Mutant Strain of Tuberculosis Is More Effective Killer

Infectious disease researchers have found that a strain of tuberculosis bacteria that had been modified by the removal of a virulence gene was actually more pathogenic than the original wild-type strain.

Tuberculosis is caused by M tuberculosis, which infects one-third of the world's population and kills two million people per year. To better understand the virulence factors that determine how the bacteria infect host cells, investigators at the University of California (Berkeley, USA) genetically engineered a strain of M tuberculosis lacking the mce1 operon. Organisms from the mutant strain and from the original wild-type strain were injected into mice.

The investigators reported in the December 8, 2003, online edition of the Proceedings of the [U.S.] National Academy of Sciences that the strain of M tuberculosis lacking the mce1 operon was unable to enter a stable persistent state of infection in mouse lungs. Instead, the mutant continued to replicate and killed the mice more rapidly than did the wild-type strain. By 27 weeks, the mutant-infected mice started to die, while their counterparts infected with the wild-type strain survived until the end of the experiment at 41 weeks.

Mouse macrophages growing in tissue culture were infected with the mutant strain. The bacteria displayed reduced ability to induce the production of tumor necrosis factor alpha, IL-6, monocyte chemoattractant protein 1, and nitric oxide (NO), but not IL-4. When the missing genes were replaced, the mutant strain stimulated tumor necrosis factor alpha and NO production by mouse macrophages at nearly the same levels as the wild-type strain. These results suggest that the mce1 operon may be involved in modulating the host inflammatory response in such a way that the bacterium can enter a persistent state without being eliminated or causing disease in the host.
"The hallmark of the TB bacterium is its ability to stay dormant in a person's body for years, making it one of the most successful bacteria around,” explained senior author Dr. Lee Riley, professor of epidemiology and infectious diseases at the University of California. "Even if we could treat all the people now with active infection, we would never be able to wipe out TB entirely because 60% of the people exposed to TB develop latent infections. TB is very difficult to treat not because it kills people rapidly, but because it stays dormant. By understanding the mechanism behind latency, we may also be able to develop new diagnostic tests to predict who will develop the active disease.”



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