungi Associated with Post-fever Retinitis (PFR)
		5.8.9 Fungi Associated with Orbital cellulitis
		5.8.10 Fungi Associated with Dry Eye Disease
		5.8.11 Fungi Associated with Meibomian Gland Dysfunction
		5.8.12 Fungi Associated with Uveitis
		5.8.13 Fungi Associated with Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
		5.8.14 Fungi Associated with Sjögren´s Syndrome
		5.8.15 Fungi Associated with Lax Eyelid Syndrome
		5.8.16 Fungi Associated with Ocular Graft Vs Host Disease
	5.9 Treatment of Ocular Infectious Diseases
	5.10 The Gap Areas
	5.11 Conclusions
	References
Chapter 6: The Mycobiome of the Human Eye
	6.1 Introduction
	6.2 What Is a Mycobiome?
		6.2.1 Amplicon Sequencing
		6.2.2 Metagenome Sequencing
		6.2.3 Data Analysis
			6.2.3.1 Taxonomic Classification of Amplicon Sequencing Reads
			6.2.3.2 Annotation of Metagenome Sequencing Reads
	6.3 Mycobiome of the Normal Human Eye
		6.3.1 Core Ocular Mycobiome
	6.4 Mycobiome of the Diseased Human Eye: Next-Generation Sequencing Approach
		6.4.1 Mycobiome Associated with Keratitis
		6.4.2 Mycobiome Associated with Endophthalmitis
		6.4.3 Mycobiome Associated with Post-Fever Retinitis (PFR)
	6.5 Conclusions
	References
Chapter 7: Viruses of the Human Eye
	7.1 Introduction
	7.2 Enumeration of Viruses
	7.3 Challenges in Studying Human Virome
	7.4 Viral Infections of the Eye
		7.4.1 Viral Conjunctivitis
		7.4.2 Viral Keratitis
			7.4.2.1 Herpes Simplex Virus Keratitis
				7.4.2.1.1 Epidemiological Features of HSV Keratitis
			7.4.2.2 Congenital and Neonatal HSV Keratitis
			7.4.2.3 Epidemics of HSV
			7.4.2.4 Necrotizing Stromal Keratitis
			7.4.2.5 Immune Stromal Keratitis or Interstitial Keratitis
			7.4.2.6 Other Diseases Caused by HSV
				7.4.2.6.1 Acute Retinal Necrosis
				7.4.2.6.2 HSV Involvement in Various Syndromes
				7.4.2.6.3 HSV in Blepharitis
		7.4.3 Ocular Complications of AIDS
		7.4.4 Ocular Diseases Caused by Varicella Zoster Virus
			7.4.4.1 Retinal Involvement of HZV
		7.4.5 Ocular Diseases Caused by Cytomegalovirus
		7.4.6 Ocular Diseases Caused by Adenovirus
		7.4.7 Ocular Diseases Caused by Molluscum Contagiosum Virus
		7.4.8 Ocular Diseases Caused by Epstein-Barr Virus
		7.4.9 Ocular Diseases Caused by Rubeola Virus
		7.4.10 Conclusions
	References
Chapter 8: Virome of the Healthy Human Eye
	8.1 Introduction
	8.2 Diversity of the Human Virome
	8.3 Virome of Different Body Sites
		8.3.1 Virome of Gastrointestinal Tract
		8.3.2 Virome of Respiratory Tract
		8.3.3 Virome of the Blood
		8.3.4 Virome of the Skin
		8.3.5 Virome of the Urogenital System
		8.3.6 Virome of the Nervous System
		8.3.7 Viromes of Other Tissues
		8.3.8 The Human Megavirome
	8.4 Development of the Human Virome
	8.5 Virome of the Eye
		8.5.1 Viruses on the Ocular Surface
		8.5.2 Ocular Surface Virome of Children
		8.5.3 Viruses in the Anophthalmic Conjunctiva
		8.5.4 Virome of the Ocular Fluids
	8.6 Factors that Shape the Ocular Virome
	8.7 Conclusions
	References
Chapter 9: Virome of the Diseased Human Eye
	9.1 Introduction
	9.2 Viral Communities in the Vitreous Fluid of Patients with Post-Fever Retinitis
		9.2.1 Viral Abundance in PFR
		9.2.2 Discriminating Families and Genera in PFR
		9.2.3 Functional Attributes of Ocular Viruses
	9.3 Conclusions
	References
Chapter 10: Cellular and Molecular Basis of Ocular Diseases
	10.1 Introduction
	10.2 Innate Immunity on the Ocular Surface
		10.2.1 Toll-Like Receptors in Innate and Adaptive Immune Responses at the Ocular Surface
	10.3 Cell-Mediated Immunity on the Ocular Surface
	10.4 Cellular and Molecular Basis of Bacterial Keratitis
		10.4.1 Pseudomonas aeruginosa Keratitis
		10.4.2 Streptococcus pneumoniae Keratitis
		10.4.3 Serratia marcescens Keratitis
		10.4.4 Staphylococcus aureus Keratitis
	10.5 Cellular and Molecular Basis of Mycotic Keratitis
	10.6 Cellular and Molecular Basis of Herpes Simplex Keratitis
	10.7 Cellular and Molecular Basis of Acanthamoeba Keratitis
	10.8 Cellular and Molecular Basis of Helminthic Keratitis
	10.9 Cellular and Molecular Basis of Sterile Corneal Inflammation
	10.10 Cellular and Molecular Basis of Uveitis
	10.11 Cellular and Molecular Basis of Scleritis
	10.12 Cellular and Molecular Basis of Conjunctivitis
	10.13 Molecular Basis of Blepharitis
	10.14 Cellular and Molecular Basis of Endophthalmitis
	10.15 Cellular and Molecular Basis of Retinitis
	10.16 Cellular and Molecular Basis of Dry Eye Disease
	10.17 Cellular and Molecular Basis of Meibomian Gland Dysfunction
	10.18 Conclusions
	References
Chapter 11: What We Need to Know About the Human Ocular Microbiome
	11.1 Introduction
	11.2 Gaps in Ocular Surface Microbiome
	11.3 Conclusions
	References