Abstract
The inducible innate immune response to infection requires a concerted process of gene expression that is regulated at multiple levels. Most global analyses of the innate immune response have focused on transcription induced by defined immunostimulatory ligands, such as lipopolysaccharide. However, the response to pathogens involves additional complexity, as pathogens interfere with virtually every step of gene expression. How cells respond to pathogen-mediated disruption of gene expression to nevertheless initiate protective responses remains unclear. We previously discovered that a pathogen-mediated blockade of host protein synthesis provokes the production of specific pro-inflammatory cytokines. It remains unclear how these cytokines are produced despite the global pathogen-induced block of translation. We addressed this question by using parallel RNAseq and ribosome profiling to characterize the response of macrophages to infection with the intracellular bacterial pathogen Legionella pneumophila. Our results reveal that mRNA superinduction is required for the inducible immune response to a bacterial pathogen.
Highlights
Gene expression is a concerted process that is regulated at multiple steps, including transcription, mRNA degradation, translation, and protein degradation
bone-marrow-derived macrophages (BMMs) were infected with a virulent DflaA strain, an avirulent T4SS-deficient DdotADflaA strain, or a D7DflaA strain that lacks the seven effectors associated with inhibition of host protein synthesis
The less robust correlation between mRNA levels and protein levels in the cell supernatant (Figure 2C) may reflect differing rates of secretion, accumulation in the supernatant over time, re-binding to cell surface receptors, and stability in the supernatant. These results suggest that the inducible immune response to L. pneumophila is controlled primarily at the level of mRNA superinduction (Figure 2)
Summary
Gene expression is a concerted process that is regulated at multiple steps, including transcription, mRNA degradation, translation, and protein degradation. One recent study analyzed the response of dendritic cells to lipopolysaccharide (LPS) and found that changes in mRNA levels accounted for ~90% of observed alterations in protein levels (Jovanovic et al, 2015). The response to infection with a virulent pathogen is certainly more complicated than the response to a purified immunostimulatory ligand such as LPS. Pathogens have evolved to disrupt or manipulate almost every cellular process involved in gene expression (Finlay and McFadden, 2006). An effective innate immune response to infection requires that host cells be able to induce appropriate responses in the face of pathogen manipulation
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