The Life Cycle of L. pneumophila: Cellular Differentiation Is Linked to Virulence and Metabolism

Abstract

Legionella pneumophila is a gram-negative bacterium that inhabits freshwater ecosystems, where it is present in biofilm or as planktonic form. L. pneumophila is mainly found associated with protozoa, which serve as protection from hostile environments and as replication niche. If inhaled within aerosols, L. pneumophila is also able to infect and replicate in human alveolar macrophages, eventually causing the Legionnaires' disease. The transition between intracellular and extracellular environments triggers a differentiation program in which metabolic as well as morphogenetic changes occur. We here describe the current knowledge on how the different developmental states of this bacterium are regulated, with a particular emphasis on the stringent response activated during the transition from the replicative phase to the infectious phase and the metabolic features going in hand. We propose that the cellular differentiation of this intracellular pathogen is closely associated to key metabolic changes in the bacterium and the host cell, which together have a crucial role in the regulation of L. pneumophila virulence.

A Two-Component System that Modulates Cyclic-di-GMP Metabolism PromotesLegionella pneumophilaDifferentiation and Viability in Low-Nutrient Conditions

“…RpoS is a key regulator of the stringent response, which facilitates bacterial adaptation to a range of stresses, including starvation (37). When nutrients become limiting, replicating L. pneumophila accumulate the alarmone ppGpp and synthesize RpoS, which activates expression of multiple genes critical for fitness in the PE phase (3).…”

“…When inhaled, contaminated water droplets transmit L. pneumophila to the human lung, where this opportunistic pathogen can infect alveolar macrophages. Studies examining the life cycle of L. pneumophila cultured in broth, macrophages, and amoebae support a developmental model in which nutrient levels govern cellular differentiation (2, 3). When nutrients are plentiful, the bacteria activate pathways that support growth; when nutrients become limiting, the progeny stop replicating and express multiple factors that promote L. pneumophila transmission to a new host, including flagella and the Dot/Icm Type IV secretion system (4).…”

“…To alternate between replication within phagocytes and persistence within nutrient-poor aquatic environments, L. pneumophila relies on multiple regulatory mechanisms that coordinate rapid adaption to changing conditions (3). For example, replication in broth requires amino acids as the primary carbon source (7, 8), and a reduction in amino acid availability activates regulatory pathways that trigger conversion from the exponential (E) phase to the post-exponential (PE) transmissive phase (9, 10).…”

“…For example, replication in broth requires amino acids as the primary carbon source (7, 8), and a reduction in amino acid availability activates regulatory pathways that trigger conversion from the exponential (E) phase to the post-exponential (PE) transmissive phase (9, 10). The L. pneumophila life cycle is governed by a sophisticated regulatory network that includes the stringent response enzymes RelA and SpoT, multiple alternative sigma factors including RpoS and FliA, two-component regulatory systems, small regulatory RNAs, and CsrA post-transcriptional repressors (3, 11, 12). Driving the E to PE differentiation is a stringent response pathway coordinated by the alarmone guanosine penta- and tetraphosphate (abbreviated here as ppGpp) (13).…”

Evasion of phagotrophic predation by protist hosts and innate immunity of metazoan hosts byLegionella pneumophila

“…Within the LCV, bacterial metabolism and nutrition-based genetic regulation based in nutrient availability governs bacterial proliferation and differentiation (W. Eisenreich, Heesemann, Rudel, & Goebel, 2013; Wolfgang Eisenreich, Rudel, Heesemann, & Goebel, 2017; Fonseca & Swanson, 2014; Grubmuller, Schauer, Goebel, Fuchs, & Eisenreich, 2014; Häuslein et al, 2017; Lama, Drennan, Johnson, Rubenstein, & Cambronne, 2017; Manske & Hilbi, 2014; Oliva, Sahr, & Buchrieser, 2018; C. T. Price, Richards, & Abu Kwaik, 2014).…”