Novel method found to kill dormant TB bacteria in stem cells

The bacteria hide inside lipid droplets and so the stem cells do not kill them, say the researchers.

Delhi-based researchers have found that inhibiting lipid synthesis inside stem cells that produce bone cells (mesenchymal stem cells) can help in killing TB bacteria that are found inside the stem cells in a dormant state and safely shielded from the host immune system and TB drugs.While TB bacteria inside the macrophages actively divide, microbes inside stem cells lie dormant and also make the stem cells less likely to replicate thus surviving for an extended period of time. Ex vivo studies with human stem cells and work on mice showed that the two cells are programmed very differently to support active and dormant TB bacteria infection. 

A team of researchers found that TB bacteria are free in the intracellular fluid (cytosol) of the mesenchymal stem cells while they are surrounded by the macrophage cell membrane on being engulfed. This allows the bacteria to promote rapid synthesis of lipids inside the stem cells and hide within the lipid droplets so created.

That mesenchymal stem cells serve as reservoirs of dormant TB bacteria was known but the mechanism by which the bacteria survive for a long period was not known. 

 Studies using human mesenchymal stem cells and macrophages and mice model studies helped us understand how TB bacteria hijack the cellular mechanism to stop the stem cells from replicating and turn themselves dormant,” says the Prof.  “The bacteria instruct the stem cells to synthesise lipids and hide inside them. The stem cells don’t kill microbes that are inside lipid droplets.

”There was sustained expression of genes controlling dormancy in the bacteria isolated from stem cells while genes that promote replication were expressed in bacteria isolated from macrophages. Mouse mesenchymal stem cells and macrophages too showed similar behaviour.In vitro studies using human stem cells showed the bacteria inhibiting stem cell replication. 

When inhibitors to block lipid synthesis were used, there was reduced expression of genes that regulate dormancy of TB bacteria and replication of stem cells. “This helped confirm that TB bacteria induce lipid synthesis in stem cells and hide inside the lipid cells to escape from anti-TB drugs,” says the first author of the paper. 

“Using a drug that inhibits lipid synthesis will prevent TB bacteria dormancy and make them susceptible to anti-TB drugs,” says Fatima. But killing the bacteria and preventing disease reactivation can be achieved by inducing autophagy (mechanism by which cells removes unnecessary or dysfunctional components) along with anti-TB drugs. 

Inhibiting autophagy is one of the ways by which TB bacteria survive inside host cells. The researchers treated human macrophages and stem cells infected with TB bacteria with an anti-TB drug (isoniazid) and/or rapamycin. While isoniazid eliminated replicating bacteria found in macrophages, rapamycin induced autophagy in stem cells to kill the microbes. Similar results were obtained in mouse models too. 

“In mouse models, inducing autophagy led to elimination of TB bacteria from stem cells. Addition of autophagy-inducing drug along with isoniazid led to sterile cure of TB and prevention of disease reactivation,” says the researcher.

“This discovery paves the way for finally getting to grips with the scourge that is tuberculosis in its dormant state, and whose resurgence poses a threat to not only treating TB but also to disease control,” says another researcher.

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New therapy makes HIV virus vanish from the blood of patient

SCIENTISTS in Britain are hopeful they may have cured HIV after the virus vanished from the blood of a patient treated with a new therapy. 

According to The Sunday Times, the 44-year-old is one of 50 people currently trialing a treatment that targets the disease even in its dormant state.

The unidentified patient, a social care worker in London, said: “It would be great if a cure has happened. My last blood test was a couple of weeks ago and there is no detectable virus.”

The therapy was created by a team of scientists from five UK universities: Oxford, Cambridge, Imperial College London, University College London and King’s College London.

Scientists told the paper the virus is currently undetectable in the man’s blood and if it stays that way it will be the first complete cure.
Mark Samuels, managing director of the UK’s National Institute for Health Research Office for Clinical Research Infrastructure, told the paper: “We are exploring the real possibility of curing HIV. This is a huge challenge and it’s still early days but the progress has been remarkable.”

HIV targets the immune system, attaching itself to the DNA of T-cells, where the disease can both hide out and reproduce.

Current antiretroviral therapies (Art) target that process but cannot spot dormant infected T-cells.

The new therapy works firstly by recognising and removing the HIV-infected cells. In the next stage, a new drug called Vorinostat turns the dormant T-cells active so that they can be spotted and then targeted by the immune system.

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