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ScienceWeek
MICROBIOLOGY: ON THE MYCOBACTERIUM OF TUBERCULOSIS
The following points are made by J. Pieters and H. Ploegh (Science 2003 302:1900):
1) Mycobacterium tuberculosis is one of the deadliest pathogens on Earth. This mycobacterium, the cause of tuberculosis, spends almost its entire life inside the macrophage, a cell designed to destroy microbial pathogens. Clearly, M. tuberculosis must have coevolved with its human host to acquire and maintain mechanisms that promote long-term cohabitation and ensure its evolutionary success.
2) Darwin et al. (1) have provided a view into an unexpected strategy used by M. tuberculosis to avoid destruction within the phagosomes of macrophages. It turns out that the proteasomes of this mycobacterium protect the microbe from the damaging effects of nitric oxide and its derivatives produced inside phagolysosomes. These findings highlight a new function for the prokaryotic proteasome and identify a new target for the development of antimycobacterial drugs.
3) Infection with M. tuberculosis usually starts with inhalation of small droplets containing the mycobacteria, which make their way to the lung, where they are internalized by alveolar macrophages. M. tuberculosis thrives within macrophage phagosomes by actively blocking their fusion with lysosomes (2), so avoiding destruction. This is one of the reasons why M. tuberculosis infections are so prevalent, affecting one-third of the global population.
4) Nonetheless, tuberculosis as an endemic disease remains confined to certain geographical areas. In healthy immunocompetent individuals, the innate immune response against tuberculosis is mediated largely by interferon-gamma (3), which up-regulates and induces expression of genes involved in the generation of specific immunity. Interferon-gamma also triggers generation of nitric oxide by activating transcription of the gene encoding inducible nitric oxide synthase (iNOS) (4,5). In turn, nitric oxide acts as a precursor for the production of reactive nitrogen intermediates (RNIs). M. tuberculosis is extremely sensitive to attack by RNIs; thus, the host's ability to generate RNIs is essential to control mycobacterial growth.
5) Darwin et al (1) reasoned that because mycobacteria survive for decades in immunocompetent hosts, the microbe must be able to counter the danger of exposure to nitric oxide and its related products. To identify potential genes required by M. tuberculosis to resist RNIs, Darwin et al used an elegant transposon-based mutagenesis scheme to isolate mycobacterial genes that are conditionally essential. A screen for mutant mycobacteria hypersensitive to mildly acidified nitrite, like that encountered inside macrophage phagosomes, identified five mutants with insertions in genes that encode a proteasome-associated adenosine triphosphatase (ATPase) called mpa (Rv2115c) and a proteasome-associated factor called paf (Rv2097c). Mice challenged with these mutant mycobacteria were able to combat infection because the mutants had reduced virulence. This finding underscores the importance of the mpa and paf genes for mycobacterial survival in vivo.
References (abridged):
1. K. H. Darwin, S. Ehrt, J.-C. Gutierrez-Ramos, N. Weich, C. F. Nathan, Science 302, 1963 (2003)
2. J. A. Armstrong, P. D. A. Hart, J. Exp. Med. 134, 713 (1971)
3. J. L. Casanova, L. Abel, Annu. Rev. Immunol. 20, 581 (2002)
4. D. Dalton et al., Science 259, 1739 (1993)
5. Q. W. Xie et al., Science 256, 225 (1992)
Science http://www.sciencemag.org
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ON MULTI-DRUG RESISTANT TUBERCULOSIS
The following points are made by C. Dye et al (Science 2002 295:2042):
1) The Mycobacterium tuberculosis complex, including its drug-resistant forms, is a group of pathogens with low reproductive rates and long generation times, causing epidemics that run over centuries. Tuberculosis ranks among the most important burdens on human health, not because the total number of cases is especially large (approximately 9 million per year worldwide), but because approximately one-quarter of sufferers die, most of them young adults. Untreated or untreatable disease would kill more, approximately half of all cases. Globally, the number of tuberculosis cases is rising at 2 percent per year, and the fear is that the number of cases resistant to antibiotics may be increasing much faster.
