Abstract
The cell wall of wild-type (WT) Mycobacterium tuberculosis (Mtb), an etiologic agent of tuberculosis (TB) and a Mtb strain disrupted in a 13-gene operon mce1 (Δmce1) varies by more than 400 lipid species. Here, we examined Mtb lipid-induced response in murine macrophage, as well as in human T-cell subpopulations in order to gain an insight into how changes in cell wall lipid composition may modulate host immune response. Relative to WT Mtb cell wall lipids, the non-polar lipid extracts from Δmce1 enhanced the mRNA expression of lipid-sense nuclear receptors TR4 and PPAR-γ and dampened the macrophage expression of genes encoding TNF-α, IL-6, and IL-1β. Relative to untreated control, WT lipid-pre-stimulated macrophages from healthy individuals induced a higher level of CD4−CD8− double negative T-cells (DN T-cells) producing TNF-α. Conversely, compared to WT, stimulation with Δmce1 lipids induced higher mean fluorescence intensity (MFI) in IL-10-producing DN T cells. Mononuclear cells from TB patients stimulated with WT Mtb lipids induced an increased production of TNF-α by CD8+ lymphocytes. Taken together, these observations suggest that changes in mce1 operon expression during a course of infection may serve as a strategy by Mtb to evade the host pro-inflammatory responses.
Highlights
Despite the availability of effective treatment regimens against Mycobacterium tuberculosis (Mtb), an etiologic agent of tuberculosis (TB), TB remains a major public health challenge, which has surpassed AIDS as the most common infectious disease cause of death in adults [1]
Mice infected with a strain of M. tuberculosis disrupted in the mce1 operon are unable to mount a strong pro-inflammatory response against WT Mtb, as evidenced by decreased levels of IL-6 and TNF-α; these animals do not form organized granulomas [6]
As the mce1 operon of WT Mtb becomes repressed during the course of infection in a mouse model of TB [7], we reasoned that the lipids in the cell wall of this mce1 mutant could be representative of the lipid composition of WT Mtb at some point during a course of in vivo infection
Summary
Despite the availability of effective treatment regimens against Mycobacterium tuberculosis (Mtb), an etiologic agent of tuberculosis (TB), TB remains a major public health challenge, which has surpassed AIDS as the most common infectious disease cause of death in adults [1]. At some point during in vitro macrophage or mouse infection, the WT strain displays the same phenotype shown by the mce operon mutant ( mce). The cell wall lipid rearrangement during infection could be a determining factor for bacterial persistence, as previously suggested [12] Such lipids have been shown to induce granuloma formation [13], leukocyte migration [14] and inflammatory cytokines expression [15], or to inhibit macrophage responses [16,17,18]. We hypothesized that by comparing responses of host immune cells challenged in vitro with lipids extracted from the mce operon mutant or WT Mtb, we may be able to demonstrate how differences in cell wall lipid composition affect host cell responses that would be advantageous to Mtb
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