Tuberculosis genetic control

Isoniazid is bactericidal against growing M. tuberculosis. Its mechanism of action remains unclear. (In the bacterium it is converted to isonicotinic acid, which is membrane impermeable, hence likely to accumulate intracellu-larly.) Isoniazid is rapidly absorbed after oral administration. In the liver, it is inactivated by acetylation, the rate of which is genetically controlled and shows a characteristic distribution in different ethnic groups (fast vs. slow acetylators). Notable adverse effects are peripheral neuropathy, optic neuritis preventable by administration of vitamin Be (pyridoxine) hepatitis, jaundice. 

Data with a polymodal distribution If we give a series of patients a standard oral dose of the anti-tuberculosis drug isoniazid, obtain a blood sample from each individual 6 h later and determine the isoniazid concentrations of those samples, the results will probably look like Figure 3.1. The data are bimodal, because the metabolism of isoniazid is genetically controlled and we all fall into one of two groups - fast or slow metabolizers. The fast metabolizers form the cluster at the low end of the concentration scale and the slow metabolizers form a distinct group with higher levels. 

Is the immune response to mycobacteria also under the control of the microbial genome Viewed from the perspective of M. tuberculosis, the 10% failure rate associated with natural immunity fully supports transmission of infection and maintenance of a healthy microbial population. Perhaps this represents a window generated by active immune subversion by the pathogen Or, from a more interactive viewpoint, pathogen variants may have been selected to exploit niches associated with variations in the immune response. To parallel the human studies, we can look for evidence of this in the genetic diversity of M. tuberculosis. 

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