Imatinib mesylate as a host directed therapeutic for mycobacterial infection Público
Cleverley, Tesia (Spring 2023)
Abstract
Mycobacterial infections remain an important cause of morbidity and mortality in humans; for example, Mycobacterium tuberculosis, the cause of tuberculosis, kills ~1.5 million and newly infects ~10 million each year. Most people effectively combat mycobacterial infections with only 10% of people exposed tuberculosis developing active disease and infections with non-tuberculosis mycobacteria being predominate in immunocompromised individuals. Treatment is compromised in at-risk individuals by an inadequate immune response and chronic inflammation, which results in chronic infection and tissue damage. Granulomas form to encase bacteria thus limiting spread of the infection. However, these structures impair tissue function and limit access of antibiotics to bacteria, which engenders antibiotic resistance. Antibiotic resistance is an ongoing concern in mycobacterial infections as the bacteria are intrinsically resistant to many antibiotics and readily acquired resistance. Current antibiotic therapies used to treat mycobacterial infections are required to be taken for months leading to side effects and poor compliance. Therefore, there is a need to develop new therapies to combat the rise of antibiotic resistance or shorten treatment regimes. Imatinib mesylate, a host directed therapeutic, has shown efficacy against mycobacteria in cell culture and mouse model systems. Imatinib was originally conceived as a cancer therapeutic that inhibits Abl and related tyrosine kinases, however inhibition of Abl has been shown to alter intracellular transit of bacteria during infection. Low doses of imatinib have also been shown to induce myelopoiesis in mice. Using systems biology approaches in conjunction with murine infections with Mycobacterium marinum, a close genetic relative of M. tuberculosis that forms tail granulomas, we report that imatinib does not fundamentally alter the anti-mycobacteria immune response at the site of infection, but rather accelerates development of the immune response. In addition, imatinib limits granuloma formation and growth resulting in less inflamed tissue. In the absence of caspase 8, imatinib is unable to limit granuloma growth. These data highlight imatinib as a possible host directed therapeutic for mycobacterial infections with the capacity to augment the immune response in at-risk individuals, and limit granuloma growth, thereby limiting tissue damage.
Table of Contents
Chapter 1: Introduction: Mycobacteria and host directed therapeutics 1
Part 1: Antibiotic Resistance in Mycobacterial infection 2
Part 2: Imatinib as a host directed therapeutic 24
Thesis Overview 35
Chapter 2: The host-directed therapeutic imatinib mesylate accelerates immune responses to Mycobacterium marinum infection and limits pathology associated with granulomas 37
Abstract 38 Introduction 40
Results 44
Discussion 57
Materials and Methods 64
Figures 71
Figure 1 71
Figure 2 73
Figure 3 75
Figure 4 77
Figure 5 79
Figure 6 81
Supplemental Figure 1 83
Supplemental Figure 2 85
Supplemental Figure 3 87
Chapter 3: Discussion: Imatinib as a host directed therapeutic 88
Citations 101
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