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Pathogen Page

Mycobacterium tuberculosis

General Information
Vaccine Related Pathogen Genes
1. Ag85B from M. tuberculosis H37Rv
2. Apa
3. bfrA
4. DnaK
5. drrC
6. EsxA (ESAT-6)
7. EsxB
8. esxV
9. esxW
10. fadD26
11. FbpA (Ag85A)
12. FbpD
13. HBHA
14. KatG
15. leuD
16. lysA
17. mce-2
18. mce-3
19. Mpt63
20. MPT64
21. MPT83
22. Mtb72F
23. panC
24. panD
25. PE20
26. PepA
27. PhoP
28. PPE14
29. PPE18
30. PPE31
31. PPE42
32. proC
33. PstS1
34. PstS3
35. RD1
36. Rv1813c
37. Rv2660c
38. SecA2
39. sigE
40. sigF
41. SodA
42. trpD
43. xyzzy
Vaccine Related Host Genes
1. APOBEC3B
2. C19orf66
3. CD70
4. Cxcl10
5. Cxcl11
6. Cxcl9
7. Defb3
8. Defb4
9. Ebi3
10. Fth1
11. Ftl
12. GPR182
13. GPX1
14. HIST1H2BE
15. HIST2H4A
16. human IFNG
17. IFNG
18. Ifng (Interferon gamma)
19. IL-1b
20. IL-6
21. IL10
22. IL10
23. Il10 (interleukin 10)
24. Il12b
25. Il15
26. Il17f
27. IL2
28. Il2
29. Il4 (interleukin 4)
30. IL6
31. lipY
32. Ltf
33. Nos2
34. PCDHB1
35. PTCD1
36. SLC11A1
37. STAG3
38. TBX21
39. TLR1
40. TNF-alpha
41. TSC22D4
Vaccine Information
References

I. General Information

1. NCBI Taxonomy ID:

1773

2. Disease:

Tuberculosis

3. Introduction

At the end of 19th century, Robert Koch discovered that Mycobacterium tuberculosis was the causative agent of tuberculosis (TB). TB is a major cause of morbidity and mortality throughout the world despite more than a half century of widespread vaccination, claiming millions of lives every year. The extraordinary high prevalence of the latent infection [estimated at one-third of the world's population] is one of the main factors contributing to the high incidence of active tuberculosis. The other factor is convergence of the TB and HIV epidemics. With HIV/AIDS fueling the TB crisis, the WHO has estimated that more than 1 billion people will be infected with TB bacilli in the next 20 years (Gupta et al., 2007).
M. tuberculosis are Gram-positive bacilli lacking both flagella and capsules. M. tuberculosis is preferentially established in the pulmonary system in a dormant state after initial infection via aerosol transmission. The M. tuberculosis complex, a group of Mycobacterium including M. tuberculosis, M. bovis, M. bovis BCG, M. africanum, and M. microti, are tuberculosis-inducing bacteria which have low horizontal gene transfer and variable levels of virulence (Ducati et al., 2006).

4. Microbial Pathogenesis

Mouse and guinea pig models have been used extensively to understand the host and pathogen-specific factors controlling pathogenesis of tuberculosis. Transmission of M. tuberculosis via intravenous route in murine models is followed by initial bacterial replication and subsequent macrophage activation via IL-6, IL-12, and TNF-mediated mechanisms. Bacterial load is significantly reduced at 2 weeks post-infection in liver and spleen. After load reduction, selected lymphocytes are activated which can then induce macrophages to begin producing nitric oxide via the iNOS pathway. Bacteria which survive the initial clearance by the host enter a viable yet non-replicating persistence stage. Factors such as immune suppression from aging, iNOS inhibition, and corticosteroid therapy can shift the dormant bacilli back into a replicative state. As an example of preferred host niche, transmission via inhalation will sometimes result in bacilli establishing infection in macrophage phagosomes in the lung. These macrophages become lodged in the calcified tubercles, and can later initiate formation of granulomas through a CD4-mediated delayed-type hypersensitivity reaction. Each granuloma can remain dormant, reduce in size and possibly disappear, initiate progressive interstitial fibrosis in lung tissue, and/or necrotize (Ernst et al., 2007). Similar mechanisms are observed in liver tissue (Ducati et al., 2006).
Numerous pathogen- and host-specific factors related to pathogenesis of tuberculosis are potential vaccine targets. For example, the Bacille-Calmette Guiren (BCG) vaccine was obtained from an M. bovine strain which lost its virulence after 39 passages (Ducati et al., 2006). Evidence from subtractive hybridization experiments, along with whole-genome microarrays and BAC arrays and other experimental evidence, suggests that the RD1 locus is the main virulence feature that is absent from 13 strains of avirulent BCG yet present in hundreds of other M. tuberculosis strains (Ernst et al., 2007). RD1 is related to the regulation of the early secreted antigen 6 kDa [ESAT-6] secretion system 1[ESX-1], an important pathway which is linked to the recruitment and infection of macrophages to initially infected sites and subsequent disease propagation (Ernst et al., 2007).

5. Host Ranges and Animal Models

Host ranges extend to many animals, including human, mouse, guinea pig, rabbit, and cattle. The most predominant animal used to study M. tuberculosis for virulence assessment and vaccine development is likely the mouse, which include C57BL/6 and BALB/c strains, mainly due to cost effectiveness for long-term vaccination/challenge studies. Dunkin Hartley guinea pigs are often used in M. tuberculosis studies as a close model for the overall pathogenesis in humans.

6. Host Protective Immunity

Although it is known that IFN-gamma is essential for protective immunity, animal and human studies have found that IFN-gamma alone is not sufficient for the prevention of TB disease. There is evidence that IL-23, a recently described member of the IL-12 family of cytokines, is important in the immuno-pathogenesis of TB. There is also evidence that regulatory T cells (Treg) are present in TB disease and that Treg may suppress effector T cell responses (Fletcher, 2007). New vaccines seek to target specific CD1, CD4+, and CD8+ T and B cell responses to assist in eradicating the disease via improved clearance of infected cells and bacterial loads.

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