More than 18,000 effectors in the Legionella genus genome provide multiple, independent combinations for replication in human cells

Laura Gomez-Valero, Christophe Rusniok, Danielle Carson, Sonia Mondino, Ana Elena Pérez-Cobas, Monica Rolando, Shivani Pasricha, Sandra Reuter, Jasmin Demirtas, Johannes Crumbach, Stephane Descorps-Declere, Elizabeth L. Hartland, Sophie Jarraud, Gordon Dougan, Gunnar N. Schroeder, Gad Frankel, Carmen Buchrieser

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The genus Legionella comprises 65 species, among which Legionella pneumophila is a human pathogen causing severe pneumonia. To understand the evolution of an environmental to an accidental human pathogen, we have functionally analyzed 80 Legionella genomes spanning 58 species. Uniquely, an immense repository of 18,000 secreted proteins encoding 137 different eukaryotic-like domains and over 200 eukaryotic-like proteins is paired with a highly conserved type IV secretion system (T4SS). Specifically, we show that eukaryotic Rho- and Rab-GTPase domains are found nearly exclusively in eukaryotes and Legionella. Translocation assays for selected Rab-GTPase proteins revealed that they are indeed T4SS secreted substrates. Furthermore, F-box, U-box, and SET domains were present in >70% of all species, suggesting that manipulation of host signal transduction, protein turnover, and chromatin modification pathways are fundamental intracellular replication strategies for legionellae. In contrast, the Sec-7 domain was restricted to L. pneumophila and seven other species, indicating effector repertoire tailoring within different amoebae. Functional screening of 47 species revealed 60% were competent for intracellular replication in THP-1 cells, but interestingly, this phenotype was associated with diverse effector assemblages. These data, combined with evolutionary analysis, indicate that the capacity to infect eukaryotic cells has been acquired independently many times within the genus and that a highly conserved yet versatile T4SS secretes an exceptional number of different proteins shaped by interdomain gene transfer. Furthermore, we revealed the surprising extent to which legionellae have coopted genes and thus cellular functions from their eukaryotic hosts, providing an understanding of how dynamic reshuffling and gene acquisition have led to the emergence of major human pathogens.

Original languageEnglish
Pages (from-to)2265-2273
Number of pages9
JournalProceedings of the National Academy of Sciences
Volume116
Issue number6
DOIs
Publication statusPublished - 5 Feb 2019

Keywords

  • Coevolution
  • Horizontal gene transfer
  • Human pathogen
  • Legionella
  • Protozoa

Cite this

Gomez-Valero, Laura ; Rusniok, Christophe ; Carson, Danielle ; Mondino, Sonia ; Pérez-Cobas, Ana Elena ; Rolando, Monica ; Pasricha, Shivani ; Reuter, Sandra ; Demirtas, Jasmin ; Crumbach, Johannes ; Descorps-Declere, Stephane ; Hartland, Elizabeth L. ; Jarraud, Sophie ; Dougan, Gordon ; Schroeder, Gunnar N. ; Frankel, Gad ; Buchrieser, Carmen. / More than 18,000 effectors in the Legionella genus genome provide multiple, independent combinations for replication in human cells. In: Proceedings of the National Academy of Sciences. 2019 ; Vol. 116, No. 6. pp. 2265-2273.
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title = "More than 18,000 effectors in the Legionella genus genome provide multiple, independent combinations for replication in human cells",
abstract = "The genus Legionella comprises 65 species, among which Legionella pneumophila is a human pathogen causing severe pneumonia. To understand the evolution of an environmental to an accidental human pathogen, we have functionally analyzed 80 Legionella genomes spanning 58 species. Uniquely, an immense repository of 18,000 secreted proteins encoding 137 different eukaryotic-like domains and over 200 eukaryotic-like proteins is paired with a highly conserved type IV secretion system (T4SS). Specifically, we show that eukaryotic Rho- and Rab-GTPase domains are found nearly exclusively in eukaryotes and Legionella. Translocation assays for selected Rab-GTPase proteins revealed that they are indeed T4SS secreted substrates. Furthermore, F-box, U-box, and SET domains were present in >70{\%} of all species, suggesting that manipulation of host signal transduction, protein turnover, and chromatin modification pathways are fundamental intracellular replication strategies for legionellae. In contrast, the Sec-7 domain was restricted to L. pneumophila and seven other species, indicating effector repertoire tailoring within different amoebae. Functional screening of 47 species revealed 60{\%} were competent for intracellular replication in THP-1 cells, but interestingly, this phenotype was associated with diverse effector assemblages. These data, combined with evolutionary analysis, indicate that the capacity to infect eukaryotic cells has been acquired independently many times within the genus and that a highly conserved yet versatile T4SS secretes an exceptional number of different proteins shaped by interdomain gene transfer. Furthermore, we revealed the surprising extent to which legionellae have coopted genes and thus cellular functions from their eukaryotic hosts, providing an understanding of how dynamic reshuffling and gene acquisition have led to the emergence of major human pathogens.",
keywords = "Coevolution, Horizontal gene transfer, Human pathogen, Legionella, Protozoa",
author = "Laura Gomez-Valero and Christophe Rusniok and Danielle Carson and Sonia Mondino and P{\'e}rez-Cobas, {Ana Elena} and Monica Rolando and Shivani Pasricha and Sandra Reuter and Jasmin Demirtas and Johannes Crumbach and Stephane Descorps-Declere and Hartland, {Elizabeth L.} and Sophie Jarraud and Gordon Dougan and Schroeder, {Gunnar N.} and Gad Frankel and Carmen Buchrieser",
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day = "5",
doi = "10.1073/pnas.1808016116",
language = "English",
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Gomez-Valero, L, Rusniok, C, Carson, D, Mondino, S, Pérez-Cobas, AE, Rolando, M, Pasricha, S, Reuter, S, Demirtas, J, Crumbach, J, Descorps-Declere, S, Hartland, EL, Jarraud, S, Dougan, G, Schroeder, GN, Frankel, G & Buchrieser, C 2019, 'More than 18,000 effectors in the Legionella genus genome provide multiple, independent combinations for replication in human cells' Proceedings of the National Academy of Sciences, vol. 116, no. 6, pp. 2265-2273. https://doi.org/10.1073/pnas.1808016116

