IGIB unravels a new mechanism TB bacteria use to subvert host defence

At this point we don’t know the causal relationship between the changes in abundance and lipid metabolism, say Sheetal Gandotra (right) and Dilip Menon.

IGIB researchers have found that besides degradative pathways, TB bacteria actively manipulate another organelle — lipid droplets in macrophages. When lipid droplets are infected with TB bacteria, the composition of 86 proteins gets altered. Based on increased abundance of certain proteins, the team found two pathways have a link with lipid metabolism.

It is well known that TB bacteria can actively manipulate the degradative pathway of macrophages (cells responsible for detecting, engulfing and destroying pathogens) such that instead of getting destroyed, the TB bacteria can actually multiply inside the macrophages. Now, researches at the Institute of Genomics and Integrative Biology (CSIR-IGIB), Delhi have for the first time found that TB bacteria actively manipulate an organelle other than those involved in the degradative pathways. They found that protein composition of lipid droplets is actively manipulated by TB bacteria.

Lipid droplets are storehouses of lipids inside the host cells but can be decorated with specific proteins. Previous studies have shown how the composition of proteins in lipid droplets gets altered during different physiological conditions. So understanding how the protein composition of macrophage lipid droplets changes in response to TB infection may help in shedding light about a new mechanism through which the TB bacteria subvert the host defences.

It is already known that TB bacteria utilise lipids from the host cells and compete with the host cell for nutrients stored inside the cells. So the team led Dr. Sheetal Gandotra from IGIB set to study how the lipid droplet organelle gets actively modified by live TB bacteria leading to changes in the protein composition.

To study this, the researchers used live and heat-killed TB bacteria to infect the macrophages. While heat-killed TB bacteria can infect the cells, they cannot manipulate the cell activity and so get cleared over a period of time. So cells infected with heat-killed bacteria served as a perfect control. The results were published in the journal ACS Infectious Diseases.

The lipid droplets in macrophages infected with live TB bacteria altered the composition of 86 proteins. While there was increased abundance of 57 proteins, the abundance reduced in the case of 29 other proteins.

“All that we know now is that there is a change in the abundance of certain proteins. But at this point we don’t know the causal relationship between the changes in abundance and lipid metabolism,” says Dr. Gandotra. “Future studies are needed to understand the reasons why protein abundance changes on lipid droplets from macrophages that are infected by TB bacteria.”

By knowing which proteins’ abundance are altered, it is possible to predict which pathways are being affected. “The lipid metabolism can impact different pathways through changes in the recruitment of proteins that are involved in these pathways or these proteins can have an impact on lipid metabolism directly,” says Dilip Menon from IGIB and first author of the paper.

Based on the increased abundance of certain proteins, the team has found that protein synthesis pathway and vesicular trafficking pathway have an unprecedented link with lipid metabolism in the context of infection.

She says the proteins that have been altered in amount may be further investigated to understand how TB bacteria manipulates host’s lipid metabolism, which seems important to the innate immune defence pathways.

Published in The Hindu on February 9, 2019

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