Activation of Host Mitogen-Activated Protein Kinases by Secreted Legionella pneumophila Effectors That Inhibit Host Protein Translation

Studies of innate immunity in metazoans have largely focused on detection of microbial molecules by host pattern recognition receptors (PRRs). A complementary mode of innate immune recognition, based on detection of pathogen-encoded activities, has long been recognized in plants, where it is termed effector-triggered immunity; however, little is known about the possibility of effector-triggered immunity in metazoans. Legionella pneumophila is an intracellular bacterial pathogen that causes Legionnaires' disease, an inflammatory pneumonia. We recently demonstrated that macrophages infected with L. pneumophila exhibit mitogen-activated protein (MAP) kinase (MAPK) activation that is independent of known PRRs but dependent on a functional bacterial secretion system. Here, we show that five secreted L. pneumophila effectors are responsible for the activation of host MAP kinases. These five effectors inhibit host translation, and their activity is required for host MAPK activation. We demonstrate that MAPK activation by these effectors shapes the host transcriptional response to L. pneumophila. Furthermore, we find that uninfected macrophages treated with two different translation inhibitors exhibit activation of MAP kinases and upregulation of target genes, indicating that translation inhibition alone is sufficient to elicit this response in macrophages. MAP kinase pathways are crucial in many aspects of the immune response, including inflammation and cell motility. Our results demonstrate that this important host pathway can be activated in response to a pathogen-encoded activity, adding to an emerging body of evidence in support of this novel mode of innate immune detection in metazoans.