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Abstract
According to most models of mycobacterial infection, inhibition of the pro-inflammatory macrophage immune responses contributes to the persistence of bacteria. Mycobacterium avium subsp. paratuberculosis (MAP) is a highly successful pathogen in cattle and sheep and is also implicated as the causative agent of Crohn’s disease in humans. Pathogenic mycobacteria such as MAP have developed multiple strategies to evade host defence mechanisms including interfering with the macrophages’ capacity to respond to IFN-γ, a feature which might be lacking in non-pathogenic mycobacteria such as M. smegmatis. We hypothesized that pre-sensitisation of macrophages with the pro-inflammatory cytokine IFN-γ would help in overcoming the inhibitory effect of MAP or its antigens on macrophage inflammatory responses. Herein we have compared a series of macrophage activation parameters in response to MAP and M. smegmatis as well as mycobacterial antigens. While IFN-γ did overcome the inhibition in immune suppressive mechanisms in response to MAP antigen as well as M. smegmatis, we could not find a clear role for IFN-γ in overcoming the inhibition of macrophage inflammatory responses to the pathogenic mycobacterium, MAP. We demonstrate that suppression of macrophage defence mechanisms by pathogenic mycobacteria is unlikely to be overcome by prior sensitization with IFN-γ alone. This indicates that IFN-γ signaling pathway-independent mechanisms may exist for overcoming inhibition of macrophage effector functions in response to pathogenic mycobacteria. These findings have important implications in understanding the survival mechanisms of pathogenic mycobacteria directed towards finding better therapeutics and vaccination strategies.
Highlights
IFN-γ pre-treatment resulted in a decrease in IL-1α levels in response to PPDB and 316v whole cell-derived antigen (316v Ag) when compared with the no pre-treatment group (Fig 1B); but these changes did not reach statistical significance
We have found that while IFN-γ pre-treatment could selectively overcome the inhibitory effect to mycobacterial antigens, including Mycobacterium avium subsp. paratuberculosis (MAP) 316v Ag, non-pathogenic M. smegmatis as well as heat-killed MAP, on some parameters, it did not have any effect on the macrophage effector responses to live MAP
We demonstrate that the inhibitory action of MAP 316v Ag and M. bovis PPDB on nitric oxide production could be overcome by pre-treatment with IFN-γ but not LPS
Summary
It is an immortal cell line that grows continuously in culture due to alteration of genes which might affect functional properties such as signalling cascades affected by microbial ligands [33, 34] Despite this drawback, several studies have utilized the RAW 264.7 cell line for studying nitric oxide production in response to mycobacterial infections [35,36,37] and have reported differences in the immune responses and gene expression elicited between nonpathogenic and pathogenic mycobacteria or variant forms of mycobacteria such as cell-wall deficient forms in murine macrophages [19, 20, 38, 39]. Macrophages exhibit differential immune responses when exposed to whole mycobacteria in comparison to mycobacterial antigens, which should be borne in mind when trying to integrate antigenic mechanisms to explain mycobacterial pathogenesis
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