European Society of Mycobacteriology - Instituto Nacional de Saúde ...

GL-9
REGULATION OF Mycobacterium tuberculosis CELL WALL LIPID
COMPOSITION AND ITS EFFECT ON IN VIVO BACTERIAL PERSISTENCE
Lee W. Riley
School of Public Health, University of California, Berkeley
The hallmark of M. tuberculosis is its ability to survive for many years in an infected host to establish latent tuberculosis
infection (LTBI). We propose a new model of latent infection that is based on the idea that this organism may simply have
readapted its “housekeeping” metabolic function to a new environment for its long-term survival. We propose that M.
tuberculosis, which evolutionarily most likely originated in soil, has readapted a soil-survival strategy its ancestral species
possessed to the granuloma environment in the human host. Granuloma cells constantly turn over every few days to
weeks, and after they die, they undergo replacement by new cells that migrate into the granuloma. Hence, M. tuberculosis
needs to readapt to this constantly changing environment, and we provide evidence that this adaptation is mediated by
M. tuberculosis remodeling its cell envelope in response to signals produced by dead granuloma cells. This remodeling
is mediated by a family of operons called mce (mce1,2,3,4). Disruption of the operons results in profound changes in
lipid profile of the cell wall. The mce1 operon mutant causes free mycolic acids (MA) to accumulate on its surface, and
other operon mutants (mce2,3,4) show evidence of lipid profile changes in the cell wall. These operon products serve as
energy-dependent lipid importers. Lipid products released from dead host granuloma cells that turnover may be used as
carbon sources for the resident M. tuberculosis. Thus, the “housekeeping” lipid metabolic function of M. tuberculosis may
have been readapted in the granuloma environment as a way for this organism to survive, similar to the way its ancestral
saprophytic organism survived in soil by scavenging dead organic materials as carbon sources. Further elucidation of the
interaction between M. tuberculosis cell wall and granuloma cell turnover may contribute to a new understanding of the
mechanism of LTBI.
34 ESM 2009