Help Stop TB
Project information
The tuberculosis (TB) bacterium has an outer coat that protects it from treatments and a patient’s immune system. The Help Stop TB project is aimed at helping scientists to better understand that coat and its role in protecting the bacteria. This understanding can help us and other scientists to design better drugs against TB in the future.
The outer protective coat of the TB bacteria contains a class of waxy or fatty molecules called mycolic acids. These are long, chain-like molecules of varying length and structure, and although they can be classified into three main groups, there are many variations within these groups that have not been modeled before.
By using World Community Grid to simulate the interactions of these molecules and their variations along with other molecules present in the coat, scientists will be able to understand for the first time how these variations affect molecule behavior. The simulation results will provide a realistic representation of the outer coat of the TB bacterium for the first time. The researchers will use these results to build a database of mycolic acid molecules that occur in the outer coat of the TB bacteria, allowing scientists to better understand how this outer coat protects the bacteria from drugs and the host immune system.
By using World Community Grid to simulate the interactions of these molecules and their variations along with other molecules present in the coat, scientists will be able to understand for the first time how these variations affect molecule behavior. The simulation results will provide a realistic representation of the outer coat of the TB bacterium for the first time. The researchers will use these results to build a database of mycolic acid molecules that occur in the outer coat of the TB bacteria, allowing scientists to better understand how this outer coat protects the bacteria from drugs and the host immune system.
The results will provide a detailed understanding of the conformational behavior of mycolic acids, which can shed light into their biological role and how it is linked to their folding pattern. With these details, we will have a greater understanding of how mycolic acids help the TB bacterium to survive and spread.
Additionally, we will be able to create a database of structures that will be used to build a detailed model of the bacterium’s outer layer. This model will be used to investigate the bacterium's biological properties further, and to assess how this knowledge can aid in TB drug development.
Additionally, we will be able to create a database of structures that will be used to build a detailed model of the bacterium’s outer layer. This model will be used to investigate the bacterium's biological properties further, and to assess how this knowledge can aid in TB drug development.
Tuberculosis is a disease caused by Mycobacterium tuberculosis (M. tb). The disease mostly affects the lungs, but if left untreated, can also spread to other organs and ultimately lead to death. TB is transmitted by small, airborne droplets resulting from coughing or sneezing from an infected person.
One factor in the increase of TB infection is related to an increase in HIV infection. People with HIV/AIDS have a weakened immune system and are therefore more susceptible to TB. Once healthy people come into contact with the TB bacteria, the bacteria can usually be fought off effectively by their immune system without developing TB. However, a person with HIV is about 30 times more likely to develop TB disease, due to their weakened immune system. It is more difficult to detect and treat TB in an HIV-infected individual, and therefore those co-infected with TB and HIV often remain reservoirs of TB for extended times, with the potential of infecting more people.
Another factor in the increased TB infection is the TB bacteria becoming increasingly resistant to TB drugs. As drug resistance has increased, it has become more difficult to treat TB successfully, requiring much longer treatment times with combinations of drugs. Often, patients fail to continue treatments to the full term which can take up to two years. When treatment stops part-way, the bacteria evolve resistance to the drugs because it lets the bacteria that survived the initial portion of treatment live and infect others. This also results in people carrying TB for a longer time, potentially infecting more people with drug resistant strains of TB that are more difficult to treat. The World Health Organization recently ranked tuberculosis as nearly tied with HIV as the deadliest infectious disease in the world, mostly due to TB building its resistance to drugs.
Another factor in the increased TB infection is the TB bacteria becoming increasingly resistant to TB drugs. As drug resistance has increased, it has become more difficult to treat TB successfully, requiring much longer treatment times with combinations of drugs. Often, patients fail to continue treatments to the full term which can take up to two years. When treatment stops part-way, the bacteria evolve resistance to the drugs because it lets the bacteria that survived the initial portion of treatment live and infect others. This also results in people carrying TB for a longer time, potentially infecting more people with drug resistant strains of TB that are more difficult to treat. The World Health Organization recently ranked tuberculosis as nearly tied with HIV as the deadliest infectious disease in the world, mostly due to TB building its resistance to drugs.
HIV, TB and malaria represent three major infectious diseases. TB is second only to HIV and the combination of HIV and TB is particularly serious since one infection promotes the other. TB and HIV each accounted for about 1.1 to 1.2 million deaths in 2014. Malaria accounted for over 500,000 deaths in 2013.
Most people who come into contact with TB do not become ill with the disease, but those who are malnourished or have weakened immune systems, such as HIV patients, are more susceptible to developing the disease once they have been exposed to the bacteria. In addition, poor living conditions and overcrowded places are the ideal conditions for TB to spread through coughing or sneezing of infected individuals.
You can help stop TB by joining World Community Grid and donating your computerâs spare computing time to this project.
It is quite common for TB patients to suffer from discrimination. Fear of infection is the most common cause of TB stigma. TB stigma has serious socioeconomic consequences and it is thought to increase diagnostic delay and treatment noncompliance. The disease is also associated with factors that can themselves create stigma, such as poverty and HIV. TB patients who are discriminated against may be isolated socially, especially in small communities. TB also has a serious economic impact, especially in developing countries. The growing cost of TB medical care is a constant drain on health systems, rendering developing countries unable to provide proper medical care for their patients.
Scientific background
Tuberculosis, or TB (short for tubercle bacillus), is an infectious disease caused by a bacterium called Mycobacterium tuberculosis. In the past, the disease was also called phthisis, from the Greek 'φΘίσις' which means 'decay', or consumption, because of the extreme weight loss TB patients suffered. TB is an airborne disease, which means that it spreads through the air when people with an active TB infection sneeze or cough.
