#Trials fusion base invader professional#

The current TB drug regimen generally requires 2-months of treatment with four first-line drugs: isoniazid, rifampicin, ethambutol, and pyrazinamide followed by 4 months of treatment with isoniazid and rifampicin ( WHO, 2016). The development of active pulmonary TB is tightly linked with a disordered immune balance, resulting in hostвЂ™s inability to keep the infection under control ( OвЂ™Garra et al., 2013). Establishment of an immune balance, orchestrated by both mycobacteria and host cells, is decisive for the outcome of the granuloma, which may either constrain the infection or promote its systemic dissemination ( Ulrichs and Kaufmann, 2006 Davis and Ramakrishnan, 2009). A hallmark feature of the bacillus is its ability to remain concealed within host cells or/and within the granulomatous caseous necrotic centers, where it can persist during the long phase of TB latency ( Barry et al., 2009). In lungs, the progressive establishment of an immune response during Mtb infection notably contributes to the aggregation of immune cells, forming an organized structure harboring macrophages at the center, surrounded by giant cells, T-lymphocytes, neutrophils, fibroblast, which is called a granuloma. Innate immune responses are essential for the outcome of TB infection as well as for the establishment of adaptive immunity ( Torrado and Cooper, 2013 Orme et al., 2015). Manipulation of intracellular macrophage signaling also impacts the cytokine environment modifying the potency of protective immune response, setting up a Mtb tolerance by the host and favoring the intracellular survival of Mtb over time ( BoseDasgupta and Pieters, 2014 Orme et al., 2015).

Following macrophage phagocytosis, mycobacterial invaders deploy an army of factors, which circumvent macrophage defenses, to escape from macrophage killing and to replicate within these phagocytes ( Ehrt and Schnappinger, 2009 Cambier et al., 2014). After inhalation, Mtb rapidly reaches the lungвЂ™s alveolar space where it is preferentially taken up by alveolar macrophages ( Armstrong and Hart, 1971 Warner and Mizrahi, 2007). TB primary infection occurs through inhalation of Mtb-containing aerosol droplets released by contagious individuals. Statistically, 5вЂ“10% of latently infected individuals might then further develop active TB during their lifetime ( Barry et al., 2009). Estimations based on immunological tests suggest that about 2 billion people might be latently infected by Mtb. Mtb is responsible for about 10 millions of new TB cases and 1.8 million deaths in 2015 ( WHO, 2016). With over a billion deaths in the past 200 years, tuberculosis (TB) caused by Mycobacterium tuberculosis ( Mtb) likely killed more people than any other infectious disease in the history of humanity ( Paulson, 2013) and remains a major cause of death also in our era. In this mini-review, we discuss recent research exploring how Mtb conquers and transforms the macrophage into a strategic base for its survival and dissemination as well as the associated defense strategies mounted by host. Comprehension of the molecular events governing Mtb survival within macrophages is fundamental for the improvement of vaccine-based and therapeutic strategies in order to help the host to better defend itself in the battle against the fierce invader Mtb. Bacterial access to the cytosolic space is determinant for specific immune responses and cell death programs, both required for the replication and the dissemination of Mtb. Within macrophages, Mtb initially resides inside phagosomes, where its survival mostly depends on its ability to take control of phagosomal processing, through inhibition of phagolysosome biogenesis and acidification processes, and by progressively getting access to the cytosol.

#Trials fusion base invader professional#

Although macrophages are known as professional killers for pathogens, Mtb has adopted remarkable strategies to circumvent host defenses, building suitable conditions to survive and proliferate. After inhaling Mtb-contaminated aerosols, TB primo-infection starts in the terminal lung airways, where Mtb is taken up by alveolar macrophages. TB still remains a major public health problem in our era, causing more than 4,400 deaths worldwide every day and killing more people than HIV. Mycobacterium tuberculosis ( Mtb), the etiological agent of human tuberculosis (TB), has plagued humans for thousands of years.

Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, Paris, France.Queval вЂ , Roland Brosch and Roxane Simeone *