More than 18,000 effectors in the Legionella genus genome provide multiple, independent combinations for replication in human cells. / Gomez-Valero, Laura; Rusniok, Christophe; Carson, Danielle; Mondino, Sonia; Pérez-Cobas, Ana Elena; Rolando, Monica; Pasricha, Shivani; Reuter, Sandra; Demirtas, Jasmin; Crumbach, Johannes; Descorps-Declere, Stephane; Hartland, Elizabeth L.; Jarraud, Sophie; Dougan, Gordon; Schroeder, Gunnar N.; Frankel, Gad; Buchrieser, Carmen.

In: Proceedings of the National Academy of Sciences, Vol. 116, No. 6, 05.02.2019, p. 2265-2273.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - More than 18,000 effectors in the Legionella genus genome provide multiple, independent combinations for replication in human cells

AU - Gomez-Valero, Laura

AU - Rusniok, Christophe

AU - Carson, Danielle

AU - Mondino, Sonia

AU - Pérez-Cobas, Ana Elena

AU - Rolando, Monica

AU - Pasricha, Shivani

AU - Reuter, Sandra

AU - Demirtas, Jasmin

AU - Crumbach, Johannes

AU - Descorps-Declere, Stephane

AU - Hartland, Elizabeth L.

AU - Jarraud, Sophie

AU - Dougan, Gordon

AU - Schroeder, Gunnar N.

AU - Frankel, Gad

AU - Buchrieser, Carmen

PY - 2019/2/5

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N2 - The genus Legionella comprises 65 species, among which Legionella pneumophila is a human pathogen causing severe pneumonia. To understand the evolution of an environmental to an accidental human pathogen, we have functionally analyzed 80 Legionella genomes spanning 58 species. Uniquely, an immense repository of 18,000 secreted proteins encoding 137 different eukaryotic-like domains and over 200 eukaryotic-like proteins is paired with a highly conserved type IV secretion system (T4SS). Specifically, we show that eukaryotic Rho- and Rab-GTPase domains are found nearly exclusively in eukaryotes and Legionella. Translocation assays for selected Rab-GTPase proteins revealed that they are indeed T4SS secreted substrates. Furthermore, F-box, U-box, and SET domains were present in >70% of all species, suggesting that manipulation of host signal transduction, protein turnover, and chromatin modification pathways are fundamental intracellular replication strategies for legionellae. In contrast, the Sec-7 domain was restricted to L. pneumophila and seven other species, indicating effector repertoire tailoring within different amoebae. Functional screening of 47 species revealed 60% were competent for intracellular replication in THP-1 cells, but interestingly, this phenotype was associated with diverse effector assemblages. These data, combined with evolutionary analysis, indicate that the capacity to infect eukaryotic cells has been acquired independently many times within the genus and that a highly conserved yet versatile T4SS secretes an exceptional number of different proteins shaped by interdomain gene transfer. Furthermore, we revealed the surprising extent to which legionellae have coopted genes and thus cellular functions from their eukaryotic hosts, providing an understanding of how dynamic reshuffling and gene acquisition have led to the emergence of major human pathogens.

AB - The genus Legionella comprises 65 species, among which Legionella pneumophila is a human pathogen causing severe pneumonia. To understand the evolution of an environmental to an accidental human pathogen, we have functionally analyzed 80 Legionella genomes spanning 58 species. Uniquely, an immense repository of 18,000 secreted proteins encoding 137 different eukaryotic-like domains and over 200 eukaryotic-like proteins is paired with a highly conserved type IV secretion system (T4SS). Specifically, we show that eukaryotic Rho- and Rab-GTPase domains are found nearly exclusively in eukaryotes and Legionella. Translocation assays for selected Rab-GTPase proteins revealed that they are indeed T4SS secreted substrates. Furthermore, F-box, U-box, and SET domains were present in >70% of all species, suggesting that manipulation of host signal transduction, protein turnover, and chromatin modification pathways are fundamental intracellular replication strategies for legionellae. In contrast, the Sec-7 domain was restricted to L. pneumophila and seven other species, indicating effector repertoire tailoring within different amoebae. Functional screening of 47 species revealed 60% were competent for intracellular replication in THP-1 cells, but interestingly, this phenotype was associated with diverse effector assemblages. These data, combined with evolutionary analysis, indicate that the capacity to infect eukaryotic cells has been acquired independently many times within the genus and that a highly conserved yet versatile T4SS secretes an exceptional number of different proteins shaped by interdomain gene transfer. Furthermore, we revealed the surprising extent to which legionellae have coopted genes and thus cellular functions from their eukaryotic hosts, providing an understanding of how dynamic reshuffling and gene acquisition have led to the emergence of major human pathogens.

KW - Coevolution

KW - Horizontal gene transfer

KW - Human pathogen

KW - Legionella

KW - Protozoa

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U2 - 10.1073/pnas.1808016116

DO - 10.1073/pnas.1808016116

M3 - Article

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EP - 2273

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

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