-->

Sunday, November 27, 2011

A novel way to fight an old foe: expression of TCRs on macrophages in granulomatous responses

Tuberculosis is caused by the bacteria Mycobacterium tuberculosis, and is characterized by an infection of the bronchi (a part of the lungs) in which macrophages (a type of white blood cell) are unable to digest the bacteria. As a result, macrophages release cytokines, small proteins, that attract T lymphocytes, which kill cells by releasing "killer proteins" and create a granuloma (a collection of immune cells surrounding infected tissue) (Knechel 2009). Tuberculosis poses a threat to the health of the world: in 2007, there were approximately 1.77 million deaths from tuberculosis—the second highest death rate of any infectious disease (Glaziou et al. 2009). It is also a highly mutative pathogen: cases of extreme-multidrug resistant tuberculosis are common, and the treatment responses are usually poor, while the mortality rates are high (Telzak et al 1995).
A recent study by Beham et al. published in PLoS pathogens examined how T-cell receptors (TCRs), which recognize a protein-complex on other cells, on macrophages affect the formation of tuberculous granulomas. To begin the study, the researchers had to establish that monocytes, precursors to macrophages, and macrophages do in fact express T-cell receptors. To do this the researchers used antibodies, proteins that target specific molecules, targeted to TCRα/TCRβ and MHC-II (this is the protein complex recognized by TCRs). From this experiment, they were able to establish that approximately 5% of monocytes expressed TCRαβ (a type of TCR). Although the presence of TCRs in monocytes appeared to be promising, the researchers continued by testing monocyte-derived macrophages from three donors. These monocytes were activated using IFNγ and IL-4, both cytokines that are responsible for initiating inflammation. The researchers found that 5% of the naïve macrophages expressed TCRs, while 9% IL-4 of and 11% of IFNγ activated macrophages expressed TCRs.


The researchers then tested to see how different the TCRs on the activated macrophages were.  Activated macrophages are cells that have come in contact with the protein (or molecule) that their TCR recognizes as well as cytokines.  They found that on macrophages activated by IFNγ the TCRs tended to be more diverse in the V region (a part of the TCR) than IL-4 activated macrophages. This becomes important when an infection is recognized in the human body. In some cases, a Th1 response (inflammatory response) is initiated, and cytokines such as IFNγ and IL-4 are released. When this happens some macrophages begin to express TCRs. Depending on the makeup of the extracellular environment, the macrophages will have a greater (or lesser) diversity of TCRs. Beham et al. then went on to test whether or not the TCR inhibited macrophage activity. By using “baits” which were beads covered in anti-TCR antibodies (targeted for TCRs), the researchers found that even after 15 minutes there was an increase in macrophage response (the increase in response was not significant until one hour however). The researchers then tested this system in vivo using Mycobacterium bovis Bacille-Calmette-Guérin (M bovis BCG) and found a response similar to the beads.

Beham et al next decided to see how the presence of mycobacteria in the macrophage influenced TCR expression and granuloma formation. Using a labeled M. bovis BCG (labeled means it can be tracked in an organism) they found that macrophages infected with the bacteria had a 400% increase in the expression of TCRs. This in turn leads to more effective clustering and granuloma formation. Interestingly, the researchers also found that a specific region of the TCR, known as the TCRvβ (T-cell receptor variable beta, another region of a TCR) region was highly conserved among the macrophages. This is important because it points to a possibility that the body has a specialized mechanism for fighting infections such as tuberculosis. Further investigation of this conserved region could lead to a better understanding of granuloma formation, and more importantly, why granulomas break apart, allowing latent infections to become active. As well, these macrophages with TCRs were found in 10 of 13 patients with pulmonary tuberculosis.

To understand why the macrophages expressed TCRs, Beham et al tested the effects of tumor necrosis factor (TNF), a cytokine associated with inflammatory and macrophage responses. They found that when blocking TNF, expression of TCRs on macrophages was suppressed within 2 hours. This suppression could be reversed however with exposure to TNF, and new TCRs would be expressed within 24 hours. This then indicates that TNF is necessary for TCR expression on macrophages. TNF blockade, a system by which TNF is blocked, caused the degradation of CD3ζ, a necessary protein for stabilization of the TCR. Understanding this allows doctors a new way to deal with tuberculosis in situations such as multi-drug resistant TB (MDR-TB) or extensively drug resistant TB (XDR-TB). Use of directed TNF as a possible aide to the immune system for forming granulomas could pose a new treatment for patients suffering from MDR-TB or XDR-TB. The researchers were then able to understand that the loss of the TCR on macrophages was associated with granuloma disorganization. By treating granulomas with anti-TNF antibodies (which remove TNF), the researchers found that granulomas dispersed, and TCR expression was suppressed.

This study sheds new light on an old foe. The classic form of treating TB with antibiotics is quickly becoming ineffective, as more programs such as directly observed treatment short-course (DOTS) are being used by the WHO and PAHO the costs of treatment and the pharmaceuticals are skyrocketing. This study, and the information that it sheds on macrophages and their role in granuloma formation (along with how the TCR and TNF affect granuloma formation) can have a huge impact in future research. It is a possibility that treatment of a patient with targeted TNF could cause an increase in TCR expressing macrophages prompting more granuloma formation and less granuloma dissolution. While the sample size of this study was small, usually around 10 patients, it signals a necessity for more research in this field. TB is on its way to become a global pandemic: it is highly infectious and fatal. Research must continue on non-classical (drug) treatments of TB and the immune response.

