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

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. The bacterium Legionella pneumophila can cause severe respiratory infection, but is typically a symbiont of free-living amoeba. Here, the authors analyse the genomes of 902 clinical and environmental isolates, and identify a bacterial gene that is strongly associated with human infection and confers resistance to complement-mediated killing.Peer reviewe

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

Background: Legionella pneumophila is the main cause of a severe pneumonic illness known as Legionnaires' disease and is a global public health threat. Whole-genome sequencing (WGS) can be applied to trace environmental origins of L pneumophila infections, providing information to guide appropriate interventions. We aim to explore the evolutionary and epidemiological relationships in a 36-year Scottish L pneumophila reference isolate collection. Methods: We investigated the genomic epidemiology of Legionnaires' disease over 36 years in Scotland, comparing genome sequences for all clinical L pneumophila isolates (1984–2020) with a sequence dataset of 3211 local and globally representative isolates. We used a stratified clustering approach to capture epidemiological relationships by core genome Multi-locus Sequence Typing, followed by high-resolution phylogenetic analysis of clusters to measure diversity and evolutionary relatedness in context with epidemiological metadata. Findings: Clustering analysis showed that 111 (57·5 %) of 193 of L pneumophila infections in Scotland were caused by ten endemic lineages with a wide temporal and geographical distribution. Phylogenetic analysis of L pneumophila identified hospital-associated sublineages that had been detected in the hospital environment up to 19 years. Furthermore, 12 (30·0%) of 40 community-associated infections (excluding a single, large outbreak) that occurred over a 13 year period (from 2000 to 2013) were caused by a single widely distributed endemic clone (ST37), consistent with enhanced human pathogenicity. Finally, our analysis revealed clusters linked by national or international travel to distinct geographical regions, indicating several previously unrecognised travel links between closely related isolates (fewer than five single nucleotide polymorphisms) connected by geography. Interpretation: Our analysis reveals the existence of previously undetected endemic clones of L pneumophila that existed for many years in hospital, community, and travel-associated environments. In light of these findings, we propose that cluster and outbreak definitions should be reconsidered, and propose WGS-based surveillance as a critical public health tool for real-time identification and mitigation of clinically important endemic clones. Funding: Chief Scientist Office, Biotechnology and Biological Sciences Research Council (UK), Medical Research Council Precision Medicine Doctoral Training Programme, Wellcome Trust, and Medical Research Council (UK)

New biphenyl iminium salt catalysts for highly enantioselective asymmetric epoxidation: role of additional substitution and dihedral angle

New biaryl iminium salt catalysts for enantioselective alkene epoxidation containing additional substitution in the heterocyclic ring are reported. The effects upon conformation and enantioselectivity of this additional substitution, and the influence of dihedral angle in these systems, has been investigated using a synthetic approach supported by density functional theory. Enantioselectivities of up to 97% ee were observed

The 5,6‐epoxycholesterol metabolic pathway in breast cancer: Emergence of new pharmacological targets

International audienceMetabolic pathways have emerged as cornerstones in carcinogenic deregulation providing new therapeutic strategies for cancer management. Recently, a new branch of cholesterol metabolism has been discovered involving the biochemical transformation of 5,6-epoxycholesterols (5,6-ECs). The 5,6-ECs are metabolized in breast cancers to the tumour promoter oncosterone whereas, in normal breast tissue, they are metabolized to the tumour suppressor metabolite, dendrogenin A (DDA). Blocking the mitogenic and invasive potential of oncosterone will present new opportunities for breast cancer treatment. The reactivation of DDA biosynthesis, or its use as a drug, represents promising therapeutic approaches such as DDA-deficiency complementation, activation of breast cancer cell re-differentiation and breast cancer chemoprevention. This review presents current knowledge of the 5,6-EC metabolic pathway in breast cancer, focusing on the 5,6-EC metabolic enzymes ChEH and HSD11B2 and on 5,6-EC metabolite targets, the oxysterol receptor (LXRβ) and the glucocorticoid receptor