The Frustrated Host Response to Legionella pneumophila Is Bypassed by MyD88-Dependent Translation of Pro-inflammatory Cytokines

Abstract

Many pathogens, particularly those that require their host for survival, have devised mechanisms to subvert the host immune response in order to survive and replicate intracellularly. Legionella pneumophila, the causative agent of Legionnaires' disease, promotes intracellular growth by translocating proteins into its host cytosol through its type IV protein secretion machinery. At least 5 of the bacterial translocated effectors interfere with the function of host cell elongation factors, blocking translation and causing the induction of a unique host cell transcriptional profile. In addition, L. pneumophila also interferes with translation initiation, by preventing cap-dependent translation in host cells. We demonstrate here that protein translation inhibition by L. pneumophila leads to a frustrated host MAP kinase response, where genes involved in the pathway are transcribed but fail to be translated due to the bacterium-induced protein synthesis inhibition. Surprisingly, few pro-inflammatory cytokines, such as IL-1α and IL-1β, bypass this inhibition and get synthesized in the presence of Legionella effectors. We show that the selective synthesis of these genes requires MyD88 signaling and takes place in both infected cells that harbor bacteria and neighboring bystander cells. Our findings offer a perspective of how host cells are able to cope with pathogen-encoded activities that disrupt normal cellular process and initiate a successful inflammatory response.

IL-1R signaling enables bystander cells to overcome bacterial blockade of host protein synthesis

“…In contrast, IL-1α and IL-1β were robustly produced by both T4SS-injected cells and uninjected cells ( Fig. 1 C and D), indicating that T4SS-injected cells selectively synthesize IL-1α and IL-1β despite the host translation block, consistent with recent findings (21). To determine whether the decreased cytokine production observed in T4SS-injected cells is due to decreased translation or transcription, we measured cytokine mRNA levels in sorted populations of T4SS-injected and uninjected cells (Fig.…”

“…1E). Both injected and uninjected cells displayed marked increases in Il1a, Il1b, Tnf, and Il6 transcript levels relative to uninfected cells, with injected cells exhibiting significantly greater increases in cytokine transcript levels than uninjected cells, consistent with recent findings (21). Thus, the decreased production of immune proteins by injected cells is not due to a lack of transcriptional activation and most likely is due to impaired translation.…”

“…At the population level, decreased host protein synthesis leads to preferential translation of the most abundant cytokine transcripts (14). At the single cell level, infected cells selectively synthesize IL-1α and IL-1β through a mechanism involving MyD88-dependent translational bypass (21). However, whether mechanisms that enable selective translation of IL-1 also apply to other key cytokines and immune effector proteins has not been determined.…”

Inhibition of host cell translation elongation by Legionella pneumophila blocks the host cell unfolded protein response

“…It has been shown that levels of protein synthesis in host cells challenged by WT L. pneumophila are ∼95% below that of uninfected cells, whereas translation in cells challenged with the Δ5 strain is still ∼80% below that of uninfected cells at an early time point postchallenge (30). Furthermore, as infection progresses, levels of translation in Δ5-infected cells continue to decrease relative to earlier time points (31). Much of this translation inhibition in the Δ5 strain can be explained by the observation that the host cell shuts down translation initiation in response to the pathogen (36).…”

Creating a customized intracellular niche: subversion of host cell signaling byLegionellatype IV secretion system effectors

“…Finally, the effector SidL is able to inhibit protein translation via an unknown mechanism (Fontana et al 2011). Interestingly, the host cell itself also reacts to infection with a block of translation (Ivanov and Roy 2013); however, this block is not complete and a number of selected transcripts, e.g., cytokines, IL-1␣, and IL-1␤, are still translated, resulting in a specific inflammatory response (Ivanov and Roy 2013;Asrat et al 2014).…”