The Phenolic Glycolipid ofMycobacterium tuberculosisDifferentially Modulates the Early Host Cytokine Response but Does Not in Itself Confer Hypervirulence

Abstract

Mycobacterium tuberculosispossesses a diversity of potential virulence factors including complex branched lipids such as the phenolic glycolipid PGL-tb. PGL-tb expression by the clinicalM. tuberculosisisolate HN878 has been associated with a less efficient Th1 response and increased virulence in mice and rabbits. It has been suggested that the W-Beijing family is the only group ofM. tuberculosisstrains with an intactpks1-15gene, required for the synthesis of PGL-tb and capable of producing PGL-tb. We have found that some strains with an intactpks1-15do not produce PGL-tb while others may produce a variant of PGL-tb. We examined the early host cytokine response to infection with these strains in vitro to better understand the effect of PGL-tb synthesis on immune responses. In addition, we generated a PGL-tb-producing H37Rv in order to determine the effect of PGL-tb production on the host immune response during infection by a strain normally devoid of PGL-tb synthesis. We observed that PGL-tb production by clinicalM. tuberculosisisolates affected cytokine production differently depending on the background of the strain. Importantly, while ectopic PGL-tb production by H37Rv suppressed the induction of several pro- and anti-inflammatory cytokines in vitro in human monocytes, it did not lead to increased virulence in infected mice and rabbits. Collectively, our data indicate that, while PGL-tb may play a role in the immunogenicity and/or virulence ofM. tuberculosis, it probably acts in concert with other bacterial factors which seem to be dependent on the background of the strain.