Boosting host immune defenses to treat tuberculosis

November 12, 2019

Current treatment regimens for Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, are long, complex, and hard for people to sustain. Moreover, the bacteria often develop drug resistance, and many people harbor multi-drug-resistant strains. In 2018 alone, nearly 1.5 million people died from tuberculosis worldwide.

Now, a study in iScience suggests a new approach that might help: making people's cells better at killing Mtb by harnessing RNA sensors in our cells, which detect the RNA of invading pathogens.

RNA sensing is part of our first-line immune defense. For the first time, researchers led by Anne Goldfeld, MD, of Boston Children's Hospital's Program in Cellular and Molecular Medicine, showed that RNA sensing is important in inhibiting Mtb's growth once it gets inside cells.

By studying infected cells, the team showed that Mtb activates several major RNA sensors -- RIG-I, MDA5, PKR, and MAVS -- that in turn inhibit bacterial growth. When they disrupted any of these sensors using gene-editing methods such as CRISPR, Mtb grew to significantly higher levels in human cells.

"This was a key breakthrough, because RNA sensor molecules were previously thought to be involved in fighting viruses and not bacteria," Goldfeld says. "It suggested that enhancing the activity of these RNA sensors via drug therapy could curb MTb growth."

Repurposing nitazoxanide for TB

Recently, Goldfeld's lab, together with the lab of her colleague Sun Hur, PhD, showed that an FDA-approved antiparasitic drug called nitazoxanide (NTZ) inhibits the Ebola virus, and that it works by amplifying RNA sensor activities. That finding, coupled with the new discovery that RNA sensors inhibit Mtb growth within cells, led Goldfield's team to try NTZ in tuberculosis.

"We showed that NTZ amplifies the activities of RNA sensors once they have been triggered by Mtb RNA," Goldfeld says. "And unexpectedly, we found that NTZ also amplifies MTB's stimulation of RNA sensor activity."

The net result was that NTZ increased production of interferon and IFITM3, important elements of the immune response against tuberculosis, and significantly inhibited Mtb growth inside cells. Although more research is needed to better understand how NTZ does all this, Goldfeld hopes these studies will open a new approach to alleviate the global burden of tuberculosis.

"NTZ is low in cost and available as an oral drug, including a syrup formulation for children, making it an easily accessible treatment," she says. "We think NTZ or a derivative drug could complement traditional tuberculosis regimens by boosting host defenses to kill Mtb. The power of this approach is that targeting host factors will not precipitate or increase antibiotic resistance in bacteria."
-end-
Shahin Ranjbar and Viraga Haridas of the Program in Cellular and Molecular Medicine (PCMM) were co-first authors on the paper. Coauthors were Aya Nambu, Luke Jasenosky, Supriya Sadhukhan, and James Falvo of PCMM; Thomas Ebert and Veit Hornung of Ludwig-Maximilians-Universität München (Munich, Germany); and Gail H. Cassell of Harvard Medical School.

This work was supported by the National Institutes of Health (AI125075), the Annenberg Foundation, the Ragon Institute, Romark Inc., John Moores, Jeanne Sullivan, the Campbell Foundation, and a lab gift from Romark, Inc., which makes NTZ.

Boston Children's Hospital

Related Bacteria Articles from Brightsurf:

Siblings can also differ from one another in bacteria
A research team from the University of Tübingen and the German Center for Infection Research (DZIF) is investigating how pathogens influence the immune response of their host with genetic variation.

How bacteria fertilize soya
Soya and clover have their very own fertiliser factories in their roots, where bacteria manufacture ammonium, which is crucial for plant growth.

Bacteria might help other bacteria to tolerate antibiotics better
A new paper by the Dynamical Systems Biology lab at UPF shows that the response by bacteria to antibiotics may depend on other species of bacteria they live with, in such a way that some bacteria may make others more tolerant to antibiotics.

Two-faced bacteria
The gut microbiome, which is a collection of numerous beneficial bacteria species, is key to our overall well-being and good health.

Microcensus in bacteria
Bacillus subtilis can determine proportions of different groups within a mixed population.

Right beneath the skin we all have the same bacteria
In the dermis skin layer, the same bacteria are found across age and gender.

Bacteria must be 'stressed out' to divide
Bacterial cell division is controlled by both enzymatic activity and mechanical forces, which work together to control its timing and location, a new study from EPFL finds.

How bees live with bacteria
More than 90 percent of all bee species are not organized in colonies, but fight their way through life alone.

The bacteria building your baby
Australian researchers have laid to rest a longstanding controversy: is the womb sterile?

Hopping bacteria
Scientists have long known that key models of bacterial movement in real-world conditions are flawed.

Read More: Bacteria News and Bacteria Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.