From Help Stop TB at WCG: “Researchers Partner with World Community Grid to Help Stop a Leading Killer”

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[I may have posted this before; but it is a worthwhile story. If you have not signed on to WCG, maybe this will give you another nudge.]

World Community Grid (WCG)

24 Mar 2016
By: Dr. Anna Croft
University of Nottingham, UK

Tuberculosis is one of the world’s most prevalent and deadly infectious diseases. Researchers from the University of Nottingham, UK, have partnered with World Community Grid to take a close look at the bacterium that causes tuberculosis, so that scientists can develop more effective treatments.

Tuberculosis (TB) is one of the biggest global killers. In 2014, there were 9.6 million newly diagnosed cases and more than 1.5 million people who died from the disease. More than 1 million of these new cases, and 140,000 deaths, were estimated for children. The World Health Organization has declared TB to be the world’s deadliest infectious disease, along with HIV. To help combat this disease, my team and I are working with World Community Grid on a [new] project called Help Stop TB.

TB is caused by infection from a bacterium known as Mycobacterium tuberculosis (M. tb). 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, which may ultimately lead to death. Treatment for an uncomplicated TB infection lasts more than six months and requires a combination of antibiotics.

I am an associate professor in the Department of Chemical and Environmental Engineering at the University of Nottingham, UK. My team and I seek to improve the understanding, and therefore the treatment, of TB. To do this, we are excited to partner with World Community Grid and its community of volunteers to study and understand the protective outer coating of M. tb, and learn how to penetrate its defenses.

Mycobacterium tuberculosis is a slow killer, often remaining dormant for long periods of time before seizing an opportunity to turn into active TB disease. Poor nutrition, old age or a weakened immune system can all precipitate the onset of active TB. It is an airborne disease, most often spreading from one person to another via a droplet from a cough entering someone’s lungs. Symptoms can start with cough, weight loss, and fever, developing into difficulty breathing and coughing up blood, and can spread to other organs.

Although a vaccine and several drugs have been developed to help combat TB, the TB bacterium has been evolving resistance to available treatments. Drug treatment can last up to two years, but when patients interrupt or discontinue treatment, the bacteria can develop resistance. This, along with inconsistent availability of drugs, and increased risk of infection for HIV patients with weakened immune systems, have all contributed to a resurgence of the disease. Nearly half of European cases are now resistant to at least one drug, and 4% of all cases worldwide are resistant to a combination of drugs.

Proposed Solution
The bacterium has an unusual coat which protects it from many drugs and the patient’s immune system. Among the fats, sugars and proteins in this coat, the TB bacterium contains a type of fatty molecules called mycolic acids. Help Stop TB will use the massive amount of computing power donated by World Community Grid members to simulate the behavior of these molecules in their many configurations to better understand how they offer protection to the TB bacteria. Scientists hope to use the resulting information to finally develop better treatments for this deadly disease.

Help Stop TB Researchers Begin First Stages of Data Analysis

21 Jul 2016

In Help Stop TB’s first project update, researcher Athina Meletiou gives an overview of why this project is important and what the team is doing with the early data.

Help Stop TB launched about four months ago, and the research team has begun the early stages of data analysis. We asked researcher Athina Meletiou to provide an overview of the project along with the first update, and to also tell us about how she came to be involved with Help Stop TB.

In the presentation below, Athina discusses the goals and importance of Help Stop TB, and gives us a behind-the-scenes look at what it takes to get a World Community Grid project ready to launch.

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.

See the full article here.

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