Universidad Nacional del Noroeste de la Provincia de Buenos Aires - Investigación
February 29, 2016 | 11 ′ 51 ′′
It is a disease that affects a third of the world population. Despite many people are infected, they never develop it. “It is the second death cause by an infectious agent and it represents the fourth part of avoidable mortality in under developing countries”, warns the UNNOBA specialist Virigina Pasquinelli, who investigates the disease’s genetic factor.
There is a popular suspicion that associates tuberculosis with an almost eradicated disease which affects only minority groups. However, this belief is far from reality: it is estimated that a third of the world population is infected in a “latent” state, which implies that a ten percent will end up developing the disease “actively”.
Tuberculosis is a contagious bacterial infection that compromises the lungs, but can spread to other organs. The most representative bacterium of this pathology is Mycobacterium tuberculosis or Koch’s bacillus. The classic symptoms imply chronic cough with blood-tinged sputum, fever, night sweat and loss of weight. The infection of other organs causes a wide variety of symptoms.
“Contrary to what people think, it is very difficult to eradicate tuberculosis. After 22 years of the sanitary emergency declaration emitted by the WHO, tuberculosis represents a first magnitude public health threat despite the availability of a cheap and efficient treatment”, explains Doctor Virgina Pasquinelli to Argentina Investiga and adds: “It is the second death cause by an infectious agent and it represents the fourth part of avoidable mortality in developing countries. The statistics are alarming: there are nearly 9 million ill people in the world according to a report from 2013 and 8,500 new cases during 2013 in our country”.
Although the bacterium is “highly pathogenic”, that is, low doses are needed for contagion, most people can control the germ thanks to their immune system. This is known as “latent tuberculosis”, which is later detected by small granulomas in the lung of the person who was in touch with the bacterium or by means of tests which detect the immune answer to the bacterium. “An individual can have latent tuberculosis all his life not knowing it. But it is important to say that of all those who have latent tuberculosis, ten percent will develop it in an active way”, warns the UNNOBA researcher. “We have to say that the person who is in the latent period does not transmit the disease”, she adds.
Although it is frequent to develop the disease with delay after a previous “latency” stage, it is possible to develop tuberculosis “primarily”. “That is, I infect and I am ill. This is more common in patients that have some kind of immunodeficiency, like HIV”, states Pasquinelli. “It also occurs in children and that is why it is very important to apply the BCG vaccine, which protects against the most severe cases of tuberculosis”, she warns.
But, why is it that not all the infected people develop the disease? Are there factors that predispose to contagion and later “activation” of tuberculosis? Undoubtedly, smokers, immunosuppressed and malnourished people and diabetic people are more prone to contract and develop the disease. One of the most important factors is environmental: “When there is deficiency of vitamin D [which is activated by the sunlight], the person is more prone. Besides, the time of exposure to the pathogenic agent has to be considered”, says the scientists and exemplifies: “There are many cases in textile factories of Gran Buenos Aires, where a lot of people work in basements without ventilation. So, if someone with active tuberculosis coughs, the healthy people have more chances to contract the disease”.
However, the environmental is not the only factor: we have to consider the genetic factor, which is investigated by Pasquinelli, as it is the focus of the research developed at the University. “On the one hand, the patient’s genetics and on the other, the pathogenic agent’s genetics. There are more severe strains than others. That is a factor which is not studied many times, and it is fundamental”, she explains.
In addition to multi-resistant strains, that is, resistant to many antibiotics, there are ultra-resistant strains, which “are resistant to practically any drug”. “The mortality rate in individuals with this infection is very high”, warns Pasquinelli. The disconcerting about this data is that the generation of these virulent bacteria is, in part, responsibility of the patients, as it is associated to treatment abandonment: “To be cured, the patient has to take the antibiotics for six months. The first month, the bacterial charge decreases a lot and the person starts to feel better: they have less night sweat and the cough and fever decrease. That is why, many times, they decide to abandon the treatment, neglecting the medical advice. After a while, the patient reactivates the disease and increases the risk of appearance of a resistant variety”.
