Population analysis of Legionella pneumophila reveals a basis for resistance to complement-mediated killing

Abstract

Legionella pneumophila is the most common cause of the severe respiratory infection known as Legionnaires’ disease. However, the microorganism is typically a symbiont of free-living amoeba, and our understanding of the bacterial factors that determine human pathogenicity is limited. Here we carried out a population genomic study of 902 L. pneumophila isolates from human clinical and environmental samples to examine their genetic diversity, global distribution and the basis for human pathogenicity. We find that the capacity for human disease is representative of the breadth of species diversity although some clones are more commonly associated with clinical infections. We identified a single gene (lag-1) to be most strongly associated with clinical isolates. lag-1, which encodes an O-acetyltransferase for lipopolysaccharide modification, has been distributed horizontally across all major phylogenetic clades of L. pneumophila by frequent recent recombination events. The gene confers resistance to complement-mediated killing in human serum by inhibiting deposition of classical pathway molecules on the bacterial surface. Furthermore, acquisition of lag-1 inhibits complement-dependent phagocytosis by human neutrophils, and promoted survival in a mouse model of pulmonary legionellosis. Thus, our results reveal L. pneumophila genetic traits linked to disease and provide a molecular basis for resistance to complement-mediated killing.

A Tale of Four Danish Cities: Legionella pneumophila Diversity in Domestic Hot Water and Spatial Variations in Disease Incidence

“…SG1 (MAb 3/1-P) might be a rare occurrence in City A that causes a disproportionate number of LD cases (2.1 culture-confirmed cases per 100,000 inhabitants per year). This finding may be supported by several studies demonstrating that the MAb 3/1-P strains have a higher virulence than other LP serogroups and subgroups [8,13,[43][44][45]. During the last four years, the only MAb 3/1-P strains that have been detected in environmental samples (primarily DHW samples) in DK are Philadelphia ST1 and Benidorm ST42, despite 63% of domestic SG1 MAb 3/1-P cases (n = 94) being caused by other Benidorm, Allentown/France, Philadelphia, and Knoxville associated STs.…”

“…Other STs are more constantly associated with an SG; ST1 is, for example, always associated with SG1. Serogroup-associated genes are both clonally distributed and horizontally acquired, as shown for the lag - 1 gene (MAb 3/1-P) that has been distributed horizontally across all major phylogenetic clades of L. pneumophila [ 45 ]. The two SNP trees (purged and unpurged) show the same overall phylogeny, and the STs (number of loci similarities and differences) are good indicators of phylogenetic relatedness.…”

Epidemiological analysis of Legionnaires' disease in Scotland: a genomic study

“…The archive contains isolates that were collected as part of outbreak investigations, enhanced surveillance, and general submissions from Scottish water testing laboratories and included 16 isolates from ships or from outside Scotland. We previously sequenced 431 Scottish isolates (NCBI BioProject Accessions: PRJEB31628 [n=395], PRJEB6631 [n=25], and PRJEB1828 [n=11]), 16 and 22 (5%) were newly sequenced for the current study, with reads uploaded to the NCBI Short Read Archive under the BioProject accession PRJEB50423.…”

A nutritional immunity blockade controls extracellular bacterial replication inLegionella pneumophilainfections

“…Majority of serogroup-1 clinical isolates unlike environmental isolates (80% vs 30%) express the lag-1 gene encoding a LPS O-acetyltransferase, which confers resistance to complement killing and neutrophil internalization. 123 Because ‘clinical’ strains are frequently isolated during outbreaks from symptomatic infections, the lag-1 gene predominance in clinical isolates links extracellular antimicrobial defenses (i.e killing by complement and neutrophils) with clinical symptomatology and disease severity. Epidemiological data also argues for host-intrinsic rather than bacteria-intrinsic drivers of disease severity because outbreaks caused by a single clinical isolate frequently produces both mild and severe disease.…”