The study results revolve around the ancient battle between the human immune system and bacterial invaders, where immune cells strive to recognize bacteria as the microbes work to evade them.Mycobacterium tuberculosisremains the leading bacterial cause of death globally because, like other successful pathogens (e.g. HIV), it goes beyond evasion to take over functions of immune cells.
The newly published study in Nature Immunology describes how tuberculosis bacteria cause mammalian immune cells, called macrophages, to make more of a key snippet of genetic material. Higher levels of this snippet, called microRNA-33 (miRNA-33), change the action of many genes to strip macrophages of their ability to package TB bacteria for destruction. At the same time, these genetic regulatory changes force the cells to build up fat for the TB bacteria to feed on. Although this study was done in mice, the same mechanisms were found in human macrophages infected with TB.
"Our study results describe precise mechanisms that enable tuberculosis bacteria to persist in the body, which is central to the infection's deadliness," says senior study author.
Upon entering macrophages, most bacteria are enfolded into vesicles called phagosomes. These pockets then fuse with lysosomes, a second set of compartments filled with bacteria-destroying chemicals. TB bacteria can evade capture by phagolysomes, getting free in the cell's cytosol where a back-up mechanism, autophagy, seeks again to deliver them to lysosomes.
While the first role of autophagy is to enfold aging cell parts into vesicles where they can be broken down and recycled, evolution has also put this mechanism to work in controlling fat (lipid) levels and as a back-up system for removing harmful bacteria. TB bacteria take advantage of this convergence of cell functions to change conditions in their favor.
Specifically, the new study found that TB bacterial proteins trigger an immune signaling pathway inside macrophages, where a protein complex called NFKappaB triggers a key gene to make more of microRNA-33. This dramatically dials down the signal delivered by several autophagy genes that would otherwise keep fat levels down.