Development of the tyrosine kinase inhibitor imatinib mesylate as a therapeutic for tuberculosis Público
Napier, Ruth Jean (2013)
Abstract
Mycobacterium tuberculosis (Mtb) remains an enormous public health concern, second only to HIV/AIDS. The emergence of multi-drug resistant and extensively-drug resistant strains of Mtb has highlighted the need for the immediate development of new anti-tuberculosis therapeutics. The work presented here investigates the use of the FDA-approved tyrosine kinase inhibitor, imatinib (Gleevec, STI-571), for treatment of tuberculosis (TB). We show that Abl-family and other host tyrosine kinases regulate Mtb and the related pathogen Mycobacterium marinum (Mm) entry, intracellular survival and co-localization with acidified vesicles in macrophages. In mice, administration of imatinib reduces bacterial load and associated pathology, and has a sterilizing effect on ~50% of animals tested. Importantly, we show imatinib has similar effects on drug-resistant strains and works in a synergistic manner with current anti-TB drugs. We also show that in vivo imatinib has a previously unreported immunomodulatory capacity in that it increases numbers of neutrophils and monocytes in the bone marrow, and facilitates their migration to peripheral sites, including blood and spleen. Imatinib treatment does not activate neutrophils per se, though activation markers increase normally upon infection. Furthermore, adoptive transfer of neutrophils from animals treated with imatinib or control animals into naïve animals decreases mycobacterial burden to the same extent, suggesting that increasing numbers of neutrophils is sufficient to reduce bacterial load. This immunomodualtory capacity of imatinib resembles increased hematopoiesis normally stimulated upon infection. As such we show pre-treatment of mice with imatinib reduces bacterial burden of pathogenic Francisella species (F. novicida and LVS), bacteria that do not require Abl or related kinases for survival in macrophages. Taken together, our findings demonstrate that (i) imatinib could be administered in conjunction with current antibiotic regimens for infections caused by pan-susceptible or drug-resistant resistant strains of Mtb; (ii) Because imatinib targets the host rather than microbial molecules, it is less likely to engender resistance compared to conventional antibiotics, and may extend the clinical lifespan of antibiotics administered concurrently; (iii) imatinib-induced neutrophilia in the bone marrow and periphery suggest that the drug may have inhibitory activity against a broad range of bacterial pathogens; and (iv) may mitigate the effects of neutropenia.
Table of Contents
CHAPTER 1:
Introduction…………………………………………………………..................................
1
Introduction
references………………………………………..................................
32
CHAPTER 2:
Imatinib-sensitive tyrosine kinases regulate mycobacterial
pathogenesis and represent therapeutic targets against
tuberculosis.…………...………………………………………….................................. 49
Chapter 2
figures…………………………………………........................................
79
Chapter 2
references…………………………………………...................................
94
CHAPTER 3:
Imatinib induces an expansion of myeloid cells in
the bone marrow and periphery of mice that facilitates
host antimicrobial activity …………...………………...................................... 102
Chapter 3
figures…………………………………………........................................
126
Chapter 3
references……………………………………….....................................
136
CHAPTER 4:
Conclusion
…………...…………………….....................................................
143
Chapter 4
references…………………………………………...................................
152
LIST OF FIGURES
CHAPTER 2
Figure 1: Src- and Abl-family tyrosine kinase inhibitors reduce
intracellular survival of Mtb and Mm in vitro....................................... 79
Figure 2: Abl-family tyrosine kinases and other imatinib-sensitive
kinases mediate intracellular survival of Mtb and Mm …………................. 80
Figure 3: Imatinib reduces bacterial load in mice infected with Mm......... 81
Figure 4: Imatinib reduces liver pathology and tail lesions in mice
infected with Mm.………………………………………………………………..................... 82
Figure 5: Imatinib reduces bacterial load in macrophages and mice
infected with rifampicin-resistant Mm.…………………..….………….................. 83
Figure 6: Imatinib and antibiotics act in synergy to reduce
mycobacteria survival.…………………..….…………………………………................... 84
Figure 7: Imatinib reduces bacterial load in mice infected with Mtb......... 85
Figure S1: Effects of inhibitors of Src- and Abl-family tyrosine kinases
on Mtb and Mm infection in vitro ………………………………………..................... 86
CHAPTER 3
Figure 1: Imatinib treatment induces expansion of myeloid cells in
mouse spleen and blood…………………………………………………..…….................. 126
Figure 2: Imatinib treatment induces neutrophilia in mouse bone marrow. 127
Figure 3: Imatinib treatment increases CXCR2 expression on neutrophils
in the bone marrow …………………………………………………..……………................. 128
Figure 4: Neutrophils from imatinib-treated mice are not activated but
remain activatable upon Mm infection.………………………..…………................. 129
Figure 5: Neutrophils are sufficient to reduce bacterial load………..………….. 130
Figure 6: Imatinib reduces bacterial load in mice infected with
pathogenic Francisella species…………………………..………..…………................. 131
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