Tuberculosis: mechanism and therapy

Hyeon-Ghil Shin Tuberculosis is known for long time ago, but there are many unclear mechanisms and few therapies available. Many population of third world still suffer from tuberculosis. Mycobacterium that causes tuberculosis survives in macrophages, and it forms granuloma, which makes hard to cure tuberculosis. Rifampicin and isoniazid has good efficiency to treat tuberculosis patients, and BCG is the only vaccine that approved to be used commonly. Here we see mechanism of tuberculosis and therapies for tuberculosis, then emphasize the need of new therapy for tuberculosis

1. Introduction Tuberculosis is threatening the world, One-third of the people in the world are suffering from tuberculosis. Even though, proportion of death caused by tuberculosis is decreasing, but actual number of the dead is still increasing because growth of population keeps rapid increasing rate. There are vaccines and drugs to treat for tuberculosis patient. However, everyone cant be cured by drugs and vaccines that have been developed up to now, and many countries in the third world shows high mortality rate by tuberculosis because of deficiency of proper drugs and vaccines. We urgently need new drugs and vaccines that can be applied to every people and new way to cut down budget that are needed to make tuberculosis drugs and vaccines to save more tuberculosis patients in the third world. In this paper, I focus on the reason that causes vaccines and drugs workout inefficiently against tuberculosis and present therapies that have been developed by this time.

2. Mechanism 2.1 Granuloma This is a mass of macrophages and lymphocytes that is observed in infection sites. It is hallmark of tuberculosis. Tuberculosis has a strong contagiosity, so only ten mycobacterium or less than ten can make host are infected. Infection process started by tuberculosis enters into the lung, and mycobacterium is phagocytized by an alveolar macrophage, which is located on surface of lung epithelium. Tuberculosis-containing macrophages are internalized into the lung, and cytokines and chemokines that are released from tuberculosis-containing macrophages recruit neutrophils and lymphocytes. Recruited cells also release cytokines and chemokines that make more macrophages and lymphocytes which will be infected by tuberculosis. Signaling cascade keep gathering mononuclear cells, and these cells form granuloma with fibrous cuff(Figure). This structure loses vascularization that causes oxygen deficiency, so necrosis started from center of it. [1] Caseation which are beginning during necrosis leads to breaking out of granuloma that releases mycobacteria. This feature gives less chance to drug that interacts with mycobacterium. Fibrous cuff makes wall to prevent other materials to contact with inside of granuloma, so drugs cant close to infection site.

Infected macrophage

TNF-

TNF-, CCL2, CXCL10, IL1-, IL1, IL18

Neutrophils natural killer T cells, CD4+ T cells, CD8+ T cells

TNF production increase

TNF-, CCL2, CXCL10, CXCL9, CCL3, CCL4, CCL5

Figure. The process of the cytokine, chemokine amplification From the infected macrophages,

Recruitment of uninfected macrophages

Inhibit proinflammatory
Recruitment of lymphocytes CD4+, CD8+, T cells, B cells

response

cytokines are released and keeps calling other immune cells. In result of this recruitment, granuloma is formed which is hallmark of tuberculosis.

IFN-

2.2 Survival after phagocytosis Mycobacterium survives inside of phagosomes. Normally, what is phagocytized by macrophages acidify rapidly to pH 5, which arrests bacterial growth, and then it fuses with lysosome to be decomposed. However, tuberculosis-containing phagosomes acidify to pH6.4 by arresting the maturation of phagosomes and also fail to fuse with lysosomes, so it isnt decomposed and just stays in phagosome. Survival of mycobacterium is achieved by modulation of the phagosome, and this mechanism is mediated by cell-wall lipids and other bacterial effectors. [1]

3. Developing drug 3.1 Rifampicin Rifampicin is antibiotics, which is especially treated to tuberculosis patients. It is isolated from Streptomyces mediterranei. It binds to RNA polymerase, so that inhibit RNA synthesis. Eukaryotic cells have DNA-dependent RNA polymerases, and peptide sequence that doesnt exist in

mammalian RAN polymerase interacts with rifampicin; this is the reason why it doesnt affect to patients cells. Two main reasons make rifampicin has high selectivity against mycobacterium over human cells. The flat naphthalene ring and several hydroxyl groups are pharmacophore of rifampicin. [2] Although it has high selectivity and efficiency against tuberculosis patients, it is expensive to be used for wide populations. 3.2 Isoniazid Isoniazid(isonicotinic acid hydrazide) was found for treatment of tuberculosis in 1952, and 1962.
[ 3 ]

In mycobacterium tuberculosis, catalase-peroxidases KatG is an unique catalase, and the peroxidase activity of KatG is responsible for activation of isoniazid. Isoniazid is a pro-drug catalyzed by KatG and formed isoniazid-NADH complex. This complex inhibit fatty acid synthase of mycobacterium, so that mycobacterium cant form cell wall, and radicals generated by isoniazid damage on mycobacterium.[4] However, many side effects on liver and CNS with many symptoms are known 3.3 Drug-resistant tuberculosis Isoniazid and rifampicin has good efficiency to treat tuberculosis. However, some mycobacterium unaffected by those two drugs. These species are appeared because drugs are not administered properly; deficiency of drugs, patients who forget to take drugs or want to halt drugs administration because they feel better. The main site for mutations associated with resistance to isoniazid is the catalase-peroxidase gene.

4. Developing vaccine Bacille Calmette-Guerin(BCG) which is live mycobacteria is the only vaccine currently licensed for treatment of tuberculosis. It was developed through serial in vitro passage of M.bovis which can

be used as a vaccine when it became toxic after serial process. It is usually treated to children and showing a high efficacy especially against severe forms of disease. However, there are several reports that BCG is efficacy for certain area, such as UK, but not in other area, like India. This phenomenon is explained by that BCG has become too weaken to generate proper immunity. Efforts to develop new vaccines are going on by other groups. [5] Most of them applying these strategies for vaccine development; improving BCG, attenuating strains of Mtb. In few years several vaccines would get approval and be used for tuberculosis patients.

Conclusion Tuberculosis has discovered before a long time ago. Records about tuberculosis are found from BC 1948. However, there are few therapies for tuberculosis patients. Diseases in developed country are focused on, and many people invest to cure these disease. In contrast, disease in developing country, which cause millions children die and should be more efforts to be invested, are scarcely paid attention. There are several groups to develop new vaccines, but it takes a few years. Even though, new vaccines are available, third world people who really urgently needs that vaccines may not get new vaccines because of its cost. Medicine is for saving people, not for money. More research for development of new therapy and new method to make drug economically are required.

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5. David G Russell, Clifton E Barry 3rd and JoAnne L Flynn, Tuberculosis: what we dont know can, and does, hurt us, Science (New York, N.Y.) 328, No. 5980 (May 14, 2010): 852-856.