Tuberculosis — or TB for short — is as old as humanity itself. It is caused by Mycobacterium tuberculosis, an exclusive human pathogen. According to the World Health Organization, in 2013, 9 million people fell ill with TB and 1.5 million died from the disease worldwide.
Although it is difficult to estimate the number of deaths caused by TB throughout history, we know that M. tuberculosis has been an ever-present scourge for humanity, and may have killed more people than any other microbial pathogen. Indeed, TB has been given many unpleasant names. From Hippocrates through to the 18th century, it was known as phthisis and consumption. During the 19th century, TB was called the white death and the great white plague. Other “historical” TB names aptly evoke images of despair and horror — the robber of youth, the captain of all these men of death, the graveyard cough, and the king’s evil.
The long-standing relationship between M. tuberculosis and humans has been present not just for a few thousands of years, but for much longer. In 2013, researchers “found evidence that TB hitched its cart to the human evolutionary horse more than 70,000 years ago, before our ancestors migrated out of Africa.” They published their findings in the scientific journal Nature Genetics. Sebastien Gagneux, an infectious diseases specialist at the Swiss Tropical and Public Health Institute in Basel and senior author of the study, said: “The old, traditional view was that tuberculosis emerged during the Neolithic transition when people started to domesticate animals and develop agriculture, which started about 10,000 years ago. Our work suggest that TB is really much older.” The researchers explained in their paper that different strains of M. tuberculosis accompanied migrations of modern humans out of Africa, and expanded as a consequence of increases in human population density during the Neolithic period.
Between the 17th and the 19th century, TB caused about 20% of all human deaths in the United States and in Europe. Until the early 20th century, people infected with tuberculosis were isolated from society and placed in sanatoriums — self-contained communities that, not surprisingly, became known as “waiting rooms for death.” Now, a new study published in the journal Nature Communications, reveals how TB took hold in 18th century Europe. The researchers analyzed samples from mummies found in a Hungarian crypt, and found evidence of multiple tuberculosis strains derived from a single Roman ancestor that circulated in the 18th-century. Mark Pallen, senior author of the study, said in a press release: “Microbiological analyses of samples from contemporary TB patients usually report a single strain of tuberculosis per patient. By contrast, five of the eight bodies in our study yielded more than one type of tuberculosis — remarkably from one individual we obtained evidence of three distinct strains.”
The samples originates from a crypt, re-discovered in 1994, located in the Dominican church of Vác in Hungary. It contained the remains — which had undergone natural mummification — of over 200 individuals, mostly affluent Catholics from the eighteenth and early nineteenth centuries.
The researchers used a technique called “metagenomics” to identify TB DNA in the historical specimens — the technique draws on the remarkable throughput and ease of use of modern DNA sequencing technologies, and allows sequencing of DNA directly from samples, without the need of growing bacteria or deliberately fishing out TB DNA. The researchers found that the samples carried the genetic signature of M. tuberculosis Lineage 4, a strain that today accounts for more than a million TB cases every year in Europe and the Americas.
Pallen said: “By showing that historical strains can be accurately mapped to contemporary lineages, we have ruled out, for early modern Europe, the kind of scenario recently proposed for the Americas — that is, replacement of one major lineage by another — and have confirmed the genotypic continuity of an infection that has ravaged the heart of Europe since prehistoric times.” He added that the struggle to contain TB is far from over, and concluded: “We have shown that metagenomic approaches can document past infections. However, we have also recently shown that metagenomics can identify and characterize pathogens in contemporary samples, so such approaches might soon also inform current and future infectious disease diagnosis and control.”
