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Research: Help Stop TB: Project Details Collapse   Expand  
About the Project

The Problem

Tuberculosis (TB) is one of the biggest global killers with the World Health Organization (WHO) reporting 9 million newly diagnosed cases and more than 1.5 million people who died from the disease in 2014. More than half a million cases were reported in children less than 15 years old.

Within the Western world, the threat of TB has decreased through diligent treatment and containment, to the point where much of the general public does not regard this disease as a risk. Nevertheless, an increase in multi-drug resistant strains and a rise in HIV infection, combined with decreasing vaccination rates in some regions, has led to a resurgence in TB. Recently awareness of this disease has been raised through the annual commemoration of World TB day on March 24th.

What is Tuberculosis
TB is caused by infection from Mycobacterium tuberculosis bacteria (M. tb). It is spread by droplets produced by sneezing or coughing of an infected person. After initial infection, if not cleared, the M. tb bacteria enter a dormant state, where they are able to evade detection from the body's immune system. However, this means that the infection can reappear months or even years later.

Typical symptoms of an active TB infection include persistent cough, fever, loss of weight, and night sweats. If the infection is left untreated, the bacteria are likely to cause increased damage to the lungs and spread throughout the body, infecting other organs. Such rampant infection may ultimately lead to death. Treatment for an uncomplicated TB infection lasts over 6 months and requires a combination of antibiotics. If treatment is not effective, or is terminated too soon, the bacteria become resistant to the drugs, followed by a spread of the infection if left unchecked.

M. tb is a particularly old disease, with cases being identified from human burials from more than 4000 years ago, and evidence from fossilized bison that the disease is at least 17,500 years old. The disease was particularly endemic in North America and Europe from the 17th to 19th centuries and is it thought to have killed more people than any other microbial disease in history. Control of TB in these regions started to be achieved after World War II, with the mass acceptance of the BCG vaccine, combined with introduction of one of the first antibiotics effective against the bacteria, Isoniazid, in 1952, followed by another class of antibiotics, the rifamycins in 1957.

Multidrug resistance
Bacterial resistance against the drugs available to treat TB is on the increase throughout the world and is making TB treatment even more challenging. Currently around 500,000 diagnosed cases are of multi-drug resistant TB (in these cases M. tb is resistant to Isoniazid and Rifampicin). A more dangerous, extensively drug-resistant (XDR) form of TB, where M. tb is resistant to the other available drugs in addition to Isoniazid and Rifampicin, has been reported in 100 countries. As these drugs lose their effectiveness, the threat of TB infection worldwide rises.

Tuberculosis and HIV
TB infection is a particular challenge in areas where Human Immunodeficiency Virus (HIV) infection is high, such as sub-Saharan Africa, and co-infection rates are estimated to be as high as 13% of the total cases. People who have both these diseases are far more likely to die, and have been harder to diagnose because of the lack of standard immunomarkers. Treatment with standard HIV drugs for patients with a latent TB infection can lead to severe complications, known as TB-immune reconstitution inflammatory syndrome (TB-IRIS), so early diagnosis and treatment of TB is critical.

Related diseases
Mycobacterium tuberculosis is part of the family of mycobacteria. Other diseases in this family include bovine TB that infects cattle and badgers (M. bovis), avian TB, that can infect HIV patients (M. avium), leprosy (M. leprae), and Buruli ulcer (M. ulcerans).

The Proposed Solution

Mycobacteria have a highly unusual outer coat, which is important for their survival and provides protection from both incoming drugs and the host immune system. We know that changes to this outer coat can result in much less dangerous bacteria. Help Stop TB is specifically targeting molecules from this outer coat.

What is special about the M. Tb outer coat?
Most bacteria have an outer coat or membrane that helps to protect them from the outside environment. These membranes typically consist of a mixture of fats, sugars and proteins, all with different functions. In particular, the fats act as a barrier against water and other water-soluble molecules from entering the bacteria. M. tb and other mycobacteria have an additional layer of fats in their cell wall. These fats are 3-5 times longer than those from other bacteria and contain a highly unique chemical signature. These special fats are known as mycolic acids, and are the molecules of interest for this project.

Immune response and the M. Tb outer coat
Mycolic acids and their derivatives are sometimes able to break free of the M. tb cell wall, and these free mycolic acids have been shown to initiate a variety of immune responses. More importantly, in HIV infected patients, they can activate alternative immune responses to those that are normally shut down in HIV infection, to give us a potential alternative way to identify TB exposure rapidly through blood tests. How mycolic acids can act as antigens (promoters of the immune response) is closely linked to how these molecules are able to fold, what shapes these folds take, and how tight these folds are. Part of the information that we are gathering for Help Stop TB will give us insight into this phenomenon.

Project Goals

The specific goals of the Help Stop TB project are:

To create a database of mycolic acid structures, covering the different variations found in the naturally occurring molecules.

To discover how these variations impact the way that these molecules fold - both in water and in more membrane-like (cell-wall) environments.

To obtain the simulation data needed in order to create full-scale membrane models that will directly contribute to a better understanding of the molecule's behaviour in its natural environment

To better understand the different effects mycolic acids and their derivatives have on the immune system.

The specific goals listed above are ultimately a way of improving our understanding of how TB protects itself from drugs and attack from the host's immune system, with the broader goal of developing strategies that evade these defences.

Other resources:

To learn more about TB:

World Health Organization: http://www.who.int/topics/tuberculosis/en/

Centers for Disease Control and Prevention: http://www.cdc.gov/tb/

National Institute of Allergy and Infectious Diseases (NIAID): https://www.niaid.nih.gov/topics/tuberculosis/Pages/Default.aspx