Tuberculosis, a potentially deadly infectious disease caused by Mycobacterium tuberculosis (Mtb), generally affects the lungs. Even today, about a quarter of the global population is estimated to have been infected with Mtb, and about 5 – 10% can develop the disease. Besides the general drug regimen of tuberculosis that contains several antimicrobials, there has been a strong interest in developing host-directed therapies (HDTs). In contrast to antimicrobials targeting microbes, HDTs empower the body’s defence systems to fight pathogens effectively. Administering HDTs in combination with regular antimicrobials could help in curing tuberculosis faster.
In a recent collaborative study published in PLoS Biology, scientists have identified a host protein, nuclear receptor corepressor (NCoR1), playing a crucial role in the progression of tuberculosis within the human body. NCoR1 significantly affects the development of tuberculosis in specific immune cells known as myeloid cells. Mtb particularly thrives within macrophages, a type of myeloid cell, by inhibiting the formation of the autophagolysosome, which are vital components of the autophagy process. Hence, reinforcing the autophagy process — the body’s natural defence mechanism — could prove beneficial in eliminating Mtb infection.
Sunil Raghav, Scientist F, Institute of Life Sciences (ILS), Bhubaneswar, who is also the lead and co-corresponding author of the study, mentions that, based on their previous studies, they noticed that removing NCoR1 from immune cells like dendritic cells or macrophages, can make the immune system less active, leading to reduced ability to fight infections. In this study, the researchers found that when they removed the NCoR1 gene from the myeloid cells of mice (NCoR1 knockout mice) using gene editing techniques, the mice had a weakened immune system and were more prone to infections. Raghav explains,
From there, we got the idea that NCoR1 might play a role in pathogenic infections like that of Mtb or Salmonella.
The authors then checked this notion using macrophages extracted from the bone marrow of NCoR1 knockout and control mice and infected them with Mtb. The bacteria survived better in macrophages obtained from the knockout mice. This was further validated in vivo in NCoR1 knockout mice.
With this intriguing observation of Mtb’s survival advantage in NCoR1 knockout mice, the group started looking into different signalling pathways. They found that in the absence of NCoR1, genes that induce autophagy were expressed at low levels and lysosome biogenesis (the process by which cells make and regulate lysosomes, which are membrane-bound organelles responsible for cellular waste disposal) was also impaired. Kaushik Sen, PhD student at ILS, Bhubaneswar, and co-first author of the study, says, “We looked at how cells use energy and autophagy pathways, trying to find a connection and how it affects Mtb survival. We noticed that without NCoR1, cells produced more ATP, the primary energy source. So, we argued that this excess ATP might influence a cellular signalling pathway called the AMPK-mTOR pathway.”
AMP-activated protein kinase (AMPK) is a cellular energy sensor activated at low energy levels. Activated AMPK suppresses mTOR activity, leading to the subsequent movement of transcription factor EB (TFEB) to the nucleus. TFEB then activates genes responsible for initiating autophagy and creating lysosomes. This also results in increased cellular energy levels.
The researchers found that increased NCoR1 expression in myeloid cells following Mtb infection affects the auto-phagolysosomal pathway through the AMPK-mTOR-TFEB signalling cascade. This modulation ultimately regulates the progression of Mtb infection.
“Though the authors showed that NCoR1 regulates autophagy and lysosome biosynthesis, the interacting partners involved in sensing ATP levels during Mtb infection in myeloid cells need further exploration. NCoR1 domain-based informatics studies may provide clues and certain leads to substantiate these findings,” mentions Ranjan Nanda, Group Leader, Translational Health Group, ICGEB, New Delhi, who was not associated with this study.
Although it was known that Mtb can control autophagy, NCoR1’s involvement in the process is a new finding. Raghav says,
This is the first time we report that NCoR1 is somehow playing a role there. So, if we can identify how NCoR1 controls autophagy, it could pave the way for potential host-directed therapies.
As NCoR1 levels are crucial for modulating Mtb infection, Raghav believes that the variation in its levels among individuals could potentially elucidate why some people are more susceptible to acquiring pathogenic infections like tuberculosis. His group is currently conducting experiments to explore such a connection.