Mycobacterium tuberculosis: Difference between revisions

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===Higher order taxa===
===Higher order taxa===


Domain: Bateria;  
Domain: Bacteria;  
Phylum: Actinobacteria;
Phylum: Actinobacteria;
Class: Actinobacteria;
Class: Actinobacteria;

Revision as of 18:35, 5 June 2007

A Microbial Biorealm page on the genus Mycobacterium tuberculosis

Classification

Higher order taxa

Domain: Bacteria; Phylum: Actinobacteria; Class: Actinobacteria; Order: Actinomycetales; family: Mycobacteriaceae; Genus: Mycobacterium

Species

The mycobacterium tuberculosis complex (MTC) consists of Mycobacterium africanum, Mycobacterium bovis, Mycobacterium canettii, Mycobacterium microti, Mycobacterium tuberculosis.

Description and significance

Mycobacterium tuberculosis is a acid fast bacteria, which can form acid-stable complexes when certain arylmethane dyes are added. (4) All species of mycobacteria has ropelike structures of peptidoglycan that are arranged in such a way to give them properties of an acid fast bacteria. (4) Mycobacteria are abundant in soil and water, but Mycobacterium tuberculosis is mainly identified as a pathogen that lives in the host. Some species in its Mycobacterium tuberculosis complex had adapted its genetic structure specifically to infect human populations.

M. tuberculosis could be isolated in labs and stored at –80 degrees to be studied extensively, and the most commonly used strain of M. tuberculosis is the H37Rv strain. One way to study M. tuberculosis in culture is to collect samples of mononuclear cells in peripheral blood samples from a healthy human donor and challenge macrophages with the MTC. M. Tuberculosis has very simple growth requirements and is able to grow slowly in harsh conditions. Their acid-fast property is the strongest when there is glycerol around. However, when glucose is the main source of nutrient, the utilization of glycerol by M. Tuberculosis is inhibited. Therefore, it’s been shown that glutatmate, and not glucose, is actually the main source of nutrient for initiating growth. (4)

Since as many as 32% of the human population is affected by Tuberculosis (TB), an airborne disease caused by infection of M. tuberculosis in one way or another, and about 10% of them becomes ill per year (6), it is not hard to imagine the significance in understanding the genome of the pathogen to develop and improve strategies for treatment by developing specific drugs that target the gene products of M. tuberculosis.

Genome structure

Mycobacterium tuberculosis has circular chromosomes of about 4,200,000 nucleotides long. The G+C content is about 65%. (13)

The genome of M. tuberculosis was studied generally using the strain M. tuberculosis H37Rv. The genome contains about 4000 genes. Genes that code for lipid metabolism are a very important part of the bacterial genome, and 8% of the genome is involved in this activity. (7)

The different species of the mycobacterium tuberculosis complex show a 95-100% DNA relatedness based on studies of DNA homology, and the sequence of the 16S rRNA gene are exactly the same for all the species. So some scientists suggest that they should be grouped as a single species while others argue that they should be grouped as varieties or subspecies of M. tuberculosis. (2)

Plasmids in M. tuberculosis is important in transferring virulence because genes on the plasmids are more easily transferred than genes located on the chromosome (plasmid), one such 18kb plasmid in the M. tuberculosis H37Rv strain was proven to conduct gene transfers.

Cell structure and metabolism

M. tuberculosis has a tough cell wall that prevents passage of nutrient into and excreted from the cell, therefore giving it the characteristic of slow growth rate. The cell wall of the pathogen looks like a Gram-positive cell wall. The cell envelope contains a polypeptide layer, peptidoglycan layer, and free lipids. In addition, there is also a complex structure of fatty acids such as mycolic acids that appear glossy. (8) The M. tuberculosis cell wall contains three classes of mycolic acids: alpha-, keto- and methoxymycolates. The cell wall also contains lipid complexes including acyl glcolipids and other complex such as free lipids and sulfolipids. There are porins in the membrane to facilitate transport. Beneath the cell wall, there are layers of arabinogalactan and peptidoglycan that lie just above the plasma membrane. (14)

The M. tuberculosis genome encodes about 190 transcriptional regulators, including 13 sigma factors, 11 two-component system and more than 140 transcription regulators. Several regulators have been found to respond to environmental distress, such as extreme cold or heat, iron starvation, and oxidative stress. (11) To survive in these harsh conditions for a prolonged period in the host, M, tuberculosis had learned to adapt to the environment by allowing or inhibiting transcription according to its surroundings.(3)