Primary Refrence:
Beham AW , Puellmann K , Laird R , Fuchs T , Streich R , et al. 2011 A TNF-Regulated Recombinatorial Macrophage Immune Receptor Implicated in Granuloma Formation in Tuberculosis. PLoS Pathog 7(11): e1002375. doi:10.1371/journal.ppat.1002375
Additional References
Edward E. Telzak, M.D., Kent Sepkowitz, M.D., Peter Alpert, M.D., Sharon Mannheimer, M.D., Franz Medard, M.D., Wafaa El-Sadr, M.D., Steve Blum, Ph.D., A. Gagliardi, M.D., Nadim Salomon, M.D., and Glenn Turett, M.D. (1995) Multidrug-Resistant Tuberculosis in Patients without HIV Infection. New England Journal of Medicine: 333:907-912
Glaziou P, Floyd K, Raviglione M (2009) Global burden and epidemiology of tuberculosis. Clin Chest Med 30: 621–636, vii.
Knechel, Nany (2009) Tuberculosis: Pathophysiology, Clinical Features, and Diagnosis. Critical Care Nurse: 29:34-43.

142 comments:

  1. As a man with little to no knowledge of this science, can you give me a more simplified version? 250 characters. much appreciated.

    ReplyDelete
  2. My knowledge on immunology isn't very extensive, but this entry was eye opening in that I was unaware of how large of an impact TB has on the word population. In the United States our exposure to TB is so limited that it is easy to forget that so many people worldwide suffer from its side effects. As Corey mentioned, if antibiotics are becoming less and less effective in treating the disease, then studies such as this one that directly address how the granulomas are created should be helpful in coming up with an effective treatment plan.

    ReplyDelete
  3. although researchers may find new, more effective treatments, do their expenses and technological advancements make them equally impractical as previous treatments for poorer countries where the epidemic is the worst?

    ReplyDelete
  4. John lee basically summed it up for me, I didn't know it had the second highest death rate in 2007. Not much news coverage on this in the news although it's a big deal.

    ReplyDelete
  5. Do you think this research would benefit from simply more time spent researching the science behind the disease? Or do you think that advances in technology and better tools would result in a larger impact on understanding how to come up with a more effective treatment?

    ReplyDelete
  6. The fact that antibiotics are becoming ineffectual in TB treatment is disconcerting. Can scientific advancements in TB research outpace the spread of antibiotic-resistant bacteria causing the disease?

    ReplyDelete
  7. Someone had told me that certain medicines would eventually become ineffective in the distant future, but I did not realize how serious and prevalent this issue is. The amount of deaths caused by TB is frightening and I hope a more effective medicine is found to cure the millions of patients suffering from this disease.

    ReplyDelete
  8. I think it is unfortunate that Tuberculosis is a disease that is overlooked by the general public because it isnt necessarily prevalent in their communities, so they arent made aware of it. Unfortunately many of the infected are people in poor living conditions such as a large Russian population that suffers from it, especially those who are incarcerated. Discovering a treatment would most likely be catalyzed if more upper class members of society and people in power were aware of this issue, rather than it simply remaining in lower class and impoverished peoples.

    ReplyDelete
  9. It is certainly clear that TB is still a theat to world health although we in the US are not concerned with it on a day to day basis. The thought of such bacteria are becoming more and more drug resistant with time is is a concern for health agencies on a global basis. Research and writing such as this keeps us all mindful of the need to continue to co,bat this and other global health threats.

    ReplyDelete
  10. Even though I understand that TB is a threat, I thought that the vaccine found in 1921 was still working. I do not understand what makes the vaccine not efficient anymore: has the disease evolved or have human bodies become immune to it?

    ReplyDelete
  11. I had no idea that macrophages could be so naïve that they expressed TCR's...

    ReplyDelete
  12. It'd be hard to raise awareness about TB because it's never been a problem. The best a company could do would be to put on those sad commercials on TV. Other major diseases have so many fundraisers and TB is so often overlooked

    ReplyDelete
  13. (now with a little moer understanding)so I understand that TB (after we slowed its evolution as a disease) is now becoming a much more serious issue. I know that before I started volunteering at the hospital back home, I had to get a TB test. I guess my main question is, where should we be ranking TB against other deadly diseases? How do we allocate funds to TB research as opposed to cancer, HIV/AIDS, STDs, or the like?

    ReplyDelete
  14. A few answers...
    Keith: the burden for finding and treating poorer nations such as India is on the developed nations and the WHO. Yes, the costs are high, but I do not believe that they are impractical. Any sort of research and drug program is going to incur costs, but I pose this question to you: how much is YOUR health worth? TB is going to come into the United States and other developed nations within our lifetime, and it is going to be deadly.

    Jake: TB is one of the most studied infectious diseases. It is also one of the oldest-evidence from mummies from 4000 BCE show signs of TB. There is a huge amount of information about the disease in literature. In my opinion, the best way to deal with MDR-TB and XDR-TB is through novel and experimental treatments (with the permission of the patients of course). Advances in technology, coupled with a better understanding of the human immune system should be investigated as a way to treat TB.

    Jesse: The key to "outpacing" TB is to not allow it to become drug resistant. Drug resistance occurs because patients with normal TB are put onto antibiotic regimens, but do not fully complete the course. As a result, not all bateria is killed off, and it becomes resistant to that antibiotic. The key to ensuring patients taking their antibiotics is a process briefly mentioned in this post. DOTS, or directly observed treatment-short course entails a patient taking their medication in front of a healthcare professional. This system then ensures that the entire antibiotic regimen is followed.

    Albert Naim: see my response to Jesse, and that should answer your question.

    Andy: I commented on this briefly in my response to Keith, but in my personal opinion, research into a cure for TB (or TB eradication programs, similar to the smallpox eradication program) should be ranked among the highest priorities of the WHO. TB will spread to developed countries, and will be rampant in urban areas. It is spread through droplets coughed up, and is highly contagious. 82% of Americans live in urban areas or suburbs-breeding grounds for TB. Where do you think TB should be placed on the "priority list"?

