NATURE REVIEWS | MICROBIOLOGY VOLUME 3 | APRIL 2005 | 1

Although Mycobacterium tuberculosisenvelope (cell wall) lipids have beenlinked to pathogenesis, how theselipids function isn’t clear. Do lipidsaffect cell-wall integrity, therebyaffecting pathogenesis, or do theyhave specific roles in pathogenesisand in the modulation of the hostresponse to infection? Now, Rao et al.report in the Journal of ExperimentalMedicine that cyclopropane modifi-cation of a cell envelope glycolipidfunctions to control the host innateimmune response in the earliest partof infection.

In addition to peptidoglycan,

which is the most common con-stituent of bacterial cell walls, morethan 60% of the cell wall of M. tuber-culosis comprises complex lipids,making this cell wall unique amongprokaryotes. Mutations in genes thatencode cell-wall components, oraffect their secretion, result inreduced virulence, but as differentmutations have different effects onbacterial growth and pathogenesis, itseems that specific cell-wall compo-nents might have distinct roles inpathogenesis.

Mycolic acids, which are long,branched fatty acids, are the majorlipid component of these unusual cellwalls, and are only synthesized byMycobacterium and Corynebacteriumspp. In addition to their structuralroles, mycolates are presented to Tcells as part of the adaptive immuneresponse. In pathogenic mycobacte-ria, mycolic acids are modified withcyclopropane residues by a family ofmethyltransferases, one of which isPcaA, an S-adenosyl methioninemethyltranferase. Mutants in pcaAare attenuated and produce lesssevere immunopathology in mice.Here, Rao et al. have focused on tre-halose dimycolate (TDM), an inflam-matory glycolipid, to monitor theeffects of cyclopropyl modificationon the earliest part of M. tuberculosisinfection.

In the first week after aerosol inoc-ulation of mice, titres of an M. tuber-culosis pcaA mutant in the lungs weremarkedly reduced — 50-fold lowerthan the wild type — but growth of

the mutant was comparable with thewild type by 2 weeks post-infection.This growth defect only occurred inthe presence of tumour necrosis fac-tor (TNF), which implicated cyclo-propane modification of glycolipidsin TNF induction. The pcaA mutantsalso induced reduced amounts ofTNF in macrophages in vitro com-pared with wild-type M. tuberculosis,which indicates that they were hypo-inflammatory. Delipidation of bacilli,which removes 90% of TDM,markedly reduced the induction ofTNF by the wild-type bacteria, andlipid-swapping experiments betweenthe wild-type and pcaA mutants con-firmed that pcaA mutant mycolateswere hypo-inflammatory. Finally,TDM purified from the wild type wasa far more potent inducer of TNF inmacrophages compared with TDMpurified from the pcaA mutant.

These results implicate mycolicacids as effector molecules that mod-ulate the innate immune response toM. tuberculosis. It is possible thatinduction of TNF by virulent M.tuberculosis might be an importantpathogenic strategy, and understand-ing how different cell-wall compo-nents function in mycobacterialpathogenesis should allow improvedrational drug design against thismajor global pathogen.

Susan JonesReferences and links

ORIGINAL RESEARCH PAPER Rao, V. et al.Mycobacterium tuberculosis controls host innateimmune activation through cyclopropanemodification of a glycolipid effector molecule. J.Exp. Med. 14 Feb 2005(doi:10.1084/jem.20041668)

Envelopes and the inflammatory response

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