Ecology

The Mycobacterium tuberculosis forms a complex with other higher related bacteria called the M. tuberculosis complex that consists of 6 members: Mycobacterium tuberculosis and Mycobacterium africanmum, which infect humans; Mycobacterium microti, which infects vole; Mycobacterium bovis, which infects other mamlian species as well as humans; M. bovis BCG, a variant of Mycobacterium bovis and Mycobacterium canettii, a pathogen that infects humans. (7) M. tuberculosis first infected humans 10,000-15,000 years ago. (10) It has been found in early hominids originated in East-Africa. Therefore, studying the population structure of the species might provide insights about Homo sapiens' migratory and demographic history.

Once inside the human host cell, Mycobacterium tuberculosis inflicts a contagious-infectious disease called tuberculosis (TB), although the disease could either be latent or active depending on the ability of the person’s immune system to defend against the pathogen. In 1993, the World Health Organization declared TB a global public health emergency. It is estimated that one third of the world population is infected by Mycobacterium tuberculosis, which leads to 8 to 10 million new cases, and 3 million deaths each year. (10) The disease especially affects those in developing countries, those of the aging population and those who are have HIV/AIDs because of their waned immune system. (10)

Because TB is an infectious disease for humans, it is important to sequence the genome of the Mycobacterium tuberculosis in order to find drugs fight against the bacteria by developing potential drug targets. Especially since Mycobacterium tuberculosis is multi-drug resistance and could cause latent infection, it is especially hard to treat and prompts scientists to research for new drug targets by looking through the Mycobacterium tuberculosis genome and gene products.


Pathology

Mycobacterium tuberculosis infects the host cell mainly in the lung macrophages. The host recruits macrophages to the site of infection and begins phagocytosis of the organism. However, M. tuberculosis could escape phagosome-lysosome fusion, inhibit acidification or maturation of phagosomes, survive even with the presence of reactive oxygen and nitrogen intermediates, and therefore prevent them from being attacked by the host immune mechanism. In the macrophages, the bacteria continue to grow in individual macrophages, and as macrophages aggregate, M. tuberculosis spread intercellularly to other macrophages in the aggregation. Then macrophages move into deeper tissues and other monocytes are recruited. As M. tuberculosis continues to grow, macrophages develop into granulomas. Although controversial, it’s been said that M. tuberculosis grow inside granulomatous lesions in the lungs. (9)

Very little is known regarding host-microbe interaction that happens before M. tuberculosis gets into the macrophages and how M. tuberculosis adheres to the host is still being researched. But some research suggests that M. tuberculosis produces tiny pili that enable them to colonize the host. (1)

The principal means of transmission of tuberculosis is by infective particles produced through coughing by patients with active TB. The release of particles in the air carrying the pathogens could be inhaled and remain in suspension for hours without dying. In most cases, they will lie in the dormant form in the host cells and establish large bacterial reservoirs in the infected individual. When the host immune response is strong, they are contained in a form of caseous necrosis. (10) The typical symptoms of an active TB patient include weakness, fever, chest pain, respiratory insufficiency, fever and cough. (10) TB is especially hard to treat because M. tuberculosis has multidrug-resistant (MDR) and extensively drug resistant (XDR) strains. General treatment include chemotherapy and a combination of different lines of drug. (10)

Application to Biotechnology

Gene for histone-like protein (hupB [Rv2986c]) of Mycobacterium tuberculosis had been used to distinguishing members of the MTB complex from other mycobacterium species and differentiating between members within the complex.

In addition, in vivo complementation in mycobacterium tuberculosis strain H37Ra can be used to identify genomic fragment associated with virulence. By studying the genes encoding for virulent gene products, a combination of drugs and vaccines could be developed to target the MDR and XDR characteristic of the pathogen.

Current Research

Since the pathogen-host interaction of Mycobacterium tuberculosis is still unknown, much of the current research is geared towards the understanding of the mechanism of virulence. For example, one such research showed that prokaryotic- and eukaryotic-like isoforms of the glyozxylate cycle enzyme isocitrate lyase (ICL) are jointly required for fatty acid catabolism and virulence in Mycobacterium tuberculosis. This discovery provides insight such as drugs that are glycoxylate cycle inhibitors could be used to treat tuberculosis. (12).

