Challenges and Solutions Against Visceral Leishmaniasis

Foreword
Preface
Contents
Editors and Contributors
1: The Burden of Visceral Leishmaniasis: Need of Review, Innovations, and Solutions
	1.1 Leishmaniasis: Problems Worldwide
	1.2 Visceral Leishmaniasis
	1.3 Innovations in Epidemiology
	1.4 Innovations in Diagnosis
	1.5 Innovations in Therapeutics
	1.6 Visceral Leishmaniasis: Elimination Strategies
	References
2: KalaCORE: A Programme to Tackle Visceral Leishmaniasis in South Asia and East Africa (2014-2019)
	2.1 Executive Summary
		2.1.1 South Asia
		2.1.2 East Africa
	2.2 Introduction
	2.3 KalaCORE Programmes in the South Asia and East Africa Regions: Two Approaches Taken
	2.4 Overall Achievements
		2.4.1 Towards the Elimination of VL in South Asia
			2.4.1.1 Elimination Targets
			2.4.1.2 Contribution of Active Case Finding
			2.4.1.3 Case Fatality Rates
			2.4.1.4 Economic Impacts
		2.4.2 Strengthening Capacity for Control of VL in East Africa
			2.4.2.1 Treatment
			2.4.2.2 Training and Mentoring
			2.4.2.3 VL Cases
			2.4.2.4 Operational Research on Effective Prevention Methods
	2.5 Challenges that Impact Sustainability of VL Control and Elimination Programmes and Recommendations for the Way Forward
		2.5.1 Integration
		2.5.2 Procurement and the Supply Chain
		2.5.3 Training
		2.5.4 Case Fatality Rate
	2.6 Overall Summary of Challenges and Remaining Issues at the Closure of the KalaCORE Programme in April 2019
		2.6.1 Asia
		2.6.2 Africa
	2.7 Conclusions
	Box 2.1: VL Endemic Areas in South Asia
	Box 2.2: VL Endemic Areas in East Africa
	References
3: Essentials in Leishmaniasis Elimination
	3.1 Introduction
	3.2 Life Cycle of Leishmania
	3.3 Clinical Manifestations
	3.4 Epidemiology
	3.5 Therapeutics Available for the Treatment of Leishmaniasis
	3.6 Limitation of Available Therapeutics
	3.7 Vaccine Against Leishmaniasis
	3.8 Vaccination in Canine
	3.9 Novel Approaches in Vaccine Development Against Leishmaniasis
	3.10 Role of Different Innate Immune Cells in Vaccine Development
	3.11 Population Relation to Vaccine
	3.12 Discussion
	References
4: Factors Affecting Leishmania Infection in Sand Fly
	4.1 Introduction
	4.2 Digestive Enzymes
	4.3 Role of Caspar and Defensin of Sand Fly in Parasite Infection
	4.4 Role of Peritrophins and Chitinase of Sand Fly in Parasite Infection
	4.5 Role of TGF-beta in Suppression of the Immune Response
	4.6 Suppression of Metacyclogenesis by Purines
	4.7 Role of Leishmania Lipophosphoglycan (LPG) and Its Receptor Galactin in Infection
	4.8 Nucleoside as a Promoter of Infection and Its Role in Immunosuppression
	4.9 Contribution of Blood and Its Derivatives in the Parasitic Infection in Sand Fly
	4.10 Effects of Second Blood Meals on Infected Flies
	4.11 Role of Sand Fly´s ``Relish´´ Protein in Imd Pathway
	4.12 Impact of Glucose Metabolism on Parasites
	4.13 Modulation of Midgut Genes by Leishmania Parasites
	4.14 Discussion and Conclusions
	References
5: Leishmania Proteomics: Insight into Diagnostics and Vaccine Development
	5.1 Background
	5.2 Structure and Biology of Leishmania Parasites
	5.3 Proteomics of Life Cycle Stages of Leishmania Parasites
		5.3.1 Membrane Proteins
			5.3.1.1 Cysteine Proteases
			5.3.1.2 Glycoprotein 63 (Gp63)
			5.3.1.3 Laminin-Binding Protein
			5.3.1.4 Kinetoplastid Membrane Protein (KMP)-11
			5.3.1.5 Glycosylated Proteins
			5.3.1.6 Proteophosphoglycans (PPG)
			5.3.1.7 ATP: Binding Cassette (ABC) Proteins
		5.3.2 Cytosolic Proteins
			5.3.2.1 Heat Shock Proteins
			5.3.2.2 A2 Protein
	5.4 Proteomics and Identification of Biomarkers for VL Diagnosis
	5.5 Proteomics and Identification of Leishmania Antigens for Vaccine
	5.6 Conclusion
	References
6: Post Kala-Azar Dermal Leishmaniasis: Diagnosis and Treatment
	6.1 Introduction
	6.2 The Interplay of Factors Leading to PKDL
	6.3 Need for Diagnosis of PKDL
	6.4 Challenges in Clinical Investigation
	6.5 Challenges in Histopathology-Based Diagnosis
	6.6 Challenges in Serological Diagnosis
	6.7 Challenges in Molecular Diagnosis
	6.8 Nanotechnology for Leishmania Detection
	6.10 Newer Treatment Regimes
	6.9 Treatment of PKDL
	References
7: Emergence of Novel Leishmania Genetic Variants: A New Challenge to the Ongoing Leishmaniasis Elimination Program in the Ind...
