Posts Tagged ‘Tuberculosis’

The battle against TB

Tuesday, December 3rd, 2013

The Guardian I have written a lot on MicrobiologyBytes about tuberculosis (TB) as a remerging disease, but the global TB situation is still poor, so it’s always worth bringing this issue to people’s attention again. Writing in The Guardian, Nick Herbert points out the painfully slow progress which has been made (The fight against TB is not over):

The rate of new cases of TB has been falling worldwide for about a decade, enough to hit a UN millennium development goal target, and deaths will have nearly halved since 1990. But a decline of 2% a year in the estimated incidence rate suggests that the disease is being beaten at a shamefully slower rate than when the west tackled it a century ago. On current progress it will take at least another 100 years. The latest World Health Organisation report, published last month, warned that 3 million people a year who develop TB are being missed by health programmes. Most worryingly, less than a quarter of drug-resistant cases are being detected and less than half of those that are detected are successfully treated.

So hats off to Mr Herbert for highlighting this important issue. But this is The Guardian, and the byline to this story includes the phrase “western leaders need to act now“. Mr Herbert points out that:

London has the highest rates of TB of any city in western Europe. The borough of Newham has rates equivalent to Nigeria.

All of which is true. Commenters on The Guardian article weren’t slow to mention that Nick Herbert is a serving Tory MP, who was previously director of public affairs at the British Field Sports Society for six years. While the editorial process at The Guardian has ensured that the facts in Mr Herbert’s article are correct, it’s hard to disentangle this piece from the Tory agenda on limiting immigration and the aftermath of the failed badger cull.

So yes, we need to do more about TB, as some of us have been pointing out for years. But we also need to be critical and questioning about where we acquire information and how we react to it. Politicians and science generally don’t mix. On the whole, that’s a good thing – there’s already too much politics in science.

 

Badger baiting – the truth about badgers and bovine tuberculosis

Thursday, August 15th, 2013

Save Our Badgers I’ve spent the last five years trying to persuade students to do a research project with me looking at issues around the scientific evidence concerning bovine tuberculosis and badgers – without success, no takers (they all want to do projects about HIV). Fortunately, now they don’t have to as the Royal Society has published a comprehensive (by which I mean yes, everything) review of the subject:

A restatement of the natural science evidence base relevant to the control of bovine tuberculosis in Great Britain. Proc. R. Soc. B August 2013 doi: 10.1098/rspb.2013.1634
Abstract: Bovine tuberculosis (bTB) is a very important disease of cattle in Great Britain, where it has been increasing in incidence and geographical distribution. In addition to cattle, it infects other species of domestic and wild animals, in particular the European badger (Meles meles). Policy to control bTB is vigorously debated and contentious because of its implications for the livestock industry and because some policy options involve culling badgers, the most important wildlife reservoir. This paper describes a project to provide a succinct summary of the natural science evidence base relevant to the control of bTB, couched in terms that are as policy-neutral as possible. Each evidence statement is placed into one of four categories describing the nature of the underlying information. The evidence summary forms the appendix to this paper and an annotated bibliography is provided in the electronic supplementary material.

Because you are unlikely to read this landmark paper O gentle reader, I’ve read it for you, and here are the highlights:

 

Why should we care about bovine tuberculosis (bTB)?
Bovine tuberculosis (bTB) is a major disease of cattle that can also affect humans, and many other livestock and wild animal species. Human infection has not been a major public health problem in developed countries since the introduction of milk pasteurization. Advanced cases in cattle experience loss of condition, and this directly affects the economic value of the animal, but in most developed countries detection of infection leads to movement restrictions being placed on the herd, mandatory slaughter and economic losses for farmers. The English and Welsh governments estimate that they have spent £0.5 billion in the last decade on testing, compensation and research with further costs being borne by the agricultural industry.

 

Why not just vaccinate cows against (bTB)?
EU law currently prohibits the vaccination of cattle as it can mask the detection of infection. Vaccination of badgers is the subject of intense current research, and vaccination has been under way in Wales since 2012. The main protective effect for cattle vaccinated with BCG is to reduce the severity of disease. This is measured experimentally at post-mortem by comparing the extent of infection within the bodies of vaccinated and control cattle. A recent field trial in Ethiopia found that the carcasses of 13 vaccinated calves had 56–68% less disease than was seen in 14 control calves. If vaccinated cattle do become infected, it is likely that a reduction in the extent of disease will limit their infectiousness, reducing onward transmission to cattle and to wildlife.

