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

Bryan A. Wee, Joana Alves, Diane S. J. Lindsay, Ross L. Cameron, Amy Pickering, Jamie Gorzynski, Jukka Corander, Pekka Marttinen, Andrew J. Smith, View ORCID ProfileJ. Ross Fitzgerald
doi: https://doi.org/10.1101/2020.08.14.250670
Bryan A. Wee
1The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, Scotland, United Kingdom
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Joana Alves
1The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, Scotland, United Kingdom
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Diane S. J. Lindsay
2Bacterial Respiratory Infections Service (Ex Mycobacteria), Scottish Microbiology Reference Laboratory, Glasgow, G31 2ER, Scotland, United Kingdom
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Ross L. Cameron
3NHS National Services Scotland, Health Protection Scotland, Glasgow, Scotland, United Kingdom
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Amy Pickering
1The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, Scotland, United Kingdom
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Jamie Gorzynski
1The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, Scotland, United Kingdom
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Jukka Corander
4Department of Mathematics and Statistics, University of Helsinki, FI-00014 Helsinki, Finland
5Department of Biostatistics, University of Oslo, Oslo, Norway, P.O. Box 1122, Blindern, 0317 Oslo, Norway
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Pekka Marttinen
6Helsinki Institute for Information Technology, Department of Computer Science, Aalto University, FIN-00076 Aalto, Finland
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Andrew J. Smith
2Bacterial Respiratory Infections Service (Ex Mycobacteria), Scottish Microbiology Reference Laboratory, Glasgow, G31 2ER, Scotland, United Kingdom
7College of Medical, Veterinary & Life Sciences, Glasgow Dental Hospital & School, University of Glasgow, Glasgow G12 8QQ, United Kingdom
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J. Ross Fitzgerald
1The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, Scotland, United Kingdom
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  • ORCID record for J. Ross Fitzgerald
  • For correspondence: ross.fitzgerald@ed.ac.uk
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Abstract

Legionella pneumophila is the most common cause of the severe respiratory infection known as Legionnaires’ disease. L. pneumophila 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 900 L. pneumophila isolates from human clinical and environmental samples to examine their genetic diversity, global distribution and the basis for human pathogenicity. We found that although some clones are more commonly associated with clinical infections, the capacity for human disease is representative of the breadth of species diversity. To investigate the bacterial genetic basis for human disease potential, we carried out a genome-wide association study that identified a single gene (lag-1), to be most strongly associated with clinical isolates. Molecular evolutionary analysis showed that lag-1, which encodes an O-acetyltransferase responsible for lipopolysaccharide modification, has been distributed horizontally across all major phylogenetic clades of L. pneumophila by frequent recent recombination events. Functional analysis revealed a correlation between the presence of a functional lag-1 gene and resistance to killing in human serum and bovine broncho-alveolar lavage. In addition, L. pneumophila strains that express lag-1 escaped complement-mediated phagocytosis by neutrophils. Importantly, we discovered that the expression of lag-1 confers the capacity to evade complement-mediated killing by inhibiting deposition of classical pathway molecules on the bacterial surface. In summary, our combined population and functional analyses identified L. pneumophila genetic traits linked to human disease and revealed the molecular basis for resistance to complement-mediated killing, a previously elusive trait of direct relevance to human disease pathogenicity.

Significance Legionella pneumophila is an environmental bacterium associated with a severe pneumonia known as Legionnaires’ disease. A small number of L. pneumophila clones are responsible for a large proportion of human infections suggesting they have enhanced pathogenicity. Here, we employed a large-scale population analysis to investigate the evolution of human pathogenicity and identified a single gene (lag-1) that was more frequently found in clinical isolates. Functional analysis revealed that the lag-1-encoded O-acetyltransferase, involved in modification of lipopolysaccharide, conferred resistance to the classical pathway of complement in human serum. These findings solve a long-standing mystery in the field regarding L. pneumophila resistance to serum killing, revealing a novel mechanism by which L. pneumophila may avoid immune defences during infection.

Competing Interest Statement

The authors have declared no competing interest.

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Population analysis of Legionella pneumophila reveals the basis of resistance to complement-mediated killing
Bryan A. Wee, Joana Alves, Diane S. J. Lindsay, Ross L. Cameron, Amy Pickering, Jamie Gorzynski, Jukka Corander, Pekka Marttinen, Andrew J. Smith, J. Ross Fitzgerald
bioRxiv 2020.08.14.250670; doi: https://doi.org/10.1101/2020.08.14.250670
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Population analysis of Legionella pneumophila reveals the basis of resistance to complement-mediated killing
Bryan A. Wee, Joana Alves, Diane S. J. Lindsay, Ross L. Cameron, Amy Pickering, Jamie Gorzynski, Jukka Corander, Pekka Marttinen, Andrew J. Smith, J. Ross Fitzgerald
bioRxiv 2020.08.14.250670; doi: https://doi.org/10.1101/2020.08.14.250670

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