Mechanisms of Effector-Mediated Immunity Revealed by the Accidental Human Pathogen Legionella pneumophila

Abstract

Many Gram-negative bacterial pathogens employ translocated virulence factors, termed effector proteins, to facilitate their parasitism of host cells and evade host anti-microbial defenses. However, eukaryotes have evolved to detect effector-mediated virulence strategies through a phenomenon termed effector-triggered immunity (ETI). Although ETI was discovered in plants, a growing body of literature demonstrates that metazoans also utilize effector-mediated immunity to detect and clear bacterial pathogens. This mini review is focused on mechanisms of effector-mediated immune responses by the accidental human pathogen Legionella pneumophila. We highlight recent advancements in the field and discuss the future prospects of harnessing effectors for the development of novel therapeutics, a critical need due to the prevalence and rapid spread of antibiotic resistance.

Keywords: Legionella pneumophila; effector-mediated immunity; effector-triggered immunity; innate immunity; macrophage.

Figure 1

Schematic representation of L. pneumophila effector-mediated host defense in macrophages. From the LCV, L. pneumophila (purple) translocates hundreds of individual effector proteins (red squares/rectangles) into the host cytosol through the Dot/Icm T4SS (orange). Multiple effectors inhibit host translation elongation (RavX, SidI, SidL, LegK4, and Lgt1-3), which results in activation of MAPK signaling and pro-inflammatory cytokine expression [AP-1 (Jun, Fos)]. The activity of Lgt1-3 also activates the mTORC1 complex, which results in downregulation of pro-inflammatory genes. However, in macrophages, mTOR signaling is attenuated by detection of pathogen-derived molecules. Activation of NF-κB downstream of PRR (TLRs shown) engagement is enhanced by LegS2, LnaB, and LegK1, the latter of which phosphorylates IκBα. L. pneumophila replication within macrophages is also impaired by LegA9 and LegC4, the latter of which augments cytokine-mediated restriction. Finally, LamA, a recently characterized L. pneumophila effector, degrades cellular glycogen, leading to increased aerobic glycolysis and proinflammatory cytokine production. For clarity, the SidE family of effectors and the role of IL-1 production by infected macrophages are not shown. Question marks indicate unknowns. See text for additional details.