    ReplyDelete
  15. Thanks Corey. You effectively illuminate many of the unfortunate issues tied to such an unknown situation. You shed light on many great points and have spurred me to research this further.

    ReplyDelete
  16. Andy, I disagree with your response. This topic is not a simple one and it canot be simplified for your understanding. I think Corey made it as clear and precise as possible considering the complexity of the topic.

    ReplyDelete
  17. If TB in fact does spread to the United States and other developed countries as soon as our lifetime, then it just doesn't seem realistic that the epidemic will receive the necessary attention beforehand considering it hasn't already. Once it becomes an immediate issue that we can see directly affecting us, we'll be forced to heavily focus our efforts there. It's unfortunate that it will take numerous deaths at home to finally acknowledge and fight this battle on a large scale when we can already anticipate it coming.

    ReplyDelete
  18. Wow. This seems like an important discovery that shouldn't be overlooked. What worries me is the possiblity of this happenining in other diseases.

    ReplyDelete
  19. Is TB considered a priority outside the US? With increased international travel epidemics have a new life outside their host communities, we should be very concerned about resistant strains and new ways to combat this disease.

    ReplyDelete
  20. DOTS appears to be an outdated system for combating TB especially MDR-TB. In fact, many doctors and scientists agree that DOTS can actually increase the prominence of MDR-TB. Good paper that is really consistent with the kind of discussion about TB on a global scale

    ReplyDelete
  21. Ben, I agree that DOTS seems to be outdated, but the issue is that there is no other way to ensure that patients continue the regimen in its entirety. What happens is the antibiotics work, and eliminate the majority of the bacteria, and the patient feels better, so they stop taking the medicine. There are a few bacterial colonies left however, and these then become drug-resistive. The numbers do not lie though Ben, between 1995 and 2009 the WHO reports that over 41 million people were treated using DOTS and its successor (a similar program) and saved up to 6 million lives. The WHO has also developed a DOTS system for MDR-TB known as DOTS-Plus. DOTS-Plus uses antibiotics that are "second line" (read: more expensive and harder to get a hold of) and bacterial cultures to individualize treatment.
    In conclusion, I agree with you Ben that DOTS is outdated, but its the best we have and it works.

    ReplyDelete
  22. Wow, this has really done wonders to illuminate an issue that was previously unknown to me.

    ReplyDelete
  23. This comment has been removed by the author.

    ReplyDelete
  24. Great Post. While I know next to nothing about what you are talking about, your extensive use of scientific terminology makes it seem to me that you know a lot about it. You really made great use of your sources to back up the points you are trying to make. I honestly did not know that TB, or the White Plague as it was previously known, was still a major problem today. I know it used to be one of the worst diseases out there. If I remember correctly, at the time of the Civil War, about 500 out of 100000 people died from it each year. I once did a research paper on Richard Nixon and I learned that two of his bothers died from tuberculosis. I remember gruesome descriptions of their suffering. This article surprised me though because I have not heard of any cases of it since the cure was invented in 1946. I just did my own research and found that while the proportion of people who suffer from TB has been steadily decreasing each year, the number of new cases is still increasing. One of the main reasons I have been oblivious to this fact is probably because 80-90% of recent cases have been in Asian and AFrican countries and I really only pay attention to America. I hope this issue does not spread because I don't want another white plague to strike the world. Thank you for enlightening me on this issue.

    ReplyDelete
  25. Matt: your post concerned me in that I wanted to avoid technical jargon. I have added explanations of the things I discussed and what they are. Please let me know if this revision helps at all for understanding the post.

    ReplyDelete
  26. Corey is right. I've never taken an immunology class before, but I do know the basics about TB and it's control/treatment. The fact of the matter is that approximately 1/3 of the world population has TB, though mostly in its latent stage. In most cases, chronic TB does not develop. I have a feeling, though I can't be sure, that if and when TB comes to the US it will develop into chronic TB less frequently than in other nations. DOTS and DOTS-Plus are effective as long as there are enough health professionals and/or trained people to administer treatment on a regular schedule. We can't stop a disease from mutating-not yet anyway-all we can do is continue to treat it the best we can until companies have more of an incentive to search for better preventative measures and new treatments.

    ReplyDelete
  27. Sorry. I did not read the other comments before I made mine. Your comments elucidating certain parts of your post was very helpful. Also, I did not mean that I didn't understand your post when I said "I know next to nothing about what you are talking about". What I meant was I know next to nothing about immunology. Again thanks for enlightening me on this issue.

    ReplyDelete
  28. Corey, thank you for bringing to light a concerning topic. TB is a frightening disease that receives very little media attention and is never really talked about.

    ReplyDelete
  29. The authors suggest that TCR expression is correlated with granuloma formation and that TNF treatment, which seems to increase TCR expression, may be a feasible treatment down the road. What sort of systemic effects does global TNF treatment and increased TCR expression have? Can it be localized to the bronchi?
    I recently read an article by Singh et al, 2008 that focused on a specific drug that targets replicating and non-replicating myobacterium. Did the authors in the paper you present compare TNF treatment or TCR expression in replicating and non-replicating myobacteria? The drug (which is currently in a clinical trial) enters the bacterium and through some metabolic processes, releases intracellular nitric oxide as a byproduct which plays a role in bacterial death. In terms of bacterial infections and potential side effects, do you think that treatments targeting the bacteria are better than treatments that target non-specific host cells?
    Good job with your article.

    ReplyDelete
  30. Great blog, Corey! But as a non-science major, I was wondering how does a disease like tuberculosis that is often treated by antibiotics become resistant to the drugs in the first place?

