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University of Dundee DOCTOR of PHILOSOPHY Arsenic, Antimony

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University of Dundee DOCTOR of PHILOSOPHY Arsenic, Antimony University of Dundee DOCTOR OF PHILOSOPHY Arsenic, antimony and visceral leishmaniasis Perry, Meghan Rose Award date: 2014 Link to publication General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Download date: 24. Sep. 2021 Arsenic, antimony and visceral leishmaniasis Meghan Rose Perry PhD Thesis July 2014 Supervisor: Professor Alan H. Fairlamb University of Dundee I Table of Contents I List of figures VIII List of tables XI Appendices XII List of abbreviations XIII Acknowledgements XV Declaration XVII Abstract XVIII Chapter 1 Introduction 1 1.1 Leishmania 2 1.1.1 Kinetoplastids 2 1.1.2 Leishmania epidemiology 3 1.1.3 Leishmania history 4 1.1.3 Leishmania biology and life cycle 5 1.1.3.1 Leishmania genome 6 1.1.4 Visceral leishmaniasis clinical features 7 1.1.5 Leishmania immunology 8 1.1.6 Leishmania diagnosis and screening 10 1.1.7 VL treatment overview 12 1.1.7.1 Amphotericin 12 1.1.7.2 Miltefosine 13 1.1.7.3 Paromomycin 14 1.1.7.4 Combination therapy 14 1.1.7.5 Outcome monitoring 15 1.1.7.6 Drug development 16 II 1.1.8 Sand flies and VL control 16 1.1.8.1 Sand fly life cycle, feeding and breeding 17 1.1.8.2 Vector control methods 18 1.1.8.3 Reservoir Control 18 1.1.8.4 Vaccination 19 1.1.8.5 Visceral Leishmaniasis Elimination Initiative 19 1.2 Antimony 20 1.2.1 Description 20 1.2.2 History of therapeutic use 20 1.2.3 Antimony in the environment and toxicities 22 1.2.4 Antimony mechanism of action 23 1.2.4.1 Direct action 24 1.2.4.2 Transport 25 1.2.4.3 Thiol perturbation 26 1.2.4.4 Action on immune system 26 1.2.5 Resistance development and mechanisms 27 1.2.5.1 Selection of Leishmania parasite resistance 28 1.2.5.2 Loss of SbV activation as a resistance mechanism 29 1.2.5.3 Changes in transport of SbIII as a resistance mechanism 30 1.2.5.4 Upregulation of thiol synthesis in leishmania as a resistance 31 mechanism 1.2.5.5 Manipulation of the immune system as a mechanism of 32 resistance 32 1.2.5.6 Additional mechanisms of resistance 32 1.2.5.7 Summary 32 1.3 Arsenic 33 III 1.3.1 Description of metalloid 33 1.3.2 Arsenic metabolism 34 1.3.3 History of therapeutic use 35 1.3.4 Arsenic contamination of water 36 1.3.4.1 Discovery and epidemiology of arsenic contamination 36 1.3.4.2 Natural causes of arsenic contamination 38 1.3.4.3 Anthropogenic arsenic contamination 39 1.3.5 Detection and assessment of exposure 40 1.3.5.1 Analytical techniques 40 1.3.5.2 Individual assessments of exposure 41 1.3.6 Health effects of arsenic 42 1.3.6.1 Exposure pathways 42 1.3.6.2 Acute arsenic poisoning 42 1.3.6.3 Chronic arsenic poisoning 43 1.3.7 Arsenic and the immune system 46 1.3.8 Mitigation of arsenic exposure 48 1.3.8.1 Treatment of contaminated water 48 1.3.8.2 Use of surface water 49 1.3.8.3 Accessing groundwater at a deeper level 49 1.3.8.4 Support for arsenic mitigation 50 1.3.9 Resistance to arsenic in microorganisms 50 1.4 Hypothesis 51 1.5 Aims of project 53 Chapter 2 Materials and Methods 54 Section A: laboratory work 55 IV 2.1 Material 55 2.2 Animals and animal ethics 55 2.3 Leishmania cell culture 56 2.3.1 L.donovani 1S2D (LdBob) 56 2.3.2 LV9 56 2.3.3 Cell density measurements 57 2.3.4 Cloning 57 2.4 Macrophage cell culture 58 2.5 Growth inhibition studies (EC50) 58 2.6 Selection of drug-resistant axenic amastigote cell lines 59 2.7 Optimisation of in macrophage assay 60 2.8 Selection of resistance in macrophage 61 2.9 Arsenic and antimony detection and quantification 61 2.9.1 Indicators 61 2.9.2 Atomic absorption spectrometry 62 2.9.3 Inductively coupled Mass Spectrometry 62 2.10 Arsenic exposure in BALB/c mice 63 2.11 Arsenic and macrophages 65 2.12 In vivo selection of SbV resistant line 65 2.13 In vivo assessment of SbV resistance 66 2.14 Analysis of resistant lines in vitro 67 2.14.1 Extraction of genomic DNA from L.donovani 67 2.14.2 Scanning Electron Microscopy (SEM) 67 2.14.3 Western blotting 68 2.14.4 Thiol analysis 69 Section B: Field work 69 V 2.15 Ethics 69 2.16 Study area 70 2.17 Study design and population 70 2.18 Evaluation of arsenic exposure 72 2.18.1 Tube well water 72 2.18.2 Urine samples 73 2.19 Data management 74 2.20 Statistical analyses 75 2.20.1 Raw data 75 2.20.1.1 Tube well water 75 2.20.1.2 Urine samples 76 2.20.2 