2) The perceived threat of drug-resistant tuberculosis is enormous. The biggest menace is multi-drug-resistant tuberculosis, caused by strains resistant to at least isoniazid and rifampcin, the two principal first-time drugs used in combination chemotherapy. Health warnings have been issued in correspondingly strong language, not just in the popular press, but also in principal scientific and medical journals. Among various readings of the evidence, the spread of multi-drug-resistant tuberculosis has been classified as a global pandemic more deadly than AIDS, with the potential to destabilize society. Drug-resistant mycobacteria are said to be on the rampage, and multi-drug-resistant tuberculosis is thought to have become the norm. In the year 2000, an estimated 273,000 of 8.7 million new tuberculosis cases were multi-drug resistant, with the highest proportion of multi-drug resistant new cases in Estonia (14 percent); Henan Province, China (11 percent); Latvia (9 percent); and the Ivanovo and Tomsk provinces in Russia (9 percent and 7 percent, respectively). Resistance is very unevenly distributed around the world: an estimated 70 percent of new multi-drug-resistant tuberculosis cases occur in just 10 countries.
Science http://www.sciencemag.org
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TUBERCULOSIS AS A GLOBAL DISEASE
Clinical tuberculosis is a disease caused by Mycobacterium tuberculosis, Mycobacterium bovis, or Mycobacterium africanum. Other *mycobacteria cause diseases similar to tuberculosis, but they generally respond poorly to drugs effective for tuberculosis. In developed countries, human tuberculosis occurs almost exclusively from inhalation of organisms dispersed as droplet nuclei from a person with pulmonary tuberculosis whose *sputum smear is positive. The organism may float in the air for several hours, thus increasing the chance of spread.
Case rates vary by country, age, race, sex, and socioeconomic status. In the US, 21,337 cases were reported in 1996. The incidence of tuberculosis has increased markedly among persons infected with human immunodeficiency virus (HIV), particularly among male drug users 25 to 44 years old. Signs of what is considered a potentially very dangerous epidemic of tuberculosis have already appeared, with the advent of HIV infection creating the circumstances not only for an increased incidence of tuberculosis, but also for the development of organisms resistant to all first-line drugs.
The following points are made by C. Dye et al (J. Amer. Med. Assoc. 1999 282:477):
1) The authors present the results of a study to estimate the risk and prevalence of Mycobacterium tuberculosis infection and tuberculosis incidence, prevalence, and mortality, including disease attributable to HIV, for 212 countries in 1997.
2) In 1997, new cases of tuberculosis worldwide ("incidence") totaled an estimated 7.96 million, including 3.52 million of infectious pulmonary disease (smear positive). 2) In 1997, there were 16.2 million existing cases of tuberculosis ("prevalence").
3) In 1997, an estimated 1.87 million people died of tuberculosis, and the global case fatality rate was 23 percent, but exceeded 50 percent in some African countries with high HIV rates.
4) In 1997, global prevalence of Mycobacterium tuberculosis infection was 32 percent (1.86 billion people). In 1997, 80 percent of all incident tuberculosis cases were found in 22 countries, with more than half the cases occurring in 5 Southeast Asian countries (India, Indonesia, Bangladesh, Thailand, Myanmar).
5) The authors conclude: "The global burden of tuberculosis remains enormous, mainly because of poor control in Southeast Asia, sub-Saharan Africa, and eastern Europe, and because of high rates of Mycobacterium tuberculosis and HIV co-infection in some African countries."
J. Am. Med. Assoc. http://www.jama.com
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Notes:
mycobacteria: The Mycobacteria are rod-shaped aerobic bacteria that do not form spores. Although they do not stain readily, once stained, they resist decoloration by acid or alcohol, and are therefore called "acid-fast" bacilli. There are more than 50 mycobacteria species. Mycobacterium leprae causes leprosy. In tissue, Mycobacterium tuberculosis bacilli are thin straight rods measuring approximately 0.4 x 3 microns. On artificial media, both spherical and rod forms occur. True tubercle bacilli are acid-fast, the characteristic dependent on the integrity of the waxy envelope of the organism.
sputum smear: A standard technique for detection of tuberculosis is examination of sputum or other material for acid- fast bacilli by Ziehl-Neelsen acid-fast staining. If acid-fast organisms are found in an appropriate specimen, this is considered presumptive evidence of mycobacterial infection.
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