    ReplyDelete
  31. Matt- Undirected TNF treatment can be fatal-it can cause systemic organ failure as well as unchecked inflammation-but what I see as having the most promise is a directed TNF treatment to the bronchi (this is being experimented with hypersensitivity). Increased TCR expression is not a very dangerous prospect, as TCRs undergo selection and for the most part are not self-reactive. The authors did not compare replicating and non-replicating mycobacteria, I imagine however that they used replicating bacteria as a majority of their experiments occurred in vivo, and required the replication of the bacteria. The drug that you discuss seems to have amazing potential, and I would love to research it further-what is the name of the drug? My only concern with the release of NO inside bacteria is when the contents of bacteria are released, in the case of a large infection, NO could also be released into the bronchi.

    ReplyDelete
  32. Alyssa: I actually explained the process by which pathogens become resistant to drugs in a comment earlier. Take a look at that and let me know if you have any more questions.

    ReplyDelete
  33. Corey: I didn't know anything about TB before this post, it's fascinating! Many medical issues seem to receive little media attention, but TB seems to need it in order to gain more space in research literature. Very insightful post, well done Corey.

    ReplyDelete
  34. Wow! Awesome job, Corey! Though, my historical understanding of TB is that it has been largely controlled over the past 40-50 years and that governments, the US in particular, are looking to quarantine it--therefore eliminating the need for new drug development to combat the mutations?

    ReplyDelete
  35. Quarantine is a good idea, only when you have small populations. As I stated in earlier posts, the global infection rate of TB is around 40 million, and about 90% of those cases are latent, or in other words those infected do not experience symptoms. As a result, they carry the infection without realizing it, and do not seek antibiotic treatment. As well, it has been controlled in the last 40-50 years, but recently with large-scale antibiotic campaigns, a number of patients have not fully completed their antibiotic regimen, resulting in drug resistant variations of the bacteria which pose a serious threat to the world.

    ReplyDelete
  36. All very interesting. Towards the end of the blog, you conclude by stating that the majority of studies are "usually around 10 patients, it signals a necessity for more research in this field". If TB is becoming as large of an issue as you state, and a potential threat to our population in the future, then why are studies such as these being conducted on a larger scale and with more immediateness? Is there anything hindering the process?

    ReplyDelete
  37. Jordan, I think the biggest issue is the fact that the majority of TB cases occur in third world countries, such as India. As a result, the researchers are bound by the countries and facilities in which they work. It is lucky however (to a degree) that TB occurs highly in India and South Africa, two nations that do have the possibility for lab testing. As well, there is a large volume of emerging literature on TB: the problem of TB is beginning to garner international concern.

    ReplyDelete
  38. Yes, I agree with Jordan. It seems like there needs to be more proof to make any sound conclusions on the research you mention considering the amount of people affected by TB. I wonder Corey if movies such as "Contagion" and other media examples where disease spirals out of control help bring the issue of infectious diseases to the forefront or actually hurt dialogue by creating misconceptions. I would guess that Hollywood does a poor job with the scientific aspects, but I do think movies at least start a discussion about what can be done about these types of diseases.

    ReplyDelete
  39. What do you propose as a strategy for TB? Do you advocate for global eradication like we did for smallpox or a call for better vaccines and treatment?

    ReplyDelete
  40. John, Contagion was actually a really great example of what could happen to the world if a novel pathogen was introduced into the environment. Granted it was a worst case senario, the public health aspect of it was spot-on. That being said, XDR- and MDR- TB are serious threats with very few treatment options, and could, if no advances in TB treatment are found, pose a similar spread as the pathogen in the movie. One thing to remember about TB is that 9 out of 10 people get what is called a "latent infection" and do not experience symptoms, but are carriers of the bacteria.

    ReplyDelete
  41. Alex, the issue with TB, is, as I've said, those people that have latent infections. It creates an issue with knowing who has it and who doesn't. This same idea has made it almost impossible to eradicate polio. The issue with vaccines is that the BCG vaccine (which is administered for TB) does not actually prevent pulmonary TB- the most common form. My opinion is that DOTS is the best possible option that we have at our disposal at the moment. Alex, what do you think should be done about TB given this information?

    ReplyDelete
  42. Do you think that requiring a TB test for all jobs and services is necessary? Working in a hospital requires it, however do you believe all sorts of jobs should demand to know their employees' status with TB?

    ReplyDelete
  43. Do latent cases necessarily give rise to active infections upon transmission? India and South Africa both possess the means to tackle this process themselves, and have China as a nearby and powerful resource. Is the amount of research dedicated to defeating TB really negligible in this case? Some might argue that other more prevalent diseases which, recently, have had a greater impact on the first world take precedence over TB. In the first world TB has been a fairly dormant concern, thought to be the 2nd world's cross to bear. Do you believe that Western society has the social strength to contribute to the effort?

    ReplyDelete
  44. Ryki, interestingly, people who have recieved TB vaccines actually test positive for TB even if they don't have it. I don't think that TB testing should be required, unless it is a sputum test, which is a better way to establish whether or not someone has TB.

    ReplyDelete
  45. This was an extremely informative post as well as worrying. The fact that the bacteria is becoming drug resistant is an issue that clearly needs to be addressed. While scientists further the research that is explained in this blog, is DOTS the only way in which we can hope to fully treat the disease? Is there any interim method of treatment that could be effective?

    ReplyDelete
  46. I agree with the DOTS option but there are many barriers for this program that would need to be overcome before it could be practical. I am primarily thinking of developing countries and their lack of infrastructure. Countries would need to improve their roads, for instance, before the government could fully commit, like being able to efficiently test for TB. Also countries would need to develop in order to prevent people from contracting existing or future forms of TB. The DOTS program would also require substantial amounts of aid from countries, and based on the current financial situation this does not seem likely. How do you propose to deal with these problems? Do you think that we can just jump into the DOTS program or that we should facilitate socioeconomic development before trying to deal with TB?