As old as this disease is, it’s interesting to note that our immune system is still incapable of effectively eliminating the pathogen in our body. You would think that after all of those thousands of years to exposure to the pathogen that our immune system would have evolved an effective mechanism to fight it off. But this can also suggest that the mycobacterium has evolved its own mechanism to evade or inactivate our immune response. For example, once the mycobacterium is engulfed by macrophages, they are able to inhibit the fusion of the phagosome-lysosome complex and escape degradation. The resistance to antibiotics by some strains of mycobacterium also shows support of their ability to overcome such attacks. The most important method of combatting the mycobacteria involves further research and understanding of our immune system and the mycobacteria’s mechanisms of escape. With a better understanding of the mycobacteria’s escape mechanisms, we could potentially build a more effective vaccine that targets these mechanisms to prevent tuberculosis altogether.
Yes I agree that because we have encountered it so many times in history we should be immune to TB. However, mycobacterium bacteria have been evolving for much longer than the human population has. This takes me to the Red Queen Theory which goes along the lines that one organism is evolving in response to another organism evolving leaving both organism at sort of a stand still. Because every time our body adjust to TB and becomes available to fight it off, TB evolves again to outmaneuver our immune system. Any research would need to go into seeing about a preemptive attack, as in being able to predict how the mycobacterium would change in response to adapting immunity.
One could ague that one of the most relevant take home messages from Pallen and his colleagues’ study is that there is now sound evidence correlating the genetic conservation of certain strains of M. tuberculosis and the ability of a single individual to be infected with multiple strains of TB within the same period of time. Consequently, this revelation plays an important role in studies focused on drug resistant strains of tuberculosis and the biological mechanisms at play which might contribute to evasion of certain drug therapies. For instance, Plazzotta et al. contends that detected mixed infections account for 10-20% of tuberculosis cases in areas in which incidences of TB are high, further asserting that this frequency is a considerable underestimation due to challenges in current diagnostic techniques. In fact, mixed infections cases have typically yielded poor treatment outcomes due, in part, to differing drug susceptibilities of co-infecting strains, which can lead to mutations conferring stronger resistance to drug therapy in particular stains. As a result, both drug resistant and drug sensitive strains inevitably compete for a susceptible host, and can even reinfect hosts already infected with one strain at a later time, giving rise to new mixed infections and drug resistant strains while also increasing the risk of transmission in high population areas. Be that as it may, current diagnostic techniques routinely used in detection of M. tuberculosis strains usually rely on cultures grown from a single strain, which often only contain the majority infecting strain and, therefore, results in misdiagnosis and inappropriate treatment in many tuberculosis cases. Moreover, Dr. Suzanne M. Hingley-Wilson proposes in her response to the article, Metagenomic Analysis of Tuberculosis in a Mummy , that improvements in diagnostic techniques which would allow for detection of mixed populations of tubercle bacilli, along with drug profiles of identified strains with varying susceptibilities, would be especially beneficial in reducing the prevalence of drug resistant strains of tuberculosis and forming tailored drug treatment therapies. Ultimately, further knowledge pertaining to the epidemiology of tuberculosis and the ways in which disease control/prevention can be regulated through drug intervention rely heavily upon the identification of different strains of TB simultaneously infecting an individual and their respective responses to different treatment methods.
The faith in the eradication of tuberculosis should not be lost. Like many other horrible diseases, tuberculosis can be rid from the world’s population. Consider smallpox, according to National Geographic , the earliest evidence of the disease is 1157 B.C. when Egyptian Pharaoh Ramses V died and his mummy was found with smallpox-like splotches on his skin. Smallpox, like tuberculosis, was a disease that caused many deaths worldwide. Through long and effective research a disease that once plagued the world is now in safe keeping only at the CDC in Atlanta, GA, and a Russian facility in Siberia. I have great faith in the technology and wonderful minds of our century to end the fight against M. tuberculosis like we won the fight against the smallpox virus.