	7.1 Introduction
	7.2 Classical Leishmaniasis
	7.3 Visceral Leishmaniasis
	7.4 Cutaneous and Mucocutaneous Leishmaniasis
	7.5 Atypical Leishmaniasis
	7.6 Atypical Visceral Leishmaniasis (AVL)
	7.7 Atypical Cutaneous Leishmaniasis (ACL)
	7.8 Insight into Genetic Analysis of Parasite to Understand Atypical VL and Atypical CL
	References
8: Atypical Leishmania donovani Infections in Sri Lanka: Challenges for Control and Elimination
	8.1 Leishmaniasis: Overview/Causative Agent in Sri Lanka
	8.2 Clinical Features of Leishmaniasis Reported in Sri Lanka
	8.3 Genetic Characterization of the Causative Agent of CL in Sri Lanka: L. donovani (MON 37)
	8.4 Strategies to Overcome Challenges Faced Against Control and Elimination
		8.4.1 Knowledge Gap
		8.4.2 Early Case Detection and Patient Management
		8.4.3 Delayed Response, Treatment Failure, and Possible Drug Resistance
		8.4.4 Vector Control
		8.4.5 Animal Reservoirs
		8.4.6 Lack of a Planned Disease Control Program and Disease Surveillance
		8.4.7 Use of Modern Tools in Surveillance, Education, and Disease Management
	References
9: Critical Roles of Micro-RNAs in the Pathogenesis and Immunoregulation of Leishmania Infection
	9.1 Introduction: Immunology of Leishmaniasis
	9.2 Overview of miRNAs: Biogenesis and Function
	9.3 Evolution of miRNAs
	9.4 Role of miRNAs in Modulating Immune Mechanism in Leishmaniasis
		9.4.1 Expression and Function of miRNAs in Leishmania-Infected Macrophages
		9.4.2 Role of miRNAs in Leishmania-Infected Dendritic Cells
		9.4.3 miRNAs as Regulators of T-Cell Subsets During Leishmania Infection
		9.4.4 miRNAs Alter B-Cell Development and Functions During Leishmaniasis
	9.5 Discussion: The Role of miRNAs as Biomarkers and Therapeutic Targets
	References
10: Heat Shock Proteins as Emerging Therapeutic and Vaccine Targets Against Leishmaniasis
	10.1 Introduction
	10.2 The Heat Shock Proteins of Leishmania and Their Functional Roles
		10.2.1 HSP100/Clp Family
		10.2.2 HSP83/90 Family
			10.2.2.1 Cochaperones of HSP83/90 in Leishmania
		10.2.3 HSP70 Family
		10.2.4 HSP60 Family Chaperones/Chaperonins
			10.2.4.1 Group I Chaperonins
			10.2.4.2 Group II Chaperonins
		10.2.5 HSP40
		10.2.6 Small Heat Shock Proteins (sHSPs)
	10.3 Targeting Chaperones as a Therapeutic Strategy Against Leishmaniasis
	10.4 Leishmania Heat Shock Proteins as Vaccine Candidates
	10.5 Chaperones and Drug Resistance in Leishmania
	10.6 Conclusion
	References
11: Advances in Antileishmanial Chemotherapy
	11.1 Introduction
		11.1.1 Leishmaniasis: Clinical Patterns
	11.2 Therapy for Leishmaniasis
	11.3 Drug Targets
		11.3.1 Potential Drug Targets in Leishmania Parasite
			11.3.1.1 Glycolytic Pathway
			11.3.1.2 Sterol Biosynthetic Pathway
			11.3.1.3 Trypanothione Reductase Enzyme
			11.3.1.4 Polyamines Biosynthetic Pathway
			11.3.1.5 Fe-Super Oxide Dismutase (Fe-SODA)
			11.3.1.6 N-myristoyltransferase (NMT)
			11.3.1.7 Folate Biosynthetic Pathway
	11.4 Advances in Antileishmanial Chemotherapy
		11.4.1 Drug Repurposing
		11.4.2 Use of Drug Delivery Vehicles
	11.5 Conclusion
	References
12: Miltefosine Unresponsiveness in Visceral Leishmaniasis
	12.1 Introduction
	12.2 Worldwide VL Epidemiology
	12.3 Miltefosine Treatment and Relapses
	12.4 Possible Causes for Relapse/Unresponsiveness
	12.5 Drug-Related Factors
		12.5.1 Parasite-Related Factors
