Pathogenicity and Virulence of Legionella: Intracellular replication and host response

Abstract

Bacteria of the genus Legionella are natural pathogens of amoebae that can cause a severe pneumonia in humans called Legionnaires' Disease. Human disease results from inhalation of Legionella-contaminated aerosols and subsequent bacterial replication within alveolar macrophages. Legionella pathogenicity in humans has resulted from extensive co-evolution with diverse genera of amoebae. To replicate intracellularly, Legionella generates a replication-permissive compartment called the Legionella-containing vacuole (LCV) through the concerted action of hundreds of Dot/Icm-translocated effector proteins. In this review, we present a collective overview of Legionella pathogenicity including infection mechanisms, secretion systems, and translocated effector function. We also discuss innate and adaptive immune responses to L. pneumophila, the implications of Legionella genome diversity and future avenues for the field.

Keywords: Legionella; host-response; innate immunity; pathogenicity; virulence.

Figure 1.

The life cycle of Legionella pneumophila within eukaryotic host cells. Bacterial uptake takes place by either coiling (shown) or conventional phagocytosis. Early after entry into the host cell, L. pneumophila loses its flagella and the Legionella containing vacuole (LCV) escapes the endocytic pathway via effector-mediated recruitment of endoplasmic reticulum (ER)-derived vesicles and transient association with mitochondria. Subsequently, the LCV becomes studded with ribosomes and effectors and exponential replication occurs (replicative phase; see text). Upon exhaustion of host nutrients, L. pneumophila become flagellated (transmissive phase; see text) and egress the host cell

Figure 2.

Innate immune signaling initiated by L. pneumophila within macrophages. The schematic represents the activation of multiple pathways upon mammalian phagocyte infection with L. pneumophila. Legionella-associated molecular patterns are recognized via pattern recognition receptors (PRRs) of the phagocyte. Activation of PRRs and cytosolic sensors triggers downstream molecules and processes that eventually lead to restriction of L. pneumophila replication. Specifically, TLR2, TLR5 and TLR9 discern bacterial lipoprotein, flagellin and dsDNA, respectively, which activate downstream NF-kB mediated proinflammatory cytokine response. Effector-dependent translation inhibition activates NF-κB and MAPK signaling to initiates a proinflammatory transcriptional response. Legionella effectors also inhibit the mTORC1 complex which negatively affects the amino acid synthesis and proinflammatory cytokine production. Legionella flagellin is recognized by the NAIP5/NLRC4 inflammasome and downstream activation of caspase-1 leads to pyroptosis and IL-1β/IL-18 cytokine release. NOD1/2 recognizes degradative products of bacterial peptidoglycan, eliciting RIPK2-dependent NF-κB activation and proinflammatory cytokine production. Bacterial DNA/RNA is sensed in the host cell cytosol by RIG-I and MDA5 which leads to type I interferon production