Legionella: From Protozoa to Humans

Pathogens that are able to enter and multiply within human cells are responsible for multiple diseases and millions of deaths worldwide. Thus, the challenge is to elucidate these pathogen-specific and cell biological mechanisms involved in intracellular growth and spread. Bacteria from the genus Legionella belong to this group of pathogens. They are environmental bacteria and ubiquitous in nature, where they parasitize protozoa. Strikingly, the capacity to grow intracellularly in protozoa like Acanthamoeba castellanii, Hartmannella sp., or Naegleria sp., has generated a pool of virulence traits during evolution, which allow Legionella to infect also human cells. Thus important human pathogens are present within the genus Legionella, the most prominent are L. pneumophila (Fraser et al., 1977; Mcdade et al., 1977) and L. longbeachae (Mckinney et al., 1981). These bacteria are the causative agents of Legionnaires’ disease, a severe pneumonia diagnosed mainly in people whose immune defenses are weakened. Legionella is transmitted through breathing infected aerosols present in many artificial water systems like air conditioning systems, cooling towers, showers, and other aerosolizing devices. When reaching the alveolar parts of the lungs Legionella is engulfed by macrophages where it is able to multiply resulting in a severe, often fatal pneumonia. Intracellular infection is a consequence of the bacterium’s capacity to manipulate host cellular processes using bacterial proteins that are delivered into the host cell by specialized secretion systems (Isberg et al., 2009; Hubber and Roy, 2010). In this Research Topic, we present a collection of Review, Opinion, Perspective, and Primary research articles that present both the well-established and the newly discovered strategies used by Legionella to achieve this intracellular lifestyle while escaping from the host immune response. Recent advance in genome sequencing has had a tremendous impact on our understanding of the pathogenesis, evolution and diversity of L. pneumophila and L. longCentral to the pathogenesis of L. pneumophila and L. longbeachae is its Type IV secretion system (T4SS) called Dot/Icm. It is predicted to translocate over 270 effector proteins into the host cell which allow this bacterium to manipulate host cell functions to its advantage and to assure intracellular survival and replication. Nagai and Kubori (2011) recapitulate our present understanding of the T4SS apparatus and its components by taking advantage of genomic and structural information. Finally, using comparative genomics information of several bacteria and plasmids carrying similar systems a comparative analysis of T4SS components is presented. The following five reviews, research, and opinion articles discuss some of the secreted effectors of this T4SS and their divers roles in pathogenesis of L. pneumophila. Hilbi et al. (2011) present evidence that L. pneumophila subverts phosphoinositide (PI) lipids by anchoring specific effectors through distinct PIs to the cytosolic face of the Legionella containing vacuole (LCV) to promote the interaction with host vesicles and organelles, catalyze guanine nucleotide exchange of small GTPases, or bind to PI-metabolizing enzymes. Interestingly, L. pneumophila secretes also three glycosyltransferases through its T4SS. Belyi et al. (2011) report on this novel family of effector proteins that are structurally similar to clostridial glycosylating toxins. However, in L. pneumophila they do not produce toxic effects but modify the eukaryotic elongation factor EF1A to inhibit protein synthesis and subsequently to induce cell death. Another exciting strategy employed by L. pneumophila by secreting proteins encoding a eukaryotic F-box domain is the exploitation of the host’s polyubiquitination and farnesylation machineries. In an original research article Al-Quadan and Kwaik (2011) discuss in detail how one of the L. pneumophila encoded F-box proteins uses these conserved eukaryotic signaling pathways to proliferate in Dictyostelium discoideum, a model ameba used as infection beachae and the knowledge of the genome sequence has guided and facilitated the research on Legionella in many laboratories. Starting this issue, Gomez Valero et al. (2011) present a comprehensive review on what we have learned from the sequencing and analyses of six L. pneumophila and five L. longbeachae genomes published since 2004. In particular, genome sequence analysis revealed the presence of proteins with high similarity to eukaryotic proteins or proteins with domains preferentially or only present in eukaryotic genomes that are mimicking host functions helping the pathogen to replicate intracellularly (Cazalet et al., 2004, 2010). Further insight in the genetic basis of host differences and the evolution of the eukaryotic like proteins in these two pathogens are given. The bacterial cell wall is at the forefront of the interaction with the host and is essential for cellular integrity and the resistance to external stress and aggressions. Shevchuk et al. (2011) provide an update on the structure, molecular composition, and virulence properties of the L. pneumophila cell envelope. In their review they show convincingly that lipopolysaccharide and several outer membrane proteins like Mip, a peptidylprolyl-cis/trans isomerase, a phospholipase A are essential virulence factors. It becomes clear that promising new fields of research will be the analyses of proteins, carbohydrates, and lipids of the cell envelope as they serve for both, structural and signaling roles. In the following review article Garduno et al. (2011) present us the current knowledge on the many functions that one of these outer membrane proteins, Hsp60 or HtpB plays in the L. pneumophila biology. This chaperonin is an unusual multifunctional protein which was discovered already as early as 1986 as an antigen that prominently reacted with patients diagnosed with Legionnaires’ disease. Over 20 years later it has been shown to have protein folding as well as protein folding independent roles and that it is associated with virulence and survival of L. pneumophila.