Monday, June 15, 2009

New and Hot: one way the TB bacteria achieves virulence

A few things were known about how the TB bacteria Mycobacterium tuberculosis infects host cells. It had been previously observed that TB bacteria were engulfed by macrophages, where they proliferate. Researchers also observed high levels of cyclic AMP, an enzyme that regulates certain cell functions, in macrophages that were infected with TB. The mechanism that produced this "cAMP burst" was unclear. And if I understand correctly, how the excess cAMP lead to disease was also not well understood.

A recent study conducted by William Bishai et al has filled in some of the gaps in this mechanism. His group found 17 genes in the TB bacteria genome that coded for cAMP production. They injected mice with bacteria that had various combinations of these 17 genes activated. The results suggest that a single gene called Rv0386 is crucial; bacteria with the gene outperformed all other microbes. Hence, they showed that "among the 17 adenylate cyclase genes present in M. tuberculosis, at least one (Rv0386) is required for virulence" (2), that Rv0386 is one of the genes that produces the cAMP burst.

Next, they suggest a further mechanism for how the cAMP burst contributes to the disease. Not only does the Rv0386 gene encode for cAMP, it also facilitates the delivery of the bacterial cAMP into the macrophage cytoplasm. In the cytoplasm, the excess cAMP sets off a chain reaction that results in the host cell producing a lot of TNF alpha, a protein that causes inflammation. Mice with the activated Rv0386 gene activated produced ten times as much TNF alpha in their lungs than mice that lacked the gene. Furthermore, excess inflammation caused by TNF alpha may be linked to the formation of lesions characteristic of TB called granulomas.

(1) News Story
(2) Nature Article

-Elaine C

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