    ReplyDelete
  47. Eliza, latent infections can sometimes develop into active pulmonary infections. It should be a concern of developed nations, as TB will eventually be found in developed population centers. In my opinion, TB is the most prevalent disease in the world- it was the 2nd most fatal infectious disease in 2007! TB research and treatment is a responsibility of the world, not just the countries affected.

    Ali, DOTS is the best we have. If you ask me, DOTS is more of an interim treatment before we find a "knock-out" for TB. Further understanding of the immune system and granuloma formation is key to finding this "knock-out".

    Alex, DOTS does require huge amounts of aid from foreign countries, WHO, and NGOs. The red cross and WHO are the largest providers of TB treatment in the world. Personally, I think that development of infrastructure in developing nations is the KEY to preventing a majority of aliments faced in these nations. I think that development of infrastructure in conjunction with DOTS is the best possible way to treat TB and develop the nations.

    ReplyDelete
  48. I noticed you only gave death toll statistics from 2007, I was curious if this number has increased or decreased in recent years, and what steps have been taken further to eradicate this terrible disease. Down with TB, all the way down.

    ReplyDelete
  49. I truely believe that these non conventional practices of studying medicine are truely the new way of "Thinking outside the box." Corey you do a great job of explaining the new technological breakthroughs and new way of looking at things.

    ReplyDelete
  50. Also... Where do you see this disease going in the future... if you predict it will still be around. Do you think it can and will mutate into a stronger form of its self?

    ReplyDelete
  51. I had no idea that TB is still so prevalent in our world. I thought it had been eradicated for the most part, perhaps due to its lack of media attention. Your post allows someone without a very strong science background to follow the reasons for TB's continued presence. Great job shedding light on such an important problem!

    ReplyDelete
  52. Josh, there is a mountain of evidence showing that TB has mutated. Depending on your definition of "stronger" it has mutated: it is drug resistant and evading our attempts to eradicate it.

    ReplyDelete
  53. Now to put it into perspective, 1.77 million of 7 billion, thats .02% of the world population. Let's just chill out for a second. I feel like as long we keep the disease within a certain area, then it will be harder for the disease to mutate into more resistant strains.

    ReplyDelete
  54. Also, my only experience with TB is through the movie Moulin Rouge. Quite a tragedy.

    ReplyDelete
  55. I'm somewhat in shock about the insensitivity explicitly expressed in the comments above. If that argument is to be presented and you actually believe that, how can you just ignore the problems of many of the people suffering from this and simply "round them up" as if they were cattle? Not to mention that the problems with resistant strains are not only of this disease, but of many of the diseases that are worldwide whether they are bacterial, viral, and parasitic, such as the highly mutative virus, HIV.

    ReplyDelete
  56. Let me rephrase, for my esteemed colleague.TB is a terrible disease that needs to be eradicated from this earth. However, TB is one of hundreds of increasingly resistant diseases that are infecting people all over the world. Like previous scares of the Avian Flu and the Swine Flu, in which people feared another pandemic facilitated by the speed of resistant mutations, there are things we can do that can help the cause not directly related to the research aspect of the project.

    ReplyDelete
  57. Wow this is all very interesting. I am intrigued!

    ReplyDelete
  58. In that aspect I can agree with you. However, discovering new methods to combat the mutative behavior of these diseases is most likely the only way to truly eradicate the issues associated with the resistances mutative pathogens. We should do the things that we can, but we should also continue to pursue a method to resolve this issue altogether, and the more fear is spread, the more awareness and focus will be placed upon researching this very severe issue.

    ReplyDelete
  59. Agreed, but this issue needs to be in a public domain that isnt a blog post, despite this excellent example. Furthermore, until TB hits the first world, I'm afraid the extra pub will not be as effective.

    ReplyDelete
  60. I would have to agree with Settle on this one. There just simply isn't enough of a threat posed by TB at this point to get worried over. There are many problems out there that are afflicting the third world, and I'm guessing TB is not the most harrowing of these problems.

    ReplyDelete
  61. I agree this shouldn't just be in a blog post. But, fellow scholars, it does have "the second highest death rate of any infectious disease," thus making it extremely important to continue to research and to devote resources to. Also, I have unfortunately not seen Moulin Rouge.

    ReplyDelete
  62. How can you say that after reading this article? It clearly states that it is the second most prevalent death rate in the world, that a pretty big problem if you ask me... Its like Settle and I have stated previously, it simply has to become a large enough problem to where it hits the first world, and all of a sudden it would be the newest favorite for the media, like diseases such as AIDS, Cancer, Staph Infection and Swine Flu have in recent years. Why cant articles such as these be more public to raise further awareness to prevent this from becoming a problem, rather than letting it be a problem , THEN drawing attention to it. It is probably the easiest way for us to lessen the spread of this horrible disease.

    ReplyDelete
  63. Very interesting post. I have to admit that I did not know much about TB and had no idea that it has the second highest death rate for an infectious disease. It's always a little scary to see how viruses/diseases become resistant to antibiotics or other treatments; it seems that more research in this area is needed! Thanks for enlightening me on the subject, I definitely learned something new!

    ReplyDelete
  64. If TB was an evangelical Christian and completed less than half of its passes, then it would get more buzz from the media.

    ReplyDelete
  65. You make some really good points. It is scary how little the public knows about their communities, and even their own, health. It seems that because this is not necessary affecting us now, we are not acknowledging the potential impact it could have on our society as a whole. How many people have to get sick before we notice what is really going on? Our world really needs to get our priorities straight, starting with further researching possible cures for horrible diseases such as TB.

    ReplyDelete
  66. as a follow up to the anonymous comment above i would like to know the percentages of the countries affected by TB.

