Illustration: Siddharth Kankaria / Research Matters
Mycobacterium, the infamous bacterium which causes Tuberculosis (TB), is of immense health concern and has been a scourge of mankind for a long time. Controlling mycobacterial infection has not been as manageable as other infections. One of the reasons could be the versatility with which the bacterium interacts with its hosts – us.
It’s not that our body does not fight back, as it does with other infections. During an infection by Mycobacterium, a host of immune responses are initiated by our body. We have a type of white blood cells that travel around the body, acting as sentinels and physically engulfing intruders. But unfortunately, these white blood cells, or macrophages, are manipulated by the bacterium. A previous study by Prof. K N Balaji and his team from the Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, had shown that the white blood cells not only stop acting against the enemy, but also start housing the invading bacterium.
Now, a new study by the same team has reported how our body regroups its immune system to fight back against the bacterium. At the heart of this defence, are molecules called ‘chemokines’, which are produced by immune cells upon infection. Chemokines are small signalling proteins, which when secreted, attract other cells towards them. Like a dog is attracted by the smell of food, other immune cells like neutrophils, T – and B- lymphocytes are attracted towards chemokines, at the site of infection. This recruitment helps to curtail the spread of the pathogen. The chemokines also arm the immune cells to increase their defences against the invader.
The study discovers a novel pathway through which these chemokines production are regulated upon infection by Mycobacterium. They also report how these chemokines arm our immune cells with antimicrobial molecules, thereby reinforcing the arsenal to fight against the bacterium. These findings promise to provide a deeper understanding of treating Tuberculosis.
When the TB bacterium infects a macrophage, it interacts with a receptor called TLR2. The receptor is a protein molecule plugged onto the cell membrane, which interacts with the outside world, including bacteria and fungi. This sets off a signalling cascade wherein information is passed from one protein to the other, until it reaches the nucleus. Once inside the nucleus, this information is used for ‘switching on’ or activating certain genes that have a role to play in response to the bacterial infection. This signal, the researchers claim, is transmitted through a specific pathway, called the ‘Hippo’ pathway. This pathway plays a crucial role in our cells, starting with controlling organ size during embryo development. Improper functioning of this pathway could result in cancer too.
The status of Hippo pathway during mycobacterial infection had, till now, remained obscure. “This study uncovers the as-yet unexplored implication of Hippo signaling pathway in mycobacterial infection; and discusses one of the possible outcomes”, says Prof. K.N. Balaji.
Mycobacterium, while infecting the cells, interacts with TLR2 receptors present on the surface of macrophages, which results in the activation of the receptor. This process, in turn, modifies two adaptor proteins, IRAK1 and IRAK4. The modification is simple – a molecule containing phosphorous is added to the protein, and it gets activated. In a signalling pathway, information is passed on through specific modifications to the component molecules -- like files, once signed or stamped, move on to the next table in an office.
The activated proteins, IRAK1 and IRAK4, further activate MST1/2 - a key regulator in the Hippo pathway. The catalytic activity of MST1/2 is required for the activation of a transcription factor called IRF3. Activated IRF3 ‘switches on’ the genes involved in the production of chemokines CXCL1 and CXCL2. These chemokines, as mentioned earlier, could recruit other immune cells like neutrophils, T – and B- lymphocytes, to the site of infection. This huddling of white blood cells could be pivotal in the control of the infection. These chemokines also armour the cells with small proteins like beta-defensins, inflammatory mediators and lysozymes -- all proteins that destroy bacteria.
The unveiling of such novel regulatory networks may help to provide better therapeutics and vaccines against TB. “Unfurling these mechanisms is essential to gain a holistic view of the infection battlefield”, remarks Prof. Balaji.