North Korea and the USA can indeed unite: in the battle against TB.

Tuberculosis (TB) is an infectious disease caused by a bacterium. It spreads through cough or sneeze from subjects with an active infection. While in most cases the disease is asymptomatic, a minority of latent infections does become active (i.e. the subject develops symptoms), and when it does, if left untreated, the disease can be deadly.

According to the CDC one third of the world's population are infected with TB, and while in the US the incidence of the disease has been declining over time, it is still a huge problem in parts of the world like Asia and sub-saharan Africa. While normally the chance of a latent TB infection becoming active is one in ten, the chance is much higher for HIV-positive subjects because their immune system is already debilitated by the HIV virus. As the CDC reports:

"TB is a leading killer of people living with HIV (PLHIV)."

A regimen of 3-4 drugs has been available for years to keep latent infections from becoming active. Sadly, TB infections from multidrug resistant strains (MDR) have been steadily increasing, setting back the progress made in the past decades.

From the World Health Organization:

"Drug resistance arises due to improper use of antibiotics in chemotherapy of drug-susceptible TB patients. This improper use is a result of a number of actions including, administration of improper treatment regimens and failure to ensure that patients complete the whole course of treatment. Essentially, drug resistance arises in areas with weak TB control programmes. A patient who develops active disease with a drug-resistant TB strain can transmit this form of TB to other individuals."

One of the countries plagued by MDR TB strains is North Korea, where the incidence of TB has dramatically advanced over the past years, reaching one of the highest incidences outside sub-saharan Africa.

In this week's issue, Science Magazine describes a joint effort between two countries that, according to the recent news, you'd least expect to pair up: North Korea and the United States. In collaboration with Stanford University, the Korean ministry of Public Health opened in 2010 a National Tuberculosis Reference Laboratory (NTRL).

"NTRL researchers can now diagnose TB cases that are resistant to first-line drug combinations, making it possible to spot patients who need more aggressive therapy. And the lab will soon add capacity to screen for extensively drug-resistant TB, known as XDR—the worst strains, some of which are close to impossible to treat."

The Science report covers stories of hope in the midst of desperation. It points to pressing issues the North Korean government has to address within its borders, and focusing on them would seem a more reasonable and logical strategy than polishing nuclear arsenals. Let's hope that the roots of this collaboration grow deeper than any political discrepancies. Let's hope that the battle against a common enemy (TB) will put an end to the empty, unfounded threats and pave the way to a broader, more civilized way of communication between countries.

Stone, R. (2013). Public Enemy Number One Science, 340 (6131), 422-425 DOI: 10.1126/science.340.6131.422

The curse of drug-resistant TB strains

Tuberculosis (TB) is a disease caused by a number of strains of mycobacteria. It affects mostly the lungs with chronic, bloody cough and fever. It can remain asymptomatic as a latent infection, though about 10% of these latent infections eventually progress to active disease.

The two most common drugs used to treat TB are isoniazid and rifampicin, but unfortunately new mycobacteria strains (called MDR strains, which stands for multi-drug resistant) have emerged that are resistant to both these powerful drugs. In other words, the pathogens have developed certain mutations that make them "immune" to the drugs. As with HIV, common thought is that these drug-resistant strains emerge during the course of the treatment in single individuals as a result of the selection pressure induced by the drugs. This is also reinforced by the fact that typically drug-resistant mutations confer a cost of fitness: though able to escape the drugs, the mutated strains tend to reproduce less quickly and/or are not able to be transmitted.

Unfortunately, that's not always true. A study published by Nature Genetics in December [1] showed that MDR TB strains do not show a fitness cost and that the most common drug-resistant mutation is present in the population with a wide variety of compensatory mutations. These are additional mutations that compensate for the loss of fitness by working in antagonistic epistasis to lessen the structural and functional instability of the affected proteins.

Comas et al. compared

"the genome sequences of ten paired clinical rifampicin-resistant isolates to the genomes of the corresponding rifampicin-susceptible isolates recovered from the same infected individual at an earlier time point. We identified all nonsynonymous and intergenic mutations found only in the rifampicin-resistant genomes. In addition, we experimentally evolved six laboratory-derived rifampicin-resistant mutants from rifampicin-susceptible ancestors during 45 weeks of serial subculture in the absence of rifampicin."

They showed that

"The high frequency of compensatory mutations in strains from Abkhazia/Georgia, Uzbekistan and Kazakhstan is consistent with the success of MDR strains in these regions, where up to 50% of individuals with TB are estimated to carry MDR strains compared to a global average of only 3%."

These findings are particularly relevant for TB treatment policies: isoniazid and rifampicin have been used not only to treat infected patients, but also as a preventive measure for people visiting countries with high TB prevalence (as for example peace corps). Furthermore, people are treated as soon as they become TB positive, but for the most part these infection are latent and all genetic information we have on TB is from active infections. There's no way to know if these drugs are effective until the infection becomes active. If these MTR strains are not only fit but also transmissible, the persistent use of these drugs will have the net effect of allowing breeding and spreading drug-resistant strains, resulting in a rise of non-treatable infections.

"In conclusion, our results suggest that the acquisition over time of particular mutations in rpoA and rpoC in rifampicin-resistant M. tuberculosis strains leads to the emergence of MDR strains with high fitness. Furthermore, our data show that these mutations occur at high frequencies in clinical settings, particularly in hotspot regions of MDR TB9. Additional studies are needed to determine whether MDR strains of M. tuberculosis with mutations in rpoA or rpoC have increased transmission rates and how these mutations contribute to the success of these strains. Use of targeted genotyping of these mutations will enable TB control programs to focus on the most transmissible MDR strains. Our findings also suggest that mathematical models that aim at predicting the future of the global MDR TB epidemic should take into account the effects of compensatory mutations as well as the time necessary for such mutations to emerge."

[1] Comas, I., Borrell, S., Roetzer, A., Rose, G., Malla, B., Kato-Maeda, M., Galagan, J., Niemann, S., & Gagneux, S. (2011). Whole-genome sequencing of rifampicin-resistant Mycobacterium tuberculosis strains identifies compensatory mutations in RNA polymerase genes Nature Genetics, 44 (1), 106-110 DOI: 10.1038/ng.1038

Photo: making progress with my macro lens! Canon 40D, focal length 100mm, shutter speed 1/100, F-stop 14, ISO speed 100.