Another group of scientists found that a newly identified protein with carboxyesterase activity is required for the virulence of Mycobacterium tuberculosis. They found that the gene MT2282 encodes a protein that is associated with carboxyesterase. It hydrolyze ester bonds of the substrate. When a mutant of this gene was used to infect mice, the mice’s life prolonged as compare with those that were infected with the wild type. (5)

In addition, as mentioned earlier, very little is known regarding host-microbe interaction that happens before M. tuberculosis gets into the macrophages and how M. tuberculosis adheres to the host is still being researched. One research suggested M. tuberculosis produces tiny pili that enable them to colonize the host by adhering to the host and invading the macrophages and epithelial cells of the host. (1) The pili produced are called MTP. The study is important because MTP could be used as vaccine because MTP-mediated events are critical for TB infection. (1)


References

1. Alteri, C.J., Xicohtencatl-Cortes, J., Hess, S. Caballero-Olin, G., Giron, J.A., and Friedman, R.L. “Mycobacterium tuberculosis produces pili during human infection.” Microbiology 2007; 104(12): 5145-5150.

2. Aranaz A, Liébana E, Gomez-Mampaso E, et al. “M. Tuberculosis subsp. caprae subsp. nov.: a taxonomic study of a new member of the Mycobacterium tuberculosis complex isolated from goats in Spain. Int J Syst Bacteriol 1999; 49:1263 73.

3. Banaiee, N., Jacobs Jr, W.R., and Ernst, J.D. “Regulation of Mycobacterium tuberculosis whiB3 in the mouse lung and macrophages.” Infection and Immunity 2006; 74: 6449-6457.

4. Barksdale, L. and Kim, K. “Mycobacterium.” Bacteriological Reviews 1977; 41: 217-372.

5. Bishai, W.R., Lun, S. “Characterization of a novel cell wall-anchored protein with carboyesterase activity required for virulence in Mycobacterium tuberculosis.” The Journal of Biological Chemistry 2007; 1-22.

6. Chen, M., Gan, H., and Rernold, H.G. “A mechanism of virulence: virulent M. Tuberculosis strain H37Rv, but not attenuated H37Ra, causes significant mitochondrial inner membrane disruption in macrophages leading to necrosis.” The Journal of Immunology 2006; 176: 3707-3716.

7. Cole, S.T. “Comparative and functional genomics of the Mycobacterium tuberculosis complex.” Microbiology (2002); 148: 2919-2928.

8. Cole, S. T. , Brosch, R. , Parkhill, J. , Garnier, T. , Churcher, C. , Harris, D. , Gordon, S. V. , Eiglmeier, K. , Gas, S. , Barry, C. E. “Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence.” Nature 1998; 393(6685): 537-44.

9. Cosma, C. L., K. Klein, R. Kim, D. Beery, and L. Ramakrishnan. “Mycobacterium marinum Erp is a virulence determinant required for cell wall integrity and intracellular survival.” Infect. Immun. 2006; 74:3125-3133.

10. Ducati, R.G., Ruffino-Netto, A., Basso, L.A., Santos, D.S. “The resumption of consumption – A review on tuberculosis.” Rio de Janeiro 2006; 101: 697-714.

11. Manganelli, R., Voskuil, M.I., Schoolnik, G.K., and Smith, I. “The Mycobacterium tuberculosis ECF sigma factor sigmaE: role in global gene expression and survival in macrophages.” Mol Microbiol 2006; 41: 423– 437.

12. Munoz-Elias, E.J., McKinney, J.D. “Mycobacterium tuberculosis isocitrate lyases 1 and 2 are jointly required for in vivo growth and virulence.” Nat Med. 2005; 11: 638-644.

13. NCBI. 24 May 2007. Welcome Trust Sanger Insitute. 2 June 2007 <http://www.ncbi.nlm.nih.gov/sites/entrez?db=genomeprj&cmd=Retrieve&dopt=Overview&list_uids=224>.

14. Riley, L.W. “Of mice, men and elephants: Mycobacterium tuberculosis cell envelope lipids and pathogenesis.” American Society for Clinical Investigation 2006; 116:1475-1478.

Edited by Ying Liu of Rachel Larsen and Kit Pogliano