			12.5.1.1 Virulence
			12.5.1.2 Drug Accumulation
			12.5.1.3 Fitness to Host Defense Mechanisms
			12.5.1.4 Modulations of Host Immune Responses
		12.5.2 Changes in the Genetic Makeup
		12.5.3 Alterations in Transcriptome
	12.6 Conclusion
	References
13: Toward a Safe and Efficacious Pan-Leishmania Vaccine
	13.1 Introduction
	13.2 Amastigote-Specific Gene Mutants of Leishmania as Candidate Vaccines for Leishmaniasis
	13.3 Immunogenicity and Efficacy Characteristics of LdCen-/- Parasites
	13.4 Evaluation of Safety Characteristics of LdCen-/- Parasites
	13.5 CRISPR-Cas9-Generated L. major Cen-/- as an Alternative to LdCen-/-
	13.6 Toward Human Clinical Trials: A Pan-Leishmania Vaccine
	References
14: Understanding the Heterogeneity in Mast Cell Role in Host Defence During Leishmaniasis
	14.1 Introduction to Leishmaniasis
	14.2 Interactions of Leishmania with Immune Cells
	14.3 Importance of Mast cells as Sentinels in Response to Pathogen
		14.3.1 Mast Cells-A Storehouse of Different Mediators
		14.3.2 Receptors on Mast Cells
		14.3.3 Antimicrobial Activity of Mast Cells
		14.3.4 Role of Mast Cells in Adaptive Immunity
			14.3.4.1 Dendritic Cells (DCs)
			14.3.4.2 T Cells
			14.3.4.3 B Cells
		14.3.5 Role of Mast Cells in Parasitic Infection
	14.4 Clinical Studies of Leishmaniasis to Study a Role for Mast Cells
	14.5 Mast Cell-Leishmania Interactions In Vivo
	14.6 MC-Leishmania Interaction Studies In Vitro
	14.7 Factors Affecting Mast Cells´ Role in Leishmaniasis
		14.7.1 Host Genetics-A Factor That Affects Disease Progression in Leishmaniasis
		14.7.2 Importance of Pathogen Genetics as a Factor Affecting Leishmaniasis
		14.7.3 Importance of Environmental Factors Affecting Leishmaniasis
	14.8 Conclusions and Future Prospects
	References
15: Feasibility of Therapeutic Vaccine for the Management and Control of VL
	15.1 Introduction
	15.2 Immunopathology of VL, PKDL, and Canine VL
		15.2.1 Human VL
		15.2.2 PKDL
		15.2.3 Canine VL (CVL)
	15.3 Preclinical Models Employed for the Evaluation of Therapeutic Vaccines
		15.3.1 Rodents
		15.3.2 Dogs
		15.3.3 Nonhuman Primates or Monkeys
	15.4 Probability of a Vaccine against VL
	15.5 Therapeutic Vaccines: Current Status
		15.5.1 Therapeutic Vaccines Under Preclinical Studies
		15.5.2 Immunotherapy with First-Generation Vaccines
		15.5.3 Immunotherapy with Second-Generation Vaccine
		15.5.4 Immunotherapy with Third-Generation Vaccines
	15.6 Therapeutic Vaccines Under Clinical/Field trials
		15.6.1 PKDL
		15.6.2 Canine VL
	15.7 Future Perspectives and Conclusion
	References
16: Worldwide Efforts for the Prevention of Visceral Leishmaniasis Using Vaccinations
	16.1 Introduction
	16.2 The Critical Aspect of Immunity and Vaccines Against Leishmaniasis
		16.2.1 Required Immunity Against Leishmaniasis
		16.2.2 Recombinant Antigens as Vaccines or Leishmanization
		16.2.3 Canine Vaccines
	16.3 Conclusion
	References
17: Emerging Concepts in Leishmania Vaccine Adjuvants
	17.1 Introduction
	17.2 Adjuvants: The Non-Specific Immune Enhancers
	17.3 Delivery Vehicles and Particulate Adjuvants
		17.3.1 Nanoparticles
		17.3.2 Immune-Stimulating Complexes (ISCOMs)
		17.3.3 Virosomes
		17.3.4 Liposomes
	17.4 Immunomodulators
		17.4.1 Aluminium Salts
		17.4.2 IL-12
		17.4.3 TLR Agonists
		17.4.4 Metabolic and Epigenetic Adjuvants
	17.5 Conclusion
	References