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

Abstract

The innate immune system is critical for host defense against microbial pathogens, yet many pathogens express virulence factors that impair immune function. Here, we used the bacterial pathogen Legionella pneumophila to understand how the immune system successfully overcomes pathogen subversion mechanisms. L. pneumophila replicates within macrophages by using a type IV secretion system to translocate bacterial effectors into the host cell cytosol. As a consequence of effector delivery, host protein synthesis is blocked at several steps, including translation initiation and elongation. Despite this translation block, infected cells robustly produce proinflammatory cytokines, but the basis for this is poorly understood. By using a reporter system that specifically discriminates between infected and uninfected cells within a population, we demonstrate here that infected macrophages produced IL-1α and IL-1β, but were poor producers of IL-6, TNF, and IL-12, which are critical mediators of host protection. Uninfected bystander cells robustly produced IL-6, TNF, and IL-12, and this bystander response required IL-1 receptor (IL-1R) signaling during early pulmonary infection. Our data demonstrate functional heterogeneity in production of critical protective cytokines and suggest that collaboration between infected and uninfected cells enables the immune system to bypass pathogen-mediated translation inhibition to generate an effective immune response.L. pneumophila | IL-1 | IL-1R | TNF | type IV secretion system

Inflammatory, anti-inflammatory and regulatory cytokines in relatively healthy lung tissue as an essential part of the local immune system

“…Importantly, IL-6 mediates the pro-inflammatory, pro-angiogenic and immunomodulatory role of other cells 19 . As observed, IL-6 is produced early during the infection from uninfected cells compared with infected cells, suggesting its regulatory role 26 . As we found, the major sources of IL-6 are structures more exposed to airborne antigens, and the understanding of IL-6 functions may be explained as a more intermediate occurrence in subsequent signalling with a regulatory role, rather than an initiating factor of immune response induction due to antigen stimulation.…”

“…Although we may speculate about the substantiation of IL-1 regulating all other cytokines, conversely, the release of IL-1 is also regulated by other pro-inflammatory, regulating and anti-inflammatory cytokines; therefore, the causality of one cytokine affecting another cytokine must be estimated in the context of multiple factors. In summary, epithelial cells are both activated by and further release the following cytokines: IL-1α, IL-4, IL-6 and IL-10 3,[5][6][7]26 . As the first exposed surface, the airway epithelium actively regulates local immunity.…”

MTOR-Driven Metabolic Reprogramming Regulates Legionella pneumophila Intracellular Niche Homeostasis

“…MTOR activation by Legionella coincided with increased gene expression of Srebf1 and its downstream target Fasn and Ldlr and preceded LCVs rupture indicating that at least partially SREBPs function in Legionella -infected cells is regulated through gene expression. However, post-transcriptional mechanisms might also contribute due to a global repression of protein synthesis that affects translation of some but not all polypeptides in infected cells [51,77,78]. Clearly, Legionella regulation of MTOR-dependent lipogenesis warrants future investigation.…”

Protective effect of mild endoplasmic reticulum stress on radiation-induced bystander effects in hepatocyte cells

“…Recently, the defense system of bystander cells responding to harmful signals has received much attention293031. Our present work disclosed that the bystander hepatocyte cells could trigger innate ER stress against the damage responses from irradiated hepatoma cells.…”