 

Which got TB first, the badger or the cow?
Cases of bTB in cattle occur more frequently in regions that support higher densities of both badgers and cattle. Most studies that have looked for an association between high badger densities and elevated cattle TB incidence have not found one. Transmission occurs within wild badger populations; there is insufficient evidence currently available to say definitively whether the disease can persist in British badger populations without on-going transmission from cattle. Little is known about how M. bovis is transmitted between badgers and cattle. Transmission may be indirect; for example, through contamination of pasture, feed and drinking water. Alternatively, direct transmission via aerosol droplets at close contact may occur, possibly inside farm buildings as well as outdoors.

 

Why not just kill the infected badgers?
(Well, apart from the moral issues around this…) Badger culling was used routinely in the past, and its effectiveness was the subject of a major experiment, the Randomised Badger Culling Trial (RBCT), which ran from 1998 to 2006. The RBCT found that annual proactive culling, as conducted in the trial, resulted in a relative reduction in new confirmed cattle herd breakdowns inside culling areas, which persisted after the final culls in 2005 but subsequently diminished over a 6-year period. While culling was being carried out, there was an increase in the incidence of confirmed herd breakdowns on land surrounding (within 2 km) the RBCT proactive culling areas, though this rapidly waned after culling stopped. Reactive culling was discontinued in 2003 because bTB in these areas were significantly higher than in no-cull areas. Culling badgers is known to disrupt badger social structure, and this has been shown to cause badgers to move more frequently and over longer distances. This effect is known as perturbation. The idea that perturbation may result in increased disease transmission. It is not currently known whether alternative culling methods (e.g. shooting of free-ranging badgers or snaring) could reduce badger densities more or less effectively in Great Britain than the cage trapping used in the RBCT, nor how different reductions in badger numbers inside culling areas would influence impacts on cattle bTB on adjoining land.

 

What about better testing?
The gamma interferon (IFNg) test is used as an auxiliary test to the cervical tuberculin test (SICCT or ‘skin’ test) and has lower relative specificity (median animal-level specificity of 98%). IFNg identifies some exposed cattle not identified by the skin test and has a median estimated animal-level sensitivity of 67%. The IFNg test requires only a single farm visit and is then conducted in the laboratory, where it can be more consistently interpreted.

 

In other (i.e. my) words, we could probably control bTB using a combination of vaccination and better testing methods. If we wanted to.

 

Is a new approach needed to fight XDR-TB?

Thursday, April 18th, 2013

Tuberculosis and HIV Co-Infection Smallpox may have been eradicated 35 years ago, but we are still battling many other major global health scourges. Malaria, for example, kills some 1.2 million people every year, and recent cholera epidemics in Zimbabwe, Somalia and Haiti have killed thousands. The death toll from HIV/AIDS is even higher, with almost 2 million deaths last year, but new drugs and health care delivery mechanisms mean that this number is falling.

But there’s one major disease where the battle is still being badly lost – tuberculosis. Mycobacterium tuberculosis still kills nearly 2 million people in the developing world every year. Even more alarmingly, in 2005 researchers in the province of KwaZulu-Natal in South Africa spotted an outbreak of a strain of M. tuberculosis that was resistant to the four key classes of drugs used to treat the disease. These super drug-resistant bugs have now been found in 58 countries, their spread fuelled by the lethal combination of HIV and TB. The mortality rate worldwide for the victims of this extensively drug resistant TB (XDR-TB) is more than 80%, making diagnosis almost a death sentence.

The scientific and medical challenges are huge. We don’t have an effective vaccine. We lack diagnostics and biomarkers. The current drug regimen – multiple drugs that must be taken reliably for six months – is virtually impossible to administer successfully in the developing world, where rural farmers may have to walk three hours to the nearest clinic. Too often, treatment simply leads to the development of drug resistance. And we have only just begun to study the bacterium’s biology and to learn how it manipulates the human immune system.

To understand TB and its deadly synergy with HIV, and to develop new diagnostics and treatments, we need more research. But the current research model could use some help. This article describes a new approach that involves bringing world-leading basic research to the epicenter of epidemics, rather than trying to fight diseases from laboratories at universities or government agencies thousands of miles away.

Point of view: Basic research at the epicenter of an epidemic. (2013) eLife 2: e00639 doi: http://dx.doi.org/10.7554/eLife.00639

 

Still a long way to go to beat TB

Wednesday, February 13th, 2013

Mycobacterium tuberculosis A new tuberculosis vaccine, MVA85A, has recently been found to be less effective than initially thought, prompting widespread consternation in the press. The excellent NHS Choices website reports that “although the stories are based on solid science, the news is actually less worrying than the headlines suggest”. MVA85A is a booster vaccine that researchers hope might help improve the effectiveness of the existing BCG vaccine. Although the BCG is effective in the UK, new vaccines and boosters are needed as it is less effective in other countries. The effectiveness of BCG against tuberculosis is variable and has been found to be less effective in countries such as South Africa, where as many as 1% of the population has TB. An effective booster vaccine would therefore be useful. Although a recent study found the new vaccine is safe, it does not appear to have performed better than the placebo in children who had already had the BCG vaccine. Despite this setback, several further lines of investigation are being pursued by researchers, who now want to look at whether the MVA85A vaccine might work better in other sub-populations, and whether it might improve protection against pulmonary tuberculosis (lung infection) in people who have HIV, for example.