    ReplyDelete
  67. What a strong, compelling argument! Good job!

    ReplyDelete
  68. Jake- TB is ubiquitous around the globe, the main issue is the MDR- and XDR-TB strains that are prevalent in places like India and much of Africa. When these strains begin to appear in developed nations and urban centers is when we will see huge numbers of people becoming infected and dying.

    ReplyDelete
  69. Why doesn't TB significantly affect first world countries?

    ReplyDelete
  70. I think that some of us and "Settle" in particular, raise a broader question concerning the use of the medias in promoting diseases. Even though it is not the subject here, it is a very problematic question. Why do the medias choose to heavily talk about some diseases (remember the virus H5N1 and the avian flu) and not about others, such as TB?

    ReplyDelete
  71. I will make one tempered response and then leave:

    you have to look at the effect of anything (especially an infectious disease) in a vacuum. You can't say that TB is better or worse than some disease, you can't say it affects third world nations or first world nations. The fact is, human beings are dying while we have the ability to save them. Nothing else matters.

    kudos!

    ReplyDelete
  72. This comment has been removed by the author.

    ReplyDelete
  73. Balin, you pose a great question, for the most part, patients in developed nations take their antibiotics through the end of the regimen. Those in developed nations tend to be more careful about sick people and don't live in the same densities as they do in slums in places like India. Finally, constant observation by doctors in developed nations is more prevalent, allowing the TB infection to be better controlled.

    ReplyDelete
  74. If this is so contagious, though, why has it taken this long to spread? I remember when the swine flu epidemic broke out, within a very short time span it was in urban centers around the globe.

    ReplyDelete
  75. Do you think the United States CDC is doing a good job of preventing the enterance and spread of the certain MDR and XDR strain into the country. Since you say they are more prevalent in places like India and Africa.

    ReplyDelete
  76. Is the reason certain strains are more widely seen in other countries because they can survive easier in their native people? if so is this due to the lack of health care and sickness prevention or is it something else?

    ReplyDelete
  77. I'm not an expert Josh, but I can't see the United States government deliberately preventing these strains. How could they regulate such a complex process?

    ReplyDelete
  78. Michael, as I said earlier, in 2007 there were over 40 million people infected with TB. The infective rate, also known as the R0 (read R-naught) is the measure of how infective a disease is. While I do not have the R0 for these diseases it appears as if the H1N1 flu has a higher R0 than TB. What makes TB dangerous however is that only about 10% of people infected display symptoms of TB, while there is another 90% of people with latent infections that do not display symptoms, but can still infect other people. Another thing that differentiates these two aliments is the mortality rates- TB has a higher mortality rate than H1N1 if untreated.

    ReplyDelete
  79. Settle although this would be tough for the United States to keep track of I do think that there can be more measures taken to protect citizens from an outbreak. Giving more funding to the scientific community could allow more experiments like this one to give us answers about how to exactly contain these viral infections. More importantly, the government has to have some type of quarantine plan ready to set in action as I consider this just as big of a national security threat as the threat of nuclear war. Simply saying the United States government is too large or too incompetent to tackle an issue like this one is a cop out, the government must be accountable or we will meet our demise.

    ReplyDelete
  80. Good blog, Corey. Fascinating stuff.

    ReplyDelete
  81. To add to the discussion here, the WHO measures "disease burden" by a factor termed "disability-adjusted life years," which is an indicator of the total number of productive work years lost to a given disease. For example, childhood diseases have a proportionately high DALY, since kids who die from diarrheal illness lose many more potential years than a person in their 70's dying from pneumonia. Based on the most recent statistics I could find (admittedly, from 2004) TB ranks 11th on the global list, and 5th among infectious diseases, behind lower respiratory infections (i.e. pneumonias and the like, which tend to kill lots of kids, #1 on the list), diarrheal diseases (ditto; #2 on the list), HIV-1 (#5), and neonatal infections (#10). It ranks just above malaria on the list (#12). One of the other big problems with TB is that it tends to track closely with HIV-1 infection, leading to problems as patients become immunocompromised and have problems with TB, especially drug-resistant strains.

    ReplyDelete
  82. What funding? We are in multi-trillion dollars of debt? It's like saying we should prevent the outbreak of killer ants. It isn't here yet, but it might someday.

    ReplyDelete
  83. Settle,
    Should we not combat global warming because it's not yet here?

    If we can stop a potential disaster before it strikes by spreading awareness and furthering research, how can you be opposed?

    ReplyDelete
  84. Also, you can't use the argument about lack of funding. We pour trillions into funding of all sorts of things. It's definitely a pressing matter that warrants shifting funds from something else.

    ReplyDelete
  85. I'm pretty sure global warming is here.....it's almost december and it was in the 50s today.

    ReplyDelete
  86. Global warming changes cost money; we don't like throwing cash at things.

    ReplyDelete
  87. I also think that this might not be as bad as everyone thinks. Our globe is overpopulated. Our unemployment rates are through the roof. An epidemic would open up jobs for those who aren't infected.

    ReplyDelete
  88. Global warming is becoming a vital national security interest as opposed to a secondary interest. It's becoming less of a choice and more of a necessity meaning we'll be forced to fund research if we plan on keeping the fishing industry alive (and the polar bears).

    ReplyDelete
  89. John,
    You're right about that, but that also shows that if we inevitably are going to need to fund this, we might as well do it now. There will be far less panic and we'll save lives.

    ReplyDelete
  90. You mentioned earlier to keith that TB would spread from the impoverished countries to more well developed ones within our lifetime. Could you be more specific as to how long this transition will take? and how will the timeframe of this transition effect future research?

    ReplyDelete
  91. According to pubmed health you are at risk of contracting TB if you have poor eating habits and have crowded/unsanitary living conditions. I would imagine if we didn't have vaccinations as readily available in the States that TB would be a problem on college campuses.

