Abstract
Macrophages are responsible for innate and adaptive immune response activation necessary for eliminating infections. Optimal activation of macrophages to phagocytize Mycobacterium tuberculosis is critical in anti-mycobacterial defense. Here, we identified a novel Rv3463 hypothetical protein that induces macrophage activation in Mtb culture filtrate. Recombinant Rv3463 activated mouse bone marrow-derived macrophages to induce the expression of surface molecules and secrete pro-inflammatory cytokines via the TLR2 and TLR4 pathways. Mitogen activated protein kinase, phospatidylinositol-4,5-bisphosphate 3-kinases, and the NF-κB signaling pathways are involved in Rv3463-mediated macrophage activation. Furthermore, Rv3463 induced bactericidal effects in Mtb-infected macrophages through phagosome maturation and phagolysosomal fusion enhanced by phospatidylinositol-4,5-bisphosphate 3-kinases and Ca2+ signaling pathways and exhibited therapeutic effects in a short-term Mtb-infection mouse model. Overexpression of Rv3463 in M. smegmatis caused rapid clearance of bacteria in macrophages and mice. Our study suggests that Rv3463 is a promising target for the development of post-exposure tuberculosis vaccines or adjunct immune-therapy.
Highlights
Mycobacterium tuberculosis (Mtb) is one of the most infectious intracellular pathogens, infecting one-third of the population in the world
We found that Rv3463 strongly activates macrophages to enhance phagosomal maturation via PI3K and Ca2+ signaling and exhibits therapeutic potential in vivo
It has been reported that several mycobacterial proteins are able to activate immune cells via the TLR2 or TLR4 signaling pathways[36,37], thereby activating innate immune and inflammatory responses
Summary
Mycobacterium tuberculosis (Mtb) is one of the most infectious intracellular pathogens, infecting one-third of the population in the world. The only available vaccine, M. bovis BCG, is not fully effective for protection against adult pulmonary TB as well as reactivation of latent TB3 These issues present an urgent need for a better understanding of factors related to mycobacterial survival, which could lead to the development of novel strategies to eradicate Mtb from infected hosts. Www.nature.com/scientificreports same time, processes such as Mitogen- activated protein kinases (MAPKs) and calcium signaling are initiated; these processes play important roles in the bactericidal response to infected cells[8]. Optimal activation of macrophages, which play an important role in the effector phase of the immune response, is critical in anti-mycobacterial defense. Candidate TB vaccines have focused on T-cell stimulating antigens, we postulate that proteins that induce the bactericidal activity in macrophages can be ideal vaccine targets, for the development of a post-infectious vaccine. These findings suggest that Rv3463 is a promising candidate for TB immunotherapy
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