Tuberculosis has plagued humankind throughout history and prehistory. Mycobaterium tuberculosis may have killed more people than any other microbial pathogen. It has existed for over 20,000 years and has been discovered even among Egyptian mummies. Evidence of TB is also found in the Middle Ages, when it was known as the “king’s evil” and was believed to be curable by the touch of a king. In the 18th century, TB reached epidemic proportions in Western Europe and North America, earning the nickname “White Plague.” In 1882, Robert Koch discovered that the causative agent of the disease was Mycobacterium tuberculosis. Around 1921, Albert Calmette and Camille Guérin developed a vaccine (BCG) against it and in 1944, streptomycin was the first antibiotic successfully used against the disease. The first oral mycobacterial drugs, rifampicin and isoniazid, followed.
TB symptoms include chronic cough with blood-tinged sputum, fever, breathlessness, chest pain, night sweats, fatigue and weight loss.
Tuberculosis typically attacks the lungs (pulmonary TB) but it can also develop in areas outside the lungs (extrapulmonary TB), such as the bones and joints, the digestive system, the bladder and reproductive system, the nervous system and the lymph nodes. Extrapulmonary TB is more common in people with a weakened immune system, such as HIV patients
TB diagnosis and treatment are very complex. Diagnosis is long, with several tests usually needed to diagnose active TB, including chest X-rays, sputum samples, microscopy and culture, CT scans and biopsies. Treatment is also long, with regimens consisting of six to nine months or more of multidrug therapy. Patients can also fall ill with what is known as latent TB infection (LTBI), which means that they are infected with TB but they don’t manifest the clinical symptoms of the disease. It is estimated that one third of the world’s population has LTBI and although they don’t have active TB they may develop it in the future. The available diagnostic tools for LTBI have serious limitations in terms of both accuracy and effectiveness, thus leaving many cases undiagnosed.
Mycobacteria are naturally resistant to antibiotics due to being surrounded by a waxy coat of lipids, called mycolic acids. This waxy coat protects the bacterium and makes it impermeable to most antibiotics. This means that even after the lengthy process of diagnosis, it is still very difficult to establish which combination of antibiotics might be successful against the bacterium.
Mycobacteria are naturally resistant to antibiotics due to being surrounded by a waxy coat of lipids, called mycolic acids. This waxy coat protects the bacterium and makes it impermeable to most antibiotics. This means that even after the lengthy process of diagnosis, it is still very difficult to establish which combination of antibiotics might be successful against the bacterium.
The usual course of treatment for pulmonary TB is two antibiotics (isoniazid and rifampicin) every day for six months and two additional antibiotics (pyrazinamide and ethambutol) every day for the first two months. It may be several weeks or even months before the patient starts feeling better. Such long treatments cause implications such as increased relapse risk, serious side effects from the drugs (such as loss of appetite, nausea, dizziness, abdominal pain and blurred vision), increased risk of clinical hepatitis, especially in cases of underlying liver disease, and, crucially, treatment noncompliance.
Additionally, there are strains of TB which are resistant to nearly all antibiotics used to treat TB. Patients with drug-resistant TB need to receive special medical treatment that can potentially cause more side effects, such as depression or psychosis, hearing loss, hepatitis, and kidney impairment. These patients will also be under greater risk of dying from the disease. Resistant TB treatment is extremely challenging as it is very expensive, lengthy and disruptive for the patients’ lives
Streptomycin, isolated from the bacterium Streptomyces griseus, was discovered in 1944 as the first antibiotic with proven activity against TB. The development of isoniazid followed in 1952, as the first oral mycobactericidal drug. This breakthrough would introduce combination therapy which reduced the typical therapy duration which up until then lasted for more than 18 months. The Medical Research Council (MRC) TB unit in the United Kingdom, in collaboration with the United States Public Health Service (USPHS), spent the next forty years developing the current treatment scheme consisting of isoniazid, rifampicin, pyrazinamide and ethambutol. The introduction of rifampicin in the therapeutic course in 1968 allowed treatment times to be shortened to 6 months when used in combination with pyrazinamide.
Currently there is one approved vaccine for TB, the Bacille Calmette Guérin (BCG) vaccine, developed in 1921. However, it is 70-80% effective against the most severe forms of TB, such as TB meningitis in children, and it is less effective in protecting from respiratory TB which is the most common form of the disease in adults. Also, it is not possible to receive booster BCG shots later in life. While several new vaccines are in development, none are yet approved for use. The data that we will produce with your help will shed light on the biological role of the bacterium’s defense to antibiotics, thus contributing to the efforts of developing new vaccines.
Resistant TB strains occur for a combination of reasons. The cell wall of the bacterium has a natural permeability barrier formed by mycolic acids (a class of waxy compounds) that protects the bacterium from drugs. Gene mutations in the bacterium can also lead to the development of resistant strains. Completion of antibiotic treatment in diagnosed TB cases is crucial. The long treatment times often discourage patients from completing their treatment, thus paving the way for resistance to develop. Finally, especially in developing countries, antibiotics often are scarce and of poor quality, thus contributing to the rise of resistant strains.
Project graphics
Here is a video of the Help Stop TB screensaver:
The right portion of the screen saver shows both the cell wall molecules and surrounding molecules, depicted as a collection of small spheres that represent the atoms of each molecule. These are the specific molecules that your device is currently working on.
The progress bar, towards the bottom of the screen saver, represents approximately how much of the current task your device has processed. When it reaches 100%, the computation is complete and the results will then be sent back to World Community Grid, where they will be packaged and delivered to the Help Stop TB researchers.
The small spheres represent the atoms in both the cell wall molecules and surrounding molecules currently being processed by your device.
The University of Nottingham, in the United Kingdom, was rated No. 8 for research power in the 2014 Research Excellence Framework and is the home of the research team behind the Help Stop TB project.
