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UC Berkeley Team Says Gene Set Increases tuberculosis Virulence

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A team of researchers at the University of California, Berkeley, were able to create a more deadly form of tuberculosis by disabling a family of genes in the pathogen that were originally believed to impair the bug’s transmissibility. The team’s findings, which were unexpected, also showed that the mutant strain can multiply more rapidly than the ordinary form.

These biomarkers, if verified, may help researchers refine diagnostic and therapeutic products for TB.

As early as two weeks after infecting a group of mice with a version of TB with the mutated gene set, called the mce1 operon, the researchers found “significantly more” bacteria than in the animals infected with a wild-type strain. Twenty-five weeks later, mice infected with the mutant strain began to die, while the ones infected with the wild-type survived until the end of the experiment, which lasted 41 weeks.

The results were unexpected because earlier studies had suggested that the mce1 operon may actually help the organism invade cells. Consequently, the team expected that mutating the genes would made it harder for the pathogen to infect the mice. Instead, the bacteria became more deadly, the researchers found.

“These findings came as a complete surprise to us,” Lee Riley, professor of epidemiology and infectious diseases at UC Berkeley’s School of Public Health and principal investigator of the study, said in a statement.

“This is one of the very few hypervirulent organisms ever created,” added Lisa Morici, who researches infectious diseases at UC Berkeley. “This breaks a long-standing assumption among scientists that disabling a potential virulence gene weakens a pathogen.”

The research appears in the Dec. 8 Proceedings of the National Academy of Sciences.

The team compared the spleens, livers, and lungs of the mice at various times throughout the experiment, beginning with 24 hours post-infection. They found that the progression of the common TB strain plateaued at about 17 weeks post-infection, while the TB strain mutated with mce1 did not stop spreading “until it killed its host.” Curious about their findings, the researchers attempted to validate them by performing a similar experiment in bacillus Calmette-Guérin, a weakened form of the TB bacteria that is known to engender an immune response but does not lead to disease. These results confirmed the original TB study.

The team speculated that the mce1 mutations triggered changes in the bacteria that negatively affected immune response in the host organism. “It appears that the host immune system does not recognize the mutated TB organisms, so the bacteria are left to grow unchecked,” Morici said in the statement.

The researchers suggests that the granuloma protects not only the host from the bacteria, but also the bacteria from the host’s immune cells and antibiotic drugs, Shimono added.

— KL

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