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

Abstract

Mycobacterium tuberculosis possesses a diversity of potential virulence factors including complex branched lipids such as the phenolic glycolipid PGL-tb. PGL-tb expression by the clinical M. tuberculosis isolate 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 of M. tuberculosis strains with an intact pks1-15 gene, required for the synthesis of PGL-tb and capable of producing PGL-tb. We have found that some strains with an intact pks1-15 do 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 clinical M. tuberculosis isolates 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 of M. tuberculosis, it probably acts in concert with other bacterial factors which seem to be dependent on the background of the strain.

A Lipid Profile Typifies the Beijing Strains of Mycobacterium tuberculosis

“…Thus, based on the results of Reed et al (13), it was thought that the production of this glycolipid was the principal cause of hypervirulence in Beijing strains. However, even within the Beijing lineage, only a minority of isolates produce PGL-tb (21,22). In addition, complementation of the laboratory strain H37Rv with a functional pks15/1 allele, allowing the production of PGLtb, does not significantly increase the virulence of this strain in the mouse and rabbit models (22).…”

“…However, even within the Beijing lineage, only a minority of isolates produce PGL-tb (21,22). In addition, complementation of the laboratory strain H37Rv with a functional pks15/1 allele, allowing the production of PGLtb, does not significantly increase the virulence of this strain in the mouse and rabbit models (22). The molecular reasons for the higher virulence of strains of the Beijing lineage therefore remain unclear.…”

Genomic Variability of Mycobacterium tuberculosis

“…The IS6110 element is present exclusively in strains of the MTBC that can harbor from zero to 25 copies per genome (Brosch et al, 2000). For this reason and due to its high degree of copy number and insertion site variation, IS6110-RFLP has been widely used for epidemiological purposes and is considered the "gold standard" to study the transmission dynamics of M. tuberculosis (van Embden et al, 1993, Small et al, 1994, Safi et al, 1997. The discriminatory power of the IS6110-RFLP method depends on there being sufficient variation and copy number to differentiate between unlinked isolates while allowing identification of specimens that are related (Wall et al, 1999).…”

“…The increased virulence of these isolates was associated with the production of a phenolic glycolipid (PGL) that affects the host immune response, and which is absent in many other M. tuberculosis families (Ordway et al, 2007, Hanekom et al, 2011. More recent work suggests that although PGL can contribute to M. tuberculosis virulence, it probably requires additional bacterial factors (Sinsimer et al, 2008). Other examples stem from studies of strains that have caused outbreaks, such as strains CDC1551 and HN878, the latter also a member of the Beijing family.…”

“…The high similarity at the DNA level suggests that this group could have resulted from a bottleneck event that led to the expansion of a successful clone that then gave rise to different host-adapted ecotypes of the same species (Smith et al, 2006). Understanding the differences that underlie the biology and evolution of the MTBC has been the focus of considerable work (Smith et al, 2009, Comas & Gagneux, 2009). Members of the MTBC have a highly clonal population structure where recent events of HGT are essentially absent (Supply et al, 2003, Gutierrez et al, 2005.…”