NHS Choices: Disappointing results for new TB vaccine

 

Another paper just published has found that whole genome sequencing of Mycobacterium tuberculosis provides more accurate information on clustering and longitudinal spread of the pathogen than the standard test (classical genotyping). Importantly, whole genome sequencing revealed that first outbreak isolates were falsely clustered by classical genotyping and do not belong to one recent transmission chain. By using whole genome sequencing, the authors estimated that the genetic material of M. tuberculosis evolved at a rate at 0.4 mutations per genome per year, suggesting that the bacterium grows in its natural host (infected people) with a doubling time of 22 hours, or 400 generations per year. This finding about the evolution of M. tuberculosis indicates how information from whole genome sequencing can be used to help trace future outbreaks. Importantly, as the costs of whole genome sequencing are declining, this test could soon become the standard method for identifying transmission patterns and rates of infectious disease outbreaks.

Whole Genome Sequencing versus Traditional Genotyping for Investigation of a Mycobacterium tuberculosis Outbreak: A Longitudinal Molecular Epidemiological Study. (2013) PLoS Med 10(2): e1001387. doi:10.1371/journal.pmed.1001387

TB’s revenge 

Wednesday, January 2nd, 2013

The world is starting to win the war against tuberculosis, but drug-resistant forms pose a new threat.
Nature News: http://goo.gl/Ua9c8

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Tuberculosis and HIV Co-Infection

Friday, April 20th, 2012

Tuberculosis and HIV Co-Infection

Tuberculosis (TB) and HIV co-infections place an immense burden on health care systems and pose particular diagnostic and therapeutic challenges. Infection with HIV is the most powerful known risk factor predisposing for Mycobacterium tuberculosis infection and progression to active disease, which increases the risk of latent TB reactivation 20-fold. TB is also the most common cause of AIDS-related death. Thus, M. tuberculosis and HIV act in synergy, accelerating the decline of immunological functions and leading to subsequent death if untreated. The mechanisms behind the breakdown of the immune defense of the co-infected individual are not well known. The aim of this review is to highlight immunological events that may accelerate the development of one of the two diseases in the presence of the co-infecting organism.

 

Tuberculosis and HIV Co-Infection. (2012) PLoS Pathog 8(2): e1002464. doi:10.1371/journal.ppat.1002464

 

Phagosomal rupture caused by Mycobacterium tuberculosis

Wednesday, February 15th, 2012

Phagosomal rupture

Mycobacterium tuberculosis is one of the most life-threatening pathogens of all time. Despite the development of vaccines and antibiotics, this pathogen is still a major public health problem. The HIV epidemic has also had an important impact on the rise of M. tuberculosis infections since immunodeficient people are highly susceptible. Commonly, M. tuberculosis has been thought to reside in a membrane-bound compartment within its host cells during the entire infection cycle from invasion to cell death.

Using a fluorescence-based method, new research provides evidence that M. tuberculosis is able to rupture its membrane-bound compartment and gain access to the host cytosol, where it can cause cell death. Importantly, the researchers were able to track the dynamics of infection to understand the consequences of M. tuberculosis phagosomal rupture. This revealed that phagosomal rupture results in cell toxicity and host cell death involving necrosis. Together, this data provides a new angle in the worldwide fight against tuberculosis and could lead to new approaches in the development of innovative treatments.

 