    ReplyDelete
  92. Guys, I think we're getting a bit off topic- I understand arguing about preventative vs reactionary, but global warming is a little far from TB. Here's something to think about in relation to health and prevention: countries that spend more money on preventative health and primary care spend less money per person on healthcare, and have higher life expectancies than the US.

    ReplyDelete
  93. Castor, I don't know who you are but I do know you are ridiculous. Another possible solution to unemployment: a president who is fiscally responsible. Maybe that would be a better option than letting people die off to make room for the healthy. Where is your heart?

    ReplyDelete
  94. In response to Corey...who says we should spend my hard earned tax dollars on preventative measures? I don't have TB, so why should I pay to prevent it? When I get it, I can get rid of it with my health insurance that I PAID FOR! My life expectancy is not the same as the country as a whole!

    ReplyDelete
  95. This is an interesting treatment with TB but doesn't seem to be getting at a real treatment of the disease. The body is clearly mounting the incorrect response to the bacteria, since it is releasing Th1 cytokines and forming granulomas, which are formed when the immune system is unable to eradicate an infection. Wouldn't it be more beneficial to find a way for the body to mount the correct Th2 response? Would strengthening granuloma formation help defeat the infection or just delay disease progression?

    ReplyDelete
  96. Jon, where do I start with your comment? First off, if you are so concerned with your "hard-earned tax dollars," it behooves you to help prevent infectious disease in the country as a whole. As I mentioned previously, disease burden is measured as a function of how much a given disease decreases the economic contribution of a person to a given country. Decreasing this burden leads to more economic productivity, leading to increased wages, etc. It is FAR cheaper to prevent disease in the first place than it is to pay for treating already established illnesses, especially those of a chronic nature. So, while you may be one of the fortunate individuals that can afford to purchase health insurance, there are many other economic costs associated with providing health care to those who cannot afford health insurance that would be alleviated by spending money on prevention. Additionally, vaccination and other preventive measures can provide the benefit of herd immunity for those individuals who cannot, for health or other reasons, get vaccinated, again increasing the productivity of the population. Finally, while your life expectancy may not reflect the country as a whole, to a certain extent your quality of life does, and by eliminating unnecessary illness, the general quality of life in a given nation is raised.

    ReplyDelete
  97. I am curious that larger studies than the one by Beham et al do not exist about innovated drug treatments for TB. Do you foresee research of TB treatment increasing in the near future and if so, why?

    ReplyDelete
  98. I found this article extremely informative, attention grabbing, and well written. Excellent job Corey!

    ReplyDelete
  99. These are really interesting findings. I would be curious to know to what extent these findings are being implemented as a cure for tuberculosis today and how long it will take before this becomes the dominant treatment for TB.

    ReplyDelete
  100. Corey, great job! This is a very important discovery to bring to light to those who may not have heard about it otherwise like myself. I am concerned that there is a slight possibility of this becoming widespread to other diseases like David mentioned. Along with that concern comes an entirely different concern of keeping healthcare costs down while in the economic crisis that we are in. Do you foresee these costs coming down at all and if so, how long will it take for the cost structure to change even the slightest bit?

    ReplyDelete
  101. Also directed at Jon--you just can't compare your own means to nationwide life expectancy. There's a point where rugged individualism ends and people have to start thinking about the collective bunch. For example, if you know you have the chicken pox, don't go to school! Some people might be tough enough to study while suffering, but it's just stupid to get everybody else sick.

    back to TB, it doesn't matter if you have health insurance to treat TB or not--TB doesn't really care about your socioeconomic background. Sometimes right-minded folks just have to realize that some causes are more important than riding it solo.

    ReplyDelete
  102. Thank you for your thoughtful explanations in the post strings. It is even more clear to me that TB is a greater problem than widely thought, but that more pressing issues and diseases in the developed countries seem to overshadow the severity of TB (since it is mostly a developing country issue). We, from a global perpsective, should be better informed and better prepared to battle TB in the short term to prevent the long term effects.

    ReplyDelete
  103. From my understanding of old diseases becoming "new" again by working in a hospital in Miami and seeing things that I thought were in the past, I appreciate your take on TB. Super strains can not be combatted by existing antibiotics, etc. However....where is funding for such an undertaking? That's the problem.

    ReplyDelete
  104. Rory: Investigation into novel treatments for TB must not only continue, but it must increase. Right now MDR and XDR-TB is largely an issue in developing nations. Once these strains begin to affect people in developed nations I believe that we will see TB research skyrocket.

    AJ: As of now, I cannot imagine that these findings are going to be implemented in treatment of patients. Due to the process by which treatments must undergo in order to be accepted (medical/drug trials) this finding, if it were to be used in treatment of TB would be used widespread in 10 years, if that. The medical world takes a long time to react to new findings.

    Matt: Money is always an issue when we talk about treating people in developing nations. The problem is usually that the drugs patients are taking are super expensive. This occurs for two reasons: 1) the drugs are not used anywhere but the developing nation or 2) the drugs are used by a large population (in both developed and developing nations) and are in high demand. The key to lowering costs then is to increase production of the drugs. This however crosses into patent rights, something that I don't really want to get into at this moment. But if drug patents were able to be conscripted or downright copied by manufactures in India, then costs would plummet. If this were the case however, there would have to be some action taken to ensure that the drugs manufactured by the "copier" manufacturer never reach developed nations.

    ReplyDelete
  105. Corey, your agugment about "copying" patented drugs is overly simplified and fails to take into consideration the motivation for research and cration of such new drugs. While the desire to do great things is a motivating factor, the companies that spend time and money doing the research must somehow reap rewards. Without delving too much into politics or economics, or giong off on a tangent, there must be a balance so that the motiviation to crete these new super drugs exists. Without patent protection guaranteeing a return in investment, what motiviation is there?