I agree as well that the fight against Tuberculosis will be won. I believe it will take a lot more research and technological advancements before we can say the fight against TB is won. There seems to be a lot of mystery and differences in opinions about the origin of disease and how long it has been around. However with all the research that is being done to account for the disease historically, I believe researchers are beginning to finally getting closer to finding a solution to the problem. I think it is going to take a lot more work than we humans imagine. We are far behind with the knowledge of TB than we actually think. The stigmas associated with TB held many from doing research in earlier years because people were isolated and basically left to die. I know that people had no other choice because of the contagiousness of the disease and the severe consequences associated with it. Now that we have technology that can allow us to study and even trace the historical roots of the disease we are beginning to get a better understanding. I have faith that Tuberculosis will one day be eradicated, but faith without work is dead. I believe so many people have the same faith; but it will take the work of many researchers, scientists, and groups/people of interest to fund further research, advance technology, and to put it all together to accomplish the common goal of eradicating TB.
As with smallpox, the first step to the process of eradicating tuberculosis is to develop a working vaccination that rids of all TB at all levels. Smallpox was eradicated with the method of ring vaccination as stated in this article . This is a method in which all people who may have even potentially been exposed to the disease were treated with care as if they had the disease. However unlike TB small pox had highly visible signs and no latent period. Symptoms showed up almost immediately making it easier to target and treat out. Polio, like TB, is also hard to eradicate because some of the cases do not present with visible symptoms, or wait in a latent phase. If a vaccination could be produced that could effectively treat TB, ring vaccination could be performed to treat all people who may have come in contact with the mycobacteria. However this poses the issue of costs, in that not all people in all areas can afford the vaccination.
While I agree and have faith that we will one day eradicate TB as a threat I feel that we still have our work cut out for us, and it will be a number of years before we are able to reach that point. Yes, TB is similar to smallpox in the fact that it is has existed for a long time and is responsible for hundreds of thousands of deaths but when it comes to formulating a vaccine for TB these are not the similarities that are crucial. The mechanisms by which the pathogens of TB and smallpox infect us are much different. Smallpox can be recognized by our immune system and can be naturally eradicated. This means that scientists are able to formulate a vaccine using a live attenuated form of the virus in order to induce our adaptive immune response and provide us with natural immunity to the disease. Sadly, this is not the same case when it comes to TB, due to the mechanism by which mycobacterium tuberculosis infects. This bacteria essentially hijacks our macrophages and resides within them after resisting degradation within the phagolysosome, as K.Soms mentioned. Due to this nature our body is unable to eradicate the pathogen naturally and so the traditional vaccination method would be ineffective here because the adaptive immune response is not enough to eliminate the pathogen. This particular disease is one example in which unnatural immunity could be the way of the future when it comes to eradicating this disease. Unnatural immunity is a new vaccination technique that aims to induce an immunological response that differs from the natural immune response. This method of immunization aims to target diseases that can not be eradicated by the natural immune response, such as TB or HIV. This vaccination technique is still relatively new but shows promise for the future in combatting these types of disease. Even still once we are able to formulate a vaccine for TB this still leaves a problem for the world population that is already infected with the disease. These individuals would need to be treated or more gravely we would have to wait until all those infected passed away and those who remain must be vaccinated to eradicate the disease. We still have years of work ahead of us but the future is bright and I too believe we will eventually be able to eradicate TB as a threat throughout the world.
I am just learning about this but i have some questions
1.can you ever be ‘immune’ to TB without having the BCG vaccination. I have family and friends who have said that after being tested they are unable to have the BCG due to being naturally immune. (live in UK). However new guidelines would state that they be investigated for latent TB.
2. if you can’t have natural immunity, does this mean my friends should be tested for latent TB
2. if you are have a mantoux read of over 10mm (no prior BCG) but your IGRA is negative, i presume it is because you have had exposure beforehand to environmental bacteria. Can you have the BCG, if not why not? what damage is it going to do if you do have it.
Sorry if these are basic questions but getting confused.
Hi Jackie, Thanks for your questions. You might be able to find some answers on the Centers for Disease Control and Prevention website. This is the link for their TB page: http://www.cdc.gov/tb/