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Mycobacterium tuberculosis has evolved to be the world's most successful pathogen. If you wanted to be a pathogen, I would argue that the strategy of just going in and killing your host is not a good one. It's not good to be like smallpox, which kills most mammalian hosts. You'd rather be like M. tuberculosis and infect everyone in the population, causing disease only when the patient is dying and you know it's time to get out. Prior to the HIV epidemic, the largest number of TB cases in the U.S. were in old folks homes where people had been infected with TB 50 years earlier, and it was controlled by their immune system. As a patient's immune system waned, M. tuberculosis caused disease in the lungs so it could be spread. In Africa and in Asia, where most everybody is infected with TB, the way that people first learn they're infected with HIV is when they become immunosuppressed and get TB.
M. tuberculosis has evolved functions to persist in the face of innate and adaptive immunity as well as drugs. You can see this persistence phenotype very clearly if you look at its growth kinetics in a mouse. TB grows exponentially for the first two and a half weeks until you get the onset of adaptive immunity. Then TB enters a hunkered-down state where it's resistant to the killing mechanisms of the immune system. This is a typical biological reaction to an adverse condition—it's not any different from the trees in my backyard that are able to survive winter. We have to figure out how to kill the hunkered-down bacteria, to tear apart how TB evades the immune system.
To prove that a phenotype—a property like virulence or drug resistance—is caused by a specific genotype, you have to isolate a mutant, clone a genotype, and transfer it. I call this Koch's corollary, after Robert Koch, the man who discovered the cause of TB in 1882. Yet, for years we couldn't fulfill Koch's corollary. We didn't know the mechanism of attenuation for BCG—a live tuberculosis vaccine developed by two French scientists that has been given to half the world's population—until more than 70 years after it was introduced. We used drugs like isoniazid for more than 40 years without knowing their targets of action. We did not know the genetic basis for any TB virulence factor.
Photo: Sean Kernan
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