African scientists make headway in grasping persistent TB bacteria

Sierra Leone Telegraph: 21 May 2016


In 2015, Tuberculosis (TB) killed 1.5 million people worldwide, and an estimated 26,000 people are infected each day. Prevalence is highest in sub-Saharan Africa, from Ethiopia to South Africa, and in Asia, particularly in India and China.

The disease is caused by Mycobacterium tuberculosis, an organism that has caused infection in humans since the stone age.

And it’s airborne – aerosols containing the bacterium remain suspended in rooms for hours after being coughed out by a person with tuberculosis. Once inhaled, the mycobacterium has a very real chance of taking up residence in your lungs, where it can lead to one of two conditions: latent TB and TB disease.

In Sierra Leone TB contributes dramatically to the burden of disease on the country’s crumbling health system, which has the third-highest prevalence of TB in the world (4). One of the priorities of the Ministry of Health and Sanitation is the control of tuberculosis (TB).

With an estimated prevalence of 574 cases per 100 000 population and new smear-positive cases of 247 per 100 000 population, the burden of TB is increasing in Sierra Leone.

The number of TB diagnostic centres in Sierra Leone increased from 116 in 2009 to 148 in 2010.[2] Anti-TB drugs provided by the Global Drug Facility are widely available in sufficient quantities across the country and there is satisfactory drug flow from the German Leprosy and Tuberculosis Relief Association drug stores to the districts.

District supervisors in Sierra Leone provide supportive supervision at all Directly Observed Chemotherapy Short Course (DOTS) centres monthly, while the National Leprosy and Tuberculosis Control Programme (NLTCP) and district health management teams jointly carry out quarterly supportive supervision.[2] Quality laboratory services are a key component in the control and management of TB. Diagnostic and management TB services are carried out in all DOTS centres. Diagnoses and treatment of TB cases is free of charge to patient at all DOTS centres in the country.

Clinical lead Doctor Al Story points to an x-ray showing a pair of lungs infected with TB (tuberculosis) during an interview with Reuters  on board the mobile X-ray unit screening for TB in Ladbroke Grove in LondonPeople with latent TB are infected, but don’t have symptoms and can’t transmit the disease.

However, latent TB can transition to TB disease when a person’s immune system is suppressed, because of an HIV infection or malnutrition, for instance.

In the West, people with latent TB are treated to prevent the infection from becoming active. About one-third of the world’s population has latent TB.

TB disease, on the other hand, is infectious. The body’s response to the bacterium leads to a hypermetabolic state, draining nutrition from the body, leading to loss of weight or wasting.

With your metabolism in overdrive, you become a skeletal vestige of yourself, waking up drenched in sweat each night.

This is accompanied by a fight between the bacterium and immune system, which takes place in your lungs, leaving you with a persistent hacking cough that ends up producing a literal bloody mess.

A person with TB disease is contagious for as long as they have TB symptoms. If untreated, it will probably kill you and could spread to people who live and work with you.

TB1But as Jomien Mouton and Samantha Sampson writes in, African scientists are making headway in grasping persistent TB bacteria. This is what they say:

The arrival of drug-resistant tuberculosis has significantly complicated global efforts to decrease the scourge of the disease.

Each year more than nine million people are infected with TB and another 1.5 million die. But the latest figures show that at least 20% of people diagnosed with the disease have “multiple-drug-resistant” TB. And about 9.7% of these also have “extensively-drug-resistant TB”.

TB is caused by bacteria that attacks the lungs. Most TB treatments target bacteria that actively grow in the body. But a very important subset of bacteria is able to survive treatment. These are known as persistent bacteria.

Though these persistent bacteria only represent a very small proportion of the bacteria that causes TB, failing to get rid of them can have devastating consequences. They are responsible for lengthy drug treatment, and could contribute to drug resistance. They therefore should also be the target of TB therapies.

The challenge with these persistent bacteria is that they are very difficult to isolate. This makes it difficult to study them and therefore difficult to develop drugs to kill them.

As a team of scientists at Stellenbosch University in South Africa, together with colleagues at Imperial College London, we found a new way to identify, isolate and target persistent bacteria. 

Our technique, which has never before been applied in TB research, will help scientists understand why some bacteria respond to treatment and others become resistant.

How this bacteria works

Persistent bacteria plays a particularly important role in latent TB – when bacteria that can cause TB hibernate in the body. Someone with latent TB will not have any clinical symptoms and will therefore not know that he or she has the disease.

Latent TB can survive in the body for decades and only flare up when someone’s immune system is compromised.

Latent TB can therefore progress to full-blown disease in people who have compromised immune systems. These are often people who have HIV/AIDS, suffer from malnutrition, are ageing or have a substance-abuse problem. About one-third of the world’s population carries latent TB.

Conventional thinking has held that persistent bacteria are also present in people who have latent TB. These bacteria are thought to either stop growing or are slowly growing, although they still survive in the body.

But emerging research has started to question this assumption on two fronts:

  • Some research shows that proportions of the bacteria continue to grow while others die.
  • Other research argues that the bacteria do not grow.

Understanding the bacteria present in latent TB is important to choose the best TB treatments. This is especially important because of the difficulties associated with treating persistent bacteria that can survive treatment.

For this reason our research is focused on finding ways to study and target persistent bacteria. We used specific bacteria-associated labels and sophisticated laser-based methods to identify and isolate this bacteria.

TB2A new method to study persistent bacteria

The technique, known as fluorescence dilution, uses two fluorescent proteins to label the bacteria.

One protein tracks live bacteria and the other measures its growth. It is applied to identify and isolate individual bacteria to study it.

The technique can best be described as using “micro-tweezers” to physically pick out the slow-growing bacteria from the rest. This enables us to find the hard-to-identify persistent bacteria.

We were able to do this by applying the same approach that’s been used to isolate the bacteria that causes food poisoning, Salmonella. This involves subjecting the bacteria to conditions that come closest to those found in the body as opposed to conditions in the laboratory.

Using this technique, we found that when bacteria entered a specific type of white blood cell, a population of non- or slowly-growing persistent bacteria appeared. White blood cells play a critical role in defending the body against invading bacteria. In the laboratory we use them to mimic the environment found in the body.

This finding is important because it shows that the numbers of persistent bacteria increase by being inside white blood cells. This means that the host’s own defences can help the bacteria to survive TB treatment.

Hope for the future

These are only the first steps, but this technique offers unique opportunities to deepen scientists’ understanding of why and how the body’s response to TB treatment results in drug resistance.

We can now, for example, begin to study what drives bacteria into a latent state. Once we understand this better it will be possible to begin designing drugs that better manage latent TB. Importantly, this could help decrease the amount of time it takes to treat TB as well as minimise drug resistance.

About the authors

Jomien Mouton is a postdoctoral research fellow in the MRC Centre for Tuberculosis Research, Stellenbosch University; and Samantha Sampson is  Associate Professor, SARChI Research Chair in Mycobactomics, Stellenbosch University.

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