Immune to tuberculosis
One of the most surprising aspects of the disease is that there are individuals that despite being in contact with the tuberculosis bacillus never get the infection or develop the disease in a “latent” way. One of the research lines developed by Virginia Pasquinelli in the UNNOBA is the basis for one of the research lines she develops: “The early detection of the pathogenic agent by the innate immune answer is one of the key factors that might mediate resistance to tuberculosis”.
The immune system recognizes the pathogenic agent from the beginning and after that, the “macrophage” start to act. Pasquinelli describes them as the “pacman of the immune system”: “They eat and kill the pathogenic agent, in this case, the tuberculosis bacillus”, explains the scientist. Then, she explains: “There is a molecule we study; it is called SLAM. Our hypothesis is that SLAM might act as a microbiological sensor of mycobacteria: this is to recognize the pathogenic agent, getting into the cell and leading it to certain structures whose function is to kill the bacterium quickly. The innate immune system is quick, although not specific: it recognizes certain structures or general patterns that are present in the pathogenic agents”.
Unlike the “innate” answer, the adaptive immune answer is more specific and has the chance to generate immune memory, the principle of vaccines. “That is, it remembers the pathogenic agent and if we are infected again, as it has an immunological memory, it is more efficient in this second encounter with the bacterium”, explained the scientist of the UNNOBA.
As the “innate immune answer” generates conditions and regulates the “immune adaptive answer”, for Pasquinelli it is crucial to study the first one: “In the case of tuberculosis, one of the things observed is that the cells of the immune adaptive answer take a long time to reach the infection place: in general, the lung. And that delay is what prevents up from controlling the pathogenic agent. So, we would tend to think that if we improve the innate answer we will improve the adaptive answer”. “We are looking for some molecule or mediator that can increase the macrophage’s function and improve the immune answer in face of tuberculosis”, she synthesizes.
In the future, the research might permit to provide the information to design treatments with immunotherapies that enable to prevent the activation of the disease in individuals with latent tuberculosis (of which, it is known, a ten percent will develop the disease). Pasquinelli explains: “Monoclonal antibodies act shooting or blocking a co-stimulating molecule. SLAM is precisely a co-stimulating molecule. If we discover that this molecule has a very important function in unchaining a protective immune answer, it is not so unlikely to think that we can have a monoclonal antibody in the future that can help to increase the molecule’s function. It is to set the bases of mechanisms that can help to design immunotherapies”.
Another research line of Dr. Pasquinelli at the UNNOBA points to study genetic susceptibility markers: “We try to see different variations in the genes of healthy, latent or ill individuals and how these variations can be associated to higher susceptibility to develop the disease or doing it more severely. We are studying genetic variations in genes we know that have a definite answer in the immune answer to tuberculosis and we try to search for susceptibility markers to develop the disease”.
A romantic disease
Tuberculosis was also called “The White Plague”, and it is one of the most antique diseases of humanity; there are paleontological evidences that it existed 8000 years before Christ. It was responsible for a fourth part of the deaths between 1400 and 1600. Between 1600 and 1800 it was epidemic in Europe, causing millions of deaths, particularly among the poor classes.
“The White Plague”, as it was known, not only referred to the ill people’s paleness, but also to the fact that it affected mainly young people. The most striking is that in the nineteenth century, the weak faces of tuberculous patients were considered attractive for beauty models that time. This deadly disease became a “romantic disease”, described by poets like John Keats and George Lord Byron, and writers like Edgar Allan Poe, Robert Louis Stevenson and Emily Brontë, many of whom died of tuberculosis.
Edgar Allan Poe described his wife Virginia like “delicate, morbid and angelical”. In 1842 Virginia had a cough attack, which Poe described like this: “Suddenly she stopped, took her throat and a wave of red blood run along her breast… she became even more ethereal”. Emily Brontë describes the heroin of Wuthering Heights as “thin” and with eyes that “shone like diamonds”. The author, his mom and siblings died of tuberculosis.
Although it was associated to “poetic inspiration” which was a privilege of the bourgeoisie and high social classes, it was a disease that affected poor people to a large extent. Undoubtedly, overcrowding and malnutrition in many sectors, which propitiated the Industrial Revolution, offered the conditions for the disease to spread.
Robert Koch identified the bacillus in 1882, showing that the disease was contagious. It was later, in 1943 that an efficient treatment was found: streptomycin, the first of a series of antibiotics that proved to be effective against the bacterium.
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