Abstract
Tuberculosis (TB) is a major health problem worldwide resulting in 1.4 million deaths, caused by Mycobacterium tuberculosis. Despite all the efforts to target and eliminate this chronic disease, the control of tuberculosis has been severely thwarted by the emergence of multidrug and extensively resistant strains. The long treatment duration and its association with various side effects result in noncompliance of the patients. To improve treatment outcomes and reduce duration of therapy, host-directed TB therapies could provide a solution for the resolution of the disease. The development of host directed therapies will be expedited by further understanding of host-mycobacterium interaction and how the pathogen hijacks host cell processes to facilitate survival. Key to this process is the regulation of host gene expression. However, very little is known about translational control by bacterial pathogens, including Mycobacterium tuberculosis and how this contributes to pathogenesis. By using Mycobacterium bovis Bacillus Calmette-Guerin (BCG) as a surrogate of Mycobacterium.tuberculosis, we aimed to dissect how Mycobacterium bovis BCG alters translation in the infected macrophages, and how the regulation of eIF4E activity participates in this response to infection. Our results suggest that mycobacterial infection induces eIF4E phosphorylation in murine macrophages. Furthermore, the kinases ERK and MNK are responsible for eIF4E phosphorylation and their activation contributes to changes in the translational state of host mRNAs, as identified by polysome profiling. These changes alter the macrophage response to mycobacteria, affecting intracellular bacterial survival and macrophage viability. As it is believed that in up to 50 % of TB exposed individuals, the infection is cleared without the involvement of the adaptive immune system, indicating that the innate immune system may be able to control or clear the infection if activated appropriately. Further testing of the mechanisms used by macrophages to keep the infection under control has been done by measuring TNFα and IL-10 production, phagosomal acidity and cellular autophagy in the presence of ERK and MNK inhibitors. We found that the activation of ERK-MNK-eIF4E pathway regulates the cytokines production, but only ERK plays a regulatory role on macrophage phagosomal acidification as well as cell autophagy. Our finding suggests that Mycobacterium bovis BCG benefits from the activated ERK-MNK- eIF4E signalling to survive inside the cell. We conclude that regulating eIF4E phosphorylation is a key component of the hostpathogen interaction during mycobacterium infection and therefore, we suggest the possibility of using selective MNK and/or ERK inhibitors as host-directed immuno-therapeutics for tuberculosis.