Secrets of a successful pathogen: legionella resistance to progression along the autophagic pathway

Abstract

To proliferate within phagocytes, Legionella pneumophila relies on Type IV secretion to modulate host cellular pathways. Autophagy is an evolutionarily conserved degradative pathway that captures and transfers a variety of microbes to lysosomes. Biogenesis of L. pneumophila-containing vacuoles and autophagosomes share several features, including endoplasmic reticulum (ER)-derived membranes, contributions by the host GTPases Rab1, Arf1 and Sar1, and a final destiny in lysosomes. We discuss morphological, molecular genetic, and immunological data that support the model that, although A/J mouse macrophages efficiently engulf L. pneumophila within autophagosomal membranes, the Type IV effector proteins DrrA/SidM, LidA, and RalF prolong association with the ER. By inhibiting immediately delivery to lysosomes, the bacteria persist in immature autophagosomal vacuoles for a period sufficient to differentiate into an acid-resistant, replicative form. Subsequent secretion of the Type IV effector LepB releases the block to autophagosome maturation, and the adapted progeny continue to replicate within autophagolysosomes. Accordingly, L. pneumophila can be exploited as a genetic tool to analyze the recruitment and function of the macrophage autophagy pathway.

Keywords: Legionella pneumophila; Rab conversion; Type IV secretion system; autophagy; vacuole maturation.

Figure 1

Model for stalled maturation of the L. pneumophila vacuole in the autophagic pathway of permissive phagocytes. ER serves as a membrane source for both L. pneumophila vacuoles and autophagosomes. Early secretory vesicles (gray circles) from the ER are recruited to both organelles in a Rab1-, Arf1-, and Sar1-dependent manner. The double-membraned, LC3 positive, autophagosome sequentially fuses with vesicles from the early endocytic pathway and finally with lysosomes, where its cargo is degraded. Maturation of L. pneumophila is stalled at an early stage when bacterial proteins (italics) DrrA and LidA persistently activate Rab1 and RalF activates Arf1. Thus, the vacuole acquires ER markers BiP, glucose-6-phosphate, calnexin, protein disulfide isomerase, YFP–KDEL, and ribosomes (filled circles). After several hours, L. pneumophila secretes LepB, an effector that inactivates Rab1, releasing it from the membrane. Subsequently, the immature autophagosomal vacuole matures to an autophagolysosome, which accumulates the lysosomal proteins cathepsin D and LAMP1. The deliberate pause coordinated by Type IV secretion effectors enables the pathogen to differentiate into an acid-resistant, replicative form that exploits lysosomes as a replication niche.