Abstract
The defective in organelle trafficking/intracellular multiplication (Dot/Icm) Type IVb secretion system (T4SS) is the essential virulence factor for the intracellular life style and pathogenicity of Legionella species. Screens demonstrated that an individual L. pneumophila strain can use the Dot/Icm T4SS to translocate an unprecedented number of more than 300 proteins into host cells, where these, so called Icm/Dot-translocated substrates (IDTS) or effectors, manipulate host cell functions to the benefit of the bacteria. Bioinformatic analysis of the pan-genus genome predicts at least 608 orthologous groups of putative effectors. Deciphering the function of these effectors is key to understanding Legionella pathogenesis; however, the analysis is challenging. Substantial functional redundancy renders classical, phenotypic screening of single gene deletion mutants mostly ineffective. Here, I review experimental approaches that were successfully used to identify, validate and functionally characterize T4SS effectors and highlight new methods, which promise to facilitate unlocking the secrets of Legionella's extraordinary weapons arsenal.
Highlights
Legionella pneumophila was recognized as human pathogen in 1976 after a devastating outbreak of pneumonia, termed Legionnaires’ disease, at an American Legion convention (Fraser et al, 1977; McDade et al, 1977)
Investigations into the epidemiological and pathological mechanisms soon established that L. pneumophila is a ubiquitous, facultative intracellular pathogen of protozoa (Rowbotham, 1980), which, after inhalation, can thrive in human alveolar macrophages
Instead the bacteria create the Legionella containing vacuole (LCV) (Horwitz, 1983b), which shelters them from intracellular defenses and intercepts nutrients, supporting replication
Summary
Legionella pneumophila was recognized as human pathogen in 1976 after a devastating outbreak of pneumonia, termed Legionnaires’ disease, at an American Legion convention (Fraser et al, 1977; McDade et al, 1977). The defective in organelle trafficking/intracellular multiplication (Dot/Icm) Type IVb secretion system (T4SS) is critical for LCV biogenesis and intracellular replication (Berger and Isberg, 1993; Segal et al, 1998) It is located at the bacterial poles and, upon membrane contact, translocates proteins into host cells (Charpentier et al, 2009; Jeong et al, 2017), which manipulate cellular. Most prominent feature, which facilitated the discovery of the first effector RalF, is the occurrence of domains with striking homology to eukaryotic proteins (Nagai et al, 2002; Cazalet et al, 2004; De Felipe et al, 2005; Gomez-Valero et al, 2011) Integration of these characteristics and parameters, such as regulatory motifs, in machine-learning approaches enabled prediction algorithms. Dot/Icm effectorfocused algorithms were applied to 38 Legionella spp., revealing 608 orthologous groups of effectors, and 99 frequently-occurring domains, which facilitate the identification of new effectors (Burstein et al, 2009, 2016; Lifshitz et al, 2013)
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