Interplay of human macrophages and Mycobacterium tuberculosis phenotypes

.......................................................................................................... 1 Populärvetenskaplig sammanfattning ................................................................ 3 List of papers ................................................................................................... 5 Abbreviations .................................................................................................. 6 Background ..................................................................................................... 8 Tuberculosis ......................................................................................................... 8 History ........................................................................................................................... 8 Epidemiology ................................................................................................................. 9 Mycobacterium tuberculosis .................................................................................. 10 Cell wall ....................................................................................................................... 11 The mycobacterial capsule ............................................................................................ 11 Transport across membranes, ESX-1 secretion and ESAT6 .......................................... 13 TB antibiotics and antibiotic resistance ........................................................................ 14 Mtb and the human immune system ................................................................... 16 Transmission and clinical outcomes ............................................................................. 16 Granuloma formation .................................................................................................. 18 Diagnosis of TB ........................................................................................................... 20 Treatment of TB .......................................................................................................... 21 TB vaccination ............................................................................................................. 22 Interplay of macrophages and Mycobacterium tuberculosis ............................................. 24 Innate immunity ....................................................................................................... 24 Polarization – heterogeneity of macrophages ............................................................. 24 Recognition and uptake of Mtb by macrophages ...................................................... 25 Phagolysosomal maturation and autophagy ............................................................... 27 Cell death and efferocytosis ....................................................................................... 30 ESX-1-secreted virulence factors and the human immune system ................................. 31 Mtb phenotypes and their interaction with the host ............................................. 33 Terminology of dormancy and persistence ................................................................... 33 Mtb in different environments ..................................................................................... 33 Mtb in different human tissues ................................................................................. 34 Conditions and adaptation inside the macrophage ................................................... 36 The environment in the granuloma .......................................................................... 40 Mtb in sputum ......................................................................................................... 42 Phenotypes of Mtb ...................................................................................................... 43 Morphologic Mtb phenotypes .................................................................................. 43 Encapsulated Mtb .................................................................................................... 44 Mechanisms and models for Mtb dormancy and persistence ........................................ 46 Intrinsic factors ......................................................................................................... 47 TB pathogenesis ....................................................................................................... 48 Host-induced phenotypes ......................................................................................... 48 Clinical implications of dormancy and persistence ....................................................... 53 Aims ............................................................................................................. 57 Results and Discussion .................................................................................. 58 Concluding remarks and outlook ................................................................... 67 References ..................................................................................................... 69 Acknowledgements ........................................................................................ 88