Logistic regression 76 2.20.2.1 Tube well water 76 2.20.2.2 Urine samples 76 2.20.3 Survival analysis 77 Chapter 3 Results 78 Section A: Laboratory work 79 3.1 Sensitivity of cell lines to metalloids 79 3.1.1 Sensitivity of Leishmania to metalloids 79 3.1.2 Sensitivity of uninfected macrophages to metalloids 81 3.2 Optimisation of in macrophage assay 81 3.3 Selection of drug resistant axenic amastigotes 83 3.4 Selection of SbV resistant L.donovani in macrophage 84 3.5 Arsenic exposure in BALB/c mice 86 3.5.1 Arsenic exposure model 86 VI 3.5.2 Arsenic exposure and macrophages 88 3.6 Selection of SbV resistance in vivo 89 3.6.1 Evaluation of a chronic visceral leishmaniasis model 89 3.6.2 Sensitivity of ex vivo amastigotes in in macrophage assay 90 3.6.3 In vivo assessment of SbV resistance 91 3.6.4 Effect of arsenic exposure on parasite load 92 Section B: Field Work 93 3.7 Study population 93 3.8 VL cases and treatment 93 3.9 Outcomes of antimonial treatment 94 3.10 Arsenic exposure 95 3.10.1 Tube well water 95 3.10.2 Urine samples 96 3.11 Treatment failure 96 3.11.1 Tube well water 96 3.11.2 Urine samples 97 3.12 Mortality 98 Chapter 4 Discussion 99 4.1 Introduction 100 4.2 Selection of antimonial resistance 103 4.2.1 Antimonial resistance selection in axenic amastigotes 103 4.2.2 Selecting for resistance in macrophage through SbV exposure 106 4.2.3 Leishmania resistance selected for by environmental arsenic exposure 107 4.2.3.1 Arsenic exposure in Bihar 108 4.2.3.2 Arsenic exposure model 108 VII 4.2.3.3 In vivo assessment of arsenic generated antimonial resistance 110 4.2.3.4 Hepatic concentrations of arsenic and antimony 111 4.2.3.5 Effect of arsenic exposure on parasite growth 112 4.2.3.6 Analysis of in vivo generated resistance 112 4.2.3.7 Stability of resistant strains 115 4.3 Pharmacokinetics of antimony related to resistance 117 4.4 The clinical relevance of stage-specific resistance 118 4.4 Antimonial resistance mechanisms, arsenic and clinical isolates 119 4.6 Antimonial treatment outcomes in the field 123 4.6.1 Antimonial treatment failure 123 4.6.2 Mortality in the antimonial treated cohort 126 4.6.3 Limitations of field work study 128 4.6.4 Rural management of VL 131 4.7 Arsenic hypothesis and summary 132 4.8 Further work 134 4.9 Conclusions 135 4.10 Lessons learnt 137 Reference List 139 Appendices Appendix A Informed Consent Form Appendix B Field Work Questionnaire Appendix C Verbal Autopsy Form VIII List of figures Chapter 1: Introduction Facing page 1.1 Human diseases caused by the Leishmania parasite 3 1.2 Status of endemicity of cutaneous leishmaniasis, worldwide, 2012 4 1.3 Status of endemicity of visceral leishmaniasis, worldwide, 2012 4 1.4 Estimates of incidence of visceral leishmaniasis in India 4 1.5 Life cycle of the Leishmania parasite 5 1.6 Factors influencing infection and clinical course in visceral 7 leishmaniasis 1.7 Chemical structures of current anti-leishmanial therapies 12 1.8 Life cycle of a sand fly 17 1.9 Periodic table 20 1.10 Postulated antimony mechanism of action 23 1.11 Decline in efficacy of antimonials at 20 mg kg-1 in Bihar: results of 27 clinical studies between 1980 and 2004 1.12 Postulated antimony mechanisms of resistance 32 1.13 Human metabolism of arsenic 34 1.14 Arsenic global geocycle 36 1.15 Worldwide distribution of arsenic in groundwater 38 1.16 Distribution of arsenic contamination in Nepal, Bihar, West Bengal and 38 Bangladesh 1.17 Three mechanisms of arsenic mobilisation by metal reducing bacteria 39 1.18 Summary of the effect of arsenic exposure on the immune system 46 1.19 Public health education picture, Samastipur, Bihar 48 1.20 Distribution of water sources in low – income countries 50 IX 1.21 District distribution of arsenic contamination, VL endemicity and 51 antimonial resistance in Bihar 1.22 Arsenic hypothesis of antimony resistance in visceral leishmaniasis 52 Chapter 2: Methods Facing page 2.1 Generation of antimonial resistant Leishmania in-macrophage 61 2.2 Experimental flow diagram of generation of antimonial resistant 65 Leishmania in vivo through oral exposure to AsIII Chapter 3: Results Facing page 3.1 Susceptibility to metalloids in Leishmania axenic amastigotes 79 3.2 Growth curve and sensitivity of axenic amastigote clones to stock 80 culture concentrations 3.3 Histogram of amastigote growth in macrophages 82 3.4 Generation of resistant lines of L.
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