Imatinib-Sensitive Tyrosine Kinases Regulate Mycobacterial Pathogenesis and Represent Therapeutic Targets against Tuberculosis

Ruth J. Napier, et al. 2011. Cell Host & Microbe 10, 475–485

Speaker: Kuan Chih Wu (武冠志)                                        Time: 15:10~16:00, April 18, 2012

Commentator: Dr. Jiunn-Jong Wu (吳俊忠博士)         Place: Room 601

Abstract:

Mycobacterium tuberculosis (Mtb), the agent of tuberculosis (TB), infects one-third of the world’s population and kills approximately 2 million people every year worldwide.¹ It was estimated that more than 90% of all cases and 98% of deaths due to TB occur in developing countries in Southeast Asia, the Western Pacific, and Africa.² Although highly effective treatments have been developed, drugs must be administered for at least six months to cure the disease. This makes the treatment difficult to patients and may cause drug resistance. Thus, new anti-TB drugs are needed to fight against drug resistance, shorten and/or simplify current treatments, provide effective therapy for patients who cannot be treated by current first-line drugs, or those with latent infection. The authors have been studying the mechanisms of bacterial and viral pathogenesis in which the host tyrosine kinases (TKs), particularly the ABL family TKs, ABL1 and ABL2, are required for the survival of pathogens in the host cell.³ In this study, the authors used the cell lines derived from mice deficient in both ABL1 and ABL2, and several tyrosine kinase inhibitors, including imatinib(Gleevec), to determine the roles of ABL family kinases in Mtb pathogenesis, and estimate the potential of imatinib in curing Mtb infection. The in vitro and in vivo data indicate that, deficiency in ABL family TKs or treatment with imatinib can result in reduced entry and intracellular survival ofMtb in the macrophage, and imatinib can act synergistically with the currently used anti-TB drugs.

References:

1.      WHO (World Health Organization). 2000. Tuberculosis. Fact Sheet

2.      Raviglione, et al. 1995. Global epidemiology of tuberculosis. Morbidity and mortality of a worldwide epidemic. JAMA 273, 220–226.

3.      Lebeis, et al. 2009. Aligning antimicrobial drug discovery with complex and redundant host-pathogen interactions. Cell Host Microbe 5,114–122.