    ReplyDelete
  106. So making a generic version of the drug is the solution? Wouldn't this undermine the value that the drug is trying to have and make it super accessible to these developed nations? I would be interested to see how this develops in terms of obtaining the patent and increasing the distribution of the drug.

    ReplyDelete
  107. Mitchell: what good is a patent is the people the drug is designed for cannot afford it? Then those people are not reaping the rewards of the patent, nor is the manufacturer reaping the monetary rewards. In this case, everyone loses. For the case when the drug is being used in developed and developing nations, ensuring that the manufacturer has a hold in the market which can afford it, while allowing a partnership with another, less expensive manufacturer to make the drug for developing nations seems like a viable solution. In this case, it then becomes the partner manufacturer's responsibility that their drugs do not end up in the patent holder's market, thereby limiting government intervention, and ensuring profits for the patent holder. Is this enough incentive for you Mitchell?

    ReplyDelete
  108. Matt, generics are a solution only for those drugs off-patent (the patent has expired) or that never were protected by patent. The governments of the developing countries have to negotiate with the drug companies (the patent owners) so that the drugs are legitimate and available at a cost that the people can afford. where they simpley can't afford it, the countries must provide. Now I am not a big fan of big phara, but many of the drug companies will supply these drug at very low to no cost to developing countries in exchange for the "good will" that such distribution builds for them. But the bottomline is that if they don't sell, they can't make a return on their investments. So, there should be room for negotiation. Understand though, that as much as I dislike big pharam, I believe that the leadership (or lack thereof) in most of these countries is more to blame than big phara and patents.

    ReplyDelete
  109. I still don't understand why the manufacturer would want to partner with another manufacturer...Won't that only limit the original manufacturer's profits?

    ReplyDelete
  110. I don't understand why Castor is getting so much hate. We will have an overpopulation problem soon, and no solution will be pretty, but maybe this will help.

    ReplyDelete
  111. Tyler- if no one in developing countries can afford the drug, how does the manufacture make a profit?

    ReplyDelete
  112. This comment has been removed by the author.

    ReplyDelete
  113. Ok I got that. So the solution is to share the costs with another company? How about the government of the developing country paying for these costs which result in the manufacturer's loss?

    ReplyDelete
  114. Really interesting article Corey thanks for posting it

    ReplyDelete
  115. Tyler- I think the issue may be these developing country's government's may not have the organization and money to pay for that.

    ReplyDelete
  116. Corey, countries have been spending millions upon millions of dollars trying to prevent the importation of unauthorized drugs. These can be both knock-offs as well a legitimate or authiorized drugs imported into countries in which they are not authorized. While theoretically your solution may be sound, in practice trying to police both knock-off drugs and "authorized" generics is at best a monumental task and in reality, likely impossible.

    ReplyDelete
  117. Corey I had no idea TB was such a problem!

    ReplyDelete
  118. For those interested, this article outlining a strategy to enhance TB research was published today in PLoS Medicine:

    www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001135

    ReplyDelete
  119. Great post Corey! Thanks for the info!

    ReplyDelete
  120. This article makes me afraid that TB is going to kill us all...

    ReplyDelete
  121. Great post and responses, you really seem to know your stuff about TB.

    ReplyDelete
  122. Thanks for increasing awareness for TB

    ReplyDelete
  123. This post is gonna come off sounding weird, but is there any way we can channel this disease and use it against our enemies (i.e. Iran and North Korea). I think it could be very effective

    ReplyDelete
  124. To the post above, you're an idiot. Haven't you read the comments? Even if we were to use it as a weapon, it would still eventually reach us, and then we'd all die. DUH

    ReplyDelete
  125. hey guys don't fear TB, I don't think Corey meant for this to scare anyone

    ReplyDelete
  126. wow great article, I never knew any of these facts prior to reading!

    ReplyDelete
  127. does this relate to anything other than TB

    ReplyDelete
  128. Anonymous at 2:45 makes a great point. This could be the atomic bomb 2.0

    ReplyDelete
  129. Corey this is a great post! You sum up the topic very well and have informed me about a topic that I didn't know too much about. Spreading awareness is the key, and this is what you are doing here, in this post, right now. Great job.

    ReplyDelete
  130. Corey,
    I hope you can get into graduate school so you can pursue helping to fight this atrocity!

    Excellent job!

    ReplyDelete
  131. Michael, you're an idiot. that's called biological warfare, something that the US says we hate. we'd just be stooping down to the level of terrorists.

    ReplyDelete
  132. Really interesting blog, Corey! Thanks for raising awareness about TB!

    ReplyDelete
  133. Thank you for posting this. The concept that a disease which was thought of as extinct in the US is on the rise again is frightening. The use of antibiotics that only breed resistant bacterial strains is short sited and untimatly more damaging to the world population.

    ReplyDelete
  134. I agree with Mike that awareness is a key factor in helping to bring about solutions to TB, and it is research such as this that can be crucial in the process of creating a cure.

    Also, I agree with Castor.

    ReplyDelete
  135. great, enlightening post corey!

    ReplyDelete
  136. great article, and great followup in the comments. you have a knack for writing. keep up the great posts!

    ReplyDelete
  137. Great post, Corey, you really have put a lot of thought and work into this

    ReplyDelete
  138. Alex- This research does shed light on other ailments. Diseases such as leprosy, schistosomiasis, some pneumonias, and even Crohn's Disease are characterized by granuloma formation. A thing to keep in mind is that granulomas are a normal immune response by cells in order to quarantine infected tissue.

    ReplyDelete
  139. pretty cool stuff in your blog posts, i hope to see more in the future. as informative as a TED talk

    ReplyDelete