Phagosomal Rupture by Mycobacterium tuberculosis Results in Toxicity and Host Cell Death. (2012) PLoS Pathog 8(2): e1002507. doi:10.1371/journal.ppat.1002507
Survival within macrophages is a central feature of Mycobacterium tuberculosis pathogenesis. Despite significant advances in identifying new immunological parameters associated with mycobacterial disease, some basic questions on the intracellular fate of the causative agent of human tuberculosis in antigen-presenting cells are still under debate. To get novel insights into this matter, we used a single-cell fluorescence resonance energy transfer (FRET)-based method to investigate the potential cytosolic access of M. tuberculosis and the resulting cellular consequences in an unbiased, quantitative way. Analysis of thousands of THP-1 macrophages infected with selected wild-type or mutant strains of the M. tuberculosis complex unambiguously showed that M. tuberculosis induced a change in the FRET signal after 3 to 4 days of infection, indicating phagolysosomal rupture and cytosolic access. These effects were not seen for the strains M. tuberculosisΔRD1 or BCG, both lacking the ESX-1 secreted protein ESAT-6, which reportedly shows membrane-lysing properties. Complementation of these strains with the ESX-1 secretion system of M. tuberculosis restored the ability to cause phagolysosomal rupture. In addition, control experiments with the fish pathogen Mycobacterium marinum showed phagolysosomal translocation only for ESX-1 intact strains, further validating our experimental approach. Most importantly, for M. tuberculosis as well as for M. marinum we observed that phagolysosomal rupture was followed by necrotic cell death of the infected macrophages, whereas ESX-1 deletion- or truncation-mutants that remained enclosed within phagolysosomal compartments did not induce such cytotoxicity. Hence, we provide a novel mechanism how ESX-1 competent, virulent M. tuberculosis and M. marinum strains induce host cell death and thereby escape innate host defenses and favor their spread to new cells. In this respect, our results also open new research directions in relation with the extracellular localization of M. tuberculosis inside necrotic lesions that can now be tackled from a completely new perspective.


As if it wasn’t bad enough

Monday, August 22nd, 2011

Sudan Sudan is a large country with a diverse population and history of civil conflict. Poverty levels are high with a gross national income per capita of less than two thousand dollars. The country has a high burden of tuberculosis (TB) with an estimated 50,000 incident cases during 2009, when the estimated prevalence was 209 cases per 100,000 of the population. Few studies have been undertaken on TB in Sudan and the prevalence of drug resistant disease is not known.

In this study Mycobacterium tuberculosis isolates from 235 patients attending three treatment centers in Sudan were screened for susceptibility to isoniazid, rifampicin, ethambutol and streptomycin by the proportion method on Lowenstein Jensen media. 232 isolates were also genotyped by spoligotyping. Demographic details of patients were recorded using a structured questionnaire. Statistical analyses were conducted to examine the associations between drug resistance with risk ratios computed for a set of risk factors (gender, age, case status – new or relapse, geographic origin of the patient, spoligotype, number of people per room, marital status and type of housing).

Multi drug-resistant tuberculosis (MDR-TB), being resistance to at least rifampicin and isoniazid, was found in 5% of new cases and 24% of previously treated patients. Drug resistance was associated with previous treatment with risk ratios of 3.51 for resistance to any drug and 5.23 for MDR-TB. Resistance was also associated with the geographic region of origin of the patient, being most frequently observed in patients from the Northern region and least in the Eastern region with risk ratios of 7.43 and 14.09 for resistance to any drug and MDR-TB.

“We conclude that emergence of drug resistant tuberculosis has the potential to be a serious public health problem in Sudan and that strengthened tuberculosis control and improved monitoring of therapy is needed. Further surveillance is required to fully ascertain the extent of the problem.”

 

Tuberculosis in Sudan: a study of Mycobacterium tuberculosis strain genotype and susceptibility to anti-tuberculosis drugs. BMC Infectious Diseases 11:219 2011

The rise and fall of the Mycobacterium tuberculosis genome

Friday, July 22nd, 2011

Mycobacterium tuberculosis genome Before the genomic era there was already a longstanding interest in understanding the origins of bacterial pathogens and the molecular attributes of virulence. Large-scale genome sequencing has provided a rapid and unbiased means of uncovering the evolution of many pathogens, contributing to both fundamental microbiological insights and the development of new disease-control strategies. For these reasons, the evolution of one of the most devastating human pathogens, Mycobacterium tuberculosis, has captivated researchers since its discovery in 1882. This interest was stimulated not only by the epidemiologic importance of the pathogen but also by the lack of consensus on its origins and its apparent exception to the stereotypes of bacterial evolution (e.g. acquisition of pathogenicity islands). So where did M. tuberculosis come from?

 

The rise and fall of the Mycobacterium tuberculosis genome. Trends Microbiol. 2011 19(4): 156-161
When studied from the perspective of non-tuberculous mycobacteria (NTM) it is apparent that Mycobacterium tuberculosis has undergone a biphasic evolutionary process involving genome expansion (gene acquisition and duplication) and reductive evolution (deletions). This scheme can instruct descriptive and experimental studies that determine the importance of ancestral events (including horizontal gene transfer) in shaping the present-day pathogen. For example, heterologous complementation in an NTM can test the functional importance of M. tuberculosis-specific genetic insertions. An appreciation of both phases of M. tuberculosis evolution is expected to improve our fundamental understanding of its pathogenicity and facilitate the evaluation of novel diagnostics and vaccines.