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Abstract
Tuberculosis (TB) is responsible for nearly 1.4 million deaths globally every year and continues to remain a serious threat to human health. The problem is further complicated by the growing incidence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB), emphasizing the need for the development of new drugs against this disease. Phagosomal maturation arrest is an important strategy employed by Mycobacterium tuberculosis to evade the host immune system. Secretory acid phosphatase (SapM) of M.tuberculosis is known to dephosphorylate phosphotidylinositol 3-phosphate (PI3P) present on phagosomes. However, there have been divergent reports on the involvement of SapM in phagosomal maturation arrest in mycobacteria. This study was aimed at reascertaining the involvement of SapM in phagosomal maturation arrest in M.tuberculosis. Further, for the first time, we have also studied whether SapM is essential for the pathogenesis of M.tuberculosis. By deleting the sapM gene of M.tuberculosis, we demonstrate that MtbΔsapM is defective in the arrest of phagosomal maturation as well as for growth in human THP-1 macrophages. We further show that MtbΔsapM is severely attenuated for growth in the lungs and spleen of guinea pigs and has a significantly reduced ability to cause pathological damage in the host when compared with the parental strain. Also, the guinea pigs infected with MtbΔsapM exhibited a significantly enhanced survival when compared with M.tuberculosis infected animals. The importance of SapM in phagosomal maturation arrest as well as in the pathogenesis of M.tuberculosis establishes it as an attractive target for the development of new therapeutic molecules against tuberculosis.
Highlights
Inspite of a rapid advancement in our understanding of the biology of Mycobacterium tuberculosis, the success towards the control of tuberculosis (TB) has been less than satisfactory as is evident from,9 million new cases of the disease that still occur globally every year [1]
When aerosol containing M.tuberculosis is inhaled by guinea pigs, the pathogen reaches lungs and is ingested by the resident alveolar macrophages
The success of M.tuberculosis as a highly adapted human pathogen has largely been attributed to its ability to survive successfully in the infected macrophages [4,30]
Summary
Inspite of a rapid advancement in our understanding of the biology of Mycobacterium tuberculosis, the success towards the control of tuberculosis (TB) has been less than satisfactory as is evident from ,9 million new cases of the disease that still occur globally every year [1]. The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of the pathogen and the rising number of HIV-TB co-infections have made the situation even more precarious. There are an estimated 440,000 new cases of MDR-TB, 25,000 cases of XDR-TB and 1.1 million cases of TB-HIV co-infection globally every year [1,2]. Despite the multitude of immune defense mechanisms that the host deploys against M.tuberculosis, the pathogen can continue to persist owing to its subtle tactics [3]. There are several ways in which M.tuberculosis modulates the macrophage defenses to promote its own survival and the inhibition of phagosomal maturation is one of the best characterized mechanisms [4,5,6,7]
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