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Tuberculosis: A mutiny against mycobacteria

Tuberculosis (TB), popularly known as the White Plague, is one of the world’s deadliest infections. ‘Consuming’ millions of lives, the disease owes its success to the fervent microbe, Mycobacterium tuberculosis (Mtb) that has been using every trick under its sleeve to outwit the host. Consequently, an understanding of host-microbe interactions has been of paramount importance to combat TB. Dr. Varadharajan Sundaramurthy and his team of researchers from the National Centre for Biological Sciences have been making significant progress in this front. In a recent paper from the lab, they show that mycobacteria (Mtb) infected cells carry a unique signature that is characterized by an abundance of lysosomal organelles. Additionally, they find that this altered homeostasis is kindled by lipid molecules that dot the surface of the bacteria. The team believes that such a strategy influences the cell’s trafficking of lysosomes and eventually, bacterial survival. These findings have been published in the Journal of Biological Chemistry.

When TB causing mycobacteria enter the lungs of the host, they are promptly attacked by cells called macrophages. Macrophages, pivotal cells of the immune system, devour foreign particles (such as bacteria) and contain them in structures called phagosomes. These pathogen filled sacs then mature and finally fuse with biomolecular shredders called lysosomes that destroy the infectious residents. In spite of such a streamlined immune response, TB continues to haunt mankind. This is because mycobacteria are constantly crafting ways to hack the host’s immune response.

“Our lab is fascinated by this balance operating in the interface between the host and bacteria in Mtb infected cells. Infected hosts sustain the bacterial infection for prolonged periods of time and enter a state of ‘equilibrium’ where, the host is unable to get rid of the bacteria and the bacteria is not entirely competent to overwhelm the host,” describes Sundaramurthy.

Kuldeep, a graduate student in his lab and lead author of this study was interested in identifying quantitative descriptors of this nimble host-microbe balance. He first decided to look at the global impact of Mtb infections on lysosomes. Like most difficult beginnings, Kuldeep says “this was the most challenging phase” because he didn’t have access to a well-protected biosafety lab (BSL3) to carry out his experiments. Thanks to some generous support from Dr. Amit Singh and Rajmani from IISc, Kuldeep was able to run his first few experiments in their BSL3 facility before he moved back to a brand new, fully furnished lab at NCBS.

These first crucial experiments revealed that macrophages (in a dish) infected with Mtb had a heightened lysosomal content when compared to uninfected ‘by-stander’ cells. Similar observations were made from lung-derived macrophages of infected mice. Kuldeep was able to establish that this is likely a distinct feature of Mtb infection because macrophages infected with another bacteria (Escherichia coli) did not show an increase in lysosomal content. Veritably, a mycobacteria specific cell wall component called sulpholipid-1 (SL-1) was found to be at the helm of this lysosomal boost.

“The level of lysosomal modulation by Mtb was so stark!” exclaims Kuldeep, who wanted to further bolster these observations. For this, he joined forces with Dr. Karthik Raman and Malvika (computational biologists in IIT-Madras). In what turned out to be an exciting collaboration, they found that a computer program, by simply looking at a few lysosomal features, could recognize infected cells from a throng of macrophages.

The field of host-microbe interactions is abreast with the fact that Mtb can infiltrate the host by tinkering with the lysosomal system. “Mycobacteria reside in vacuoles distinct from lysosomes, so Mtb are known to actively avoid contact with lysosomes. More recently, there is recognition of additional mechanisms, where Mtb can be delivered to lysosomes and adapt to the harsh conditions and survive,” elaborates Sundaramurthy. However, in this mutiny between Mtb and the host macrophage – each one seems to be actively and reciprocally controlling the other.

“These findings are rather counter-intuitive, which is that the increased lysosomes have a host protective effect and help in containment of the bacteria,” he explains. But why would Mtb litter the cell with lysosomes – an organelle that’s just waiting to splinter it? Experiments seem to suggest that although there is an increase in the number of lysosomal vesicles, a substantial proportion of the bacteria evade themselves from getting drawn into this death pit. The puzzle however doesn’t end here. It only gets more mysterious. “Can we modulate the bacteria inside the cell by 'tuning' the lysosomes? How will this impact the physiology of the bacteria?” wonders Sundaramurthy, whose enthusiastic battalion is now actively pursuing answers to these questions.

Source: National Centre for Biological Sciences news release written by Preethi Ravi

 

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