Harnessing RNA sensors inhibits growth of tuberculosis bacterium

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New research indicates enhancing human body cells so that they are more attuned to killing invasive Mycobacterium tuberculosis is an effective means for controlling the spread of the disease. The approach involves harnessing RNA sensors, which detect the RNA of invading pathogens. The research is also of wider pathology interest since RNA sensor molecules were previously thought to be involved in fighting viruses and not bacteria; the new study shows their role in combating invasive bacteria.

Mycobacterium tuberculosis

Tuberculosis is a disease caused by Mycobacterium tuberculosis. While it is an ‘ancient disease’ it is increasingly becoming a communicable disease of concern [1]. According to the WHO, an estimated 1.7 million people die from such an infection worldwide every year. To select a more local example, reports suggest that cases in the UK have increased in the past 15 years; moreover, incidents in the UK are above the Western European average: 14 per 100,000 people for the UK and 12 per 100,000 throughout Western Europe [2]. Epidemiological data has been enhanced in recent years due to advances with whole-genome sequencing, which provides more detailed insights into understanding transmission pathways and networks [3], and through the application of bioinformatics.

Tuberculosis infection occurs through inhalation of the bacterium, which then travels to the alveoli of the lungs. Most people who carry the bacterium do not show any symptoms (latent tuberculosis); however, the condition can become serious for people with weak immune systems [4]. Symptoms include fever, fatigue and, in some cases, the coughing up of blood. Patients who have pulmonary or laryngeal tuberculosis pose a particular risk of infection, especially if they are coughing due to the generation of aerosols, there are also risks of cross-infection from asymptomatic patients [5].

A major challenge arises because the infectious bacteria often develop drug resistance, and many people harbour multidrug-resistant strains [6].

Infection mechanism and RNA sensors

During an infection M. tuberculosis secretes a large number of effector proteins through type VII secretion systems. These are nanomachines composed of proteins that reside in the cell envelope. These effector proteins are specialized in fighting the immune defence or enable the uptake of nutrients to ensure the bacterial survival in the host.

The new research strand aims to trigger human cells to become effective at killing M. tuberculosis cells by harnessing RNA sensors [7]. The aim is to enhance the detection of invading pathogens and to increase the possibility of the body’s immune system in killing the invaders before they can secrete effector proteins. RNA sensors are part of the innate immune system and they are initiated by recognition of pathogen-associated molecular patterns. Such recognition initiates signalling cascades that culminate in a coordinated intracellular innate immune response designed to control infection.

Researchers, at the Boston Children’s Hospital’s Program (MA, USA) in Cellular and Molecular Medicine, have demonstrated that RNA sensing is a necessary step for inhibiting M. tuberculosis growth once it enters inside cells. A series of experiments revealed that M. tuberculosis activates several major RNA sensors, coded as RIG-I, MDA5, PKR, and MAVS. In turn these sensors inhibit bacterial growth. This was evidenced by demonstrating that whenever any of the sensors was inactivated, using the gene-editing method CRISPR, M. tuberculosis grew to significantly higher levels in human cells.

Opportunities to fight TB with resupposed medicines

In terms of how this new understanding can be put to practical use, the research laboratory demonstrated that a medicine, approved for a different infectious disease, could be resupposed to help combat M. tuberculosis. A study, using primary human monocyte-derived macrophages, showed that an antiparasitic drug called nitazoxanide, which also inhibits the Ebola virus by amplifying RNA sensor activities, could potentially be applied to combatting M. tuberculosis. Nitazoxanide is a member of the thiazolides, which are a class of synthetic nitrothiazolyl-salicylamide derivatives [8].

An initial study indicated that nitazoxanide amplifies the activities of RNA sensors once they have been triggered by M. tuberculosis RNA. Furthermore, the drug mechanism also amplifies M. tuberculosis’ stimulation of RNA sensor activity. Closer examination revealed that nitazoxanide increased production of interferon and interferon induced transmembrane protein 3 (IFITM3), both of which have now been identified as important elements of the immune response against the tuberculosis-causing bacterium, leading to inhibition of M. tuberculosis growth inside cells. IFITM3 has previously been established as playing a critical role in the immune system’s defence against swine flu (any strain of the influenza family of viruses that is endemic in pigs)[i]. Hence, mycobacteria appear to directly trigger cytosolic RNA sensors that lead to transcription of IFITM3, hitherto only thought to be involved in the antiviral axis.

The research remains at an early stage and additional inquiries will be required to understand more fully how nitazoxanide causes the inhibition of the organism. If the study can be replicated and the mechanisms at play more fully revealed, then the impact on global health could be significant given that nitazoxanide is a relatively low-cost medicine and it has the advantage of being administered orally.

Summary

M. tuberculosis infection is an issue of global concern, both due to rates of the disease and the factor of antimicrobial resistance. A new mechanism, based on RNA sensors, can improve the chances reducing infection by inhibiting the bacterium. To deliver this, a resupposed medicine called nitazoxanide may be the answer to delivering the microbial inhibiting remedy, by boosting host defences, alongside traditional tuberculosis regimens.

  1.  European Centre for Disease Prevention and Control/WHO Regional Office for Europe. Tuberculosis surveillance and monitoring in Europe 2014. Stockholm: European Centre for Disease Prevention and Control (2014).
  2. Public Health England. Tuberculosis in England 2019 report: Executive Summary. Public Health England, London, UK (2019).
  3. Dlamini MT, Lessells R, Iketleng T, de Oliveira T. Whole genome sequencing for drug-resistant tuberculosis management in South Africa: What gaps would this address and what are the challenges to implementation? Clin. Tuberc. Other Mycobact. Dis. 16, 100115 (2019)
  4. Sandle, T. The possible origins of tuberculosis in South America, Ancient Diseases & Preventive Remedies, 2 (2), 1–2 (2014).
  5. Gebhard A, van den Hof S, Cobelens F. How do the new definitions for multidrug-resistant tuberculosis treatment outcomes really perform? J. Respir. Crit. Care Med. 192(1), 117 (2015).
  6. Udwadia Z, Furin J. Quality of drug-resistant tuberculosis care: Gaps and solutions, Clin. Tuberc. Other Mycobact. Dis. 16, 100101 (2019)
  7. Ranjbar S, Haridas V, Nambu A et al. Cytoplasmic RNA sensor pathways and nitazoxanide broadly inhibit intracellular Mycobacterium tuberculosis iScience, doi:10.1016/j.isci.2019.11.001 (2019)
  8. Stockis A, Allemon AM, De Bruyn S, Gengler C. Nitazoxanide pharmacokinetics and tolerability in man using single ascending oral doses. J. Clin. Pharmacol. Ther. 40, (5) 213–220 (2002)
  9. Lewin AR, Reid LE, McMahon M, Stark GR, Kerr IM. Molecular analysis of a human interferon-inducible gene family. J. Biochem. 199 (2), 417–423 (1991)

[i] Lewin AR, Reid LE, McMahon M, Stark GR, Kerr IM (Aug 1991). “Molecular analysis of a human interferon-inducible gene family”. Eur J Biochem. 199 (2): 417–423.

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