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Transcriptomic buffering of cryptic genetic variation contributes to meningococcal virulence

View Article: PubMed Central - PubMed

ABSTRACT

Background: Commensal bacteria like Neisseria meningitidis sometimes cause serious disease. However, genomic comparison of hyperinvasive and apathogenic lineages did not reveal unambiguous hints towards indispensable virulence factors. Here, in a systems biological approach we compared gene expression of the invasive strain MC58 and the carriage strain α522 under different ex vivo conditions mimicking commensal and virulence compartments to assess the strain-specific impact of gene regulation on meningococcal virulence.

Results: Despite indistinguishable ex vivo phenotypes, both strains differed in the expression of over 500 genes under infection mimicking conditions. These differences comprised in particular metabolic and information processing genes as well as genes known to be involved in host-damage such as the nitrite reductase and numerous LOS biosynthesis genes. A model based analysis of the transcriptomic differences in human blood suggested ensuing metabolic flux differences in energy, glutamine and cysteine metabolic pathways along with differences in the activation of the stringent response in both strains. In support of the computational findings, experimental analyses revealed differences in cysteine and glutamine auxotrophy in both strains as well as a strain and condition dependent essentiality of the (p)ppGpp synthetase gene relA and of a short non-coding AT-rich repeat element in its promoter region.

Conclusions: Our data suggest that meningococcal virulence is linked to transcriptional buffering of cryptic genetic variation in metabolic genes including global stress responses. They further highlight the role of regulatory elements for bacterial virulence and the limitations of model strain approaches when studying such genetically diverse species as N. meningitidis.

Electronic supplementary material: The online version of this article (doi:10.1186/s12864-017-3616-7) contains supplementary material, which is available to authorized users.

No MeSH data available.


Related in: MedlinePlus

Graphical summary and hypothesis relating major findings of this work and published data. The figure is not intended to give a comprehensive overview of the entire metabolism and stress responses in N. meningitidis but to illustrate pathways that link metabolism, protein sequence and gene expression differences of selected (virulence-associated) genes and the pathogenesis of IMD as described in the main text. Accordingly, genes and pathways that were highly expressed in MC58 in blood and/or that are strongly upregulated between saliva and blood in MC58 are depicted in red, and genes and pathways that are highly expressed in α522 or that are strongly upregulated between saliva and blood in α522 are depicted in green. Asterisks next to enzyme or protein names indicate that the corresponding proteins have a less than average sequence similarity (BSRP < 0.958) or are entirely missing in strain α522. Arrows with plus signs indicate (predominantly) activating regulatory interactions, and arrows with minus signs (predominantly) inhibitory regulatory interactions. For further details and abbreviations see main text. The literature cited in the figure is indicated by bracketed numerals next to the respective arrows: (1) Newcombe et al. (2005) [33], (2) Delany et al. (2006) [70], (3) Fantappie et al. (2009) [74], (4) Monaco et al. (2006) [87], (5) Huis in’t Veld et al. (2011) [72], (6) Tala et al. (2011) [86], (7) Takahashi et al. (2015) [124], (8) Gunesekere et al. [71], (9) Criss and Seifert (2012) [38], (10) Seib et al. (2006) [84], (11) Schmitt et al. (2009) [83], (12) Stevanin et al. (2007) [52], (13) Kobsar et al. (2011) [51], (14) Coureuil et al. (2014) [125], (15) Virji (2009) [49], (16) Hellerud et al. (2015) [48]
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Fig8: Graphical summary and hypothesis relating major findings of this work and published data. The figure is not intended to give a comprehensive overview of the entire metabolism and stress responses in N. meningitidis but to illustrate pathways that link metabolism, protein sequence and gene expression differences of selected (virulence-associated) genes and the pathogenesis of IMD as described in the main text. Accordingly, genes and pathways that were highly expressed in MC58 in blood and/or that are strongly upregulated between saliva and blood in MC58 are depicted in red, and genes and pathways that are highly expressed in α522 or that are strongly upregulated between saliva and blood in α522 are depicted in green. Asterisks next to enzyme or protein names indicate that the corresponding proteins have a less than average sequence similarity (BSRP < 0.958) or are entirely missing in strain α522. Arrows with plus signs indicate (predominantly) activating regulatory interactions, and arrows with minus signs (predominantly) inhibitory regulatory interactions. For further details and abbreviations see main text. The literature cited in the figure is indicated by bracketed numerals next to the respective arrows: (1) Newcombe et al. (2005) [33], (2) Delany et al. (2006) [70], (3) Fantappie et al. (2009) [74], (4) Monaco et al. (2006) [87], (5) Huis in’t Veld et al. (2011) [72], (6) Tala et al. (2011) [86], (7) Takahashi et al. (2015) [124], (8) Gunesekere et al. [71], (9) Criss and Seifert (2012) [38], (10) Seib et al. (2006) [84], (11) Schmitt et al. (2009) [83], (12) Stevanin et al. (2007) [52], (13) Kobsar et al. (2011) [51], (14) Coureuil et al. (2014) [125], (15) Virji (2009) [49], (16) Hellerud et al. (2015) [48]

Mentions: Despite the substantial genetic differences between both strains affecting surface antigens as well as metabolic genes likely affecting Cys and Gln biosynthesis (summarized in Fig. 8), both were surprisingly similar in a variety of in vitro virulence assays and in their growth behavior under infection mimicking conditions (Table 1 and Fig. 5). In particular, the finding that both strains have the same fitness in human blood and CSF despite the large differences in the disease/carriage ratios between CC ST-32 and CC ST-35 strains further indicates that the ability to grow under infection mimicking conditions might be necessary but not sufficient for explaining the invasive property of certain meningococcal lineages. Virulence, i.e. host damage, might rather be related to the way how meningococci accomplish growth in this environment. In line with this hypothesis, the large transcriptome differences observed particularly in human blood (Fig. 1) indicate that different transcriptional programs probably compensate for the differences in the genetic backgrounds of both strains in response to host components. This so called phenotypic buffering is a general property of complex gene-regulatory networks [25, 36].Fig. 8


Transcriptomic buffering of cryptic genetic variation contributes to meningococcal virulence
Graphical summary and hypothesis relating major findings of this work and published data. The figure is not intended to give a comprehensive overview of the entire metabolism and stress responses in N. meningitidis but to illustrate pathways that link metabolism, protein sequence and gene expression differences of selected (virulence-associated) genes and the pathogenesis of IMD as described in the main text. Accordingly, genes and pathways that were highly expressed in MC58 in blood and/or that are strongly upregulated between saliva and blood in MC58 are depicted in red, and genes and pathways that are highly expressed in α522 or that are strongly upregulated between saliva and blood in α522 are depicted in green. Asterisks next to enzyme or protein names indicate that the corresponding proteins have a less than average sequence similarity (BSRP < 0.958) or are entirely missing in strain α522. Arrows with plus signs indicate (predominantly) activating regulatory interactions, and arrows with minus signs (predominantly) inhibitory regulatory interactions. For further details and abbreviations see main text. The literature cited in the figure is indicated by bracketed numerals next to the respective arrows: (1) Newcombe et al. (2005) [33], (2) Delany et al. (2006) [70], (3) Fantappie et al. (2009) [74], (4) Monaco et al. (2006) [87], (5) Huis in’t Veld et al. (2011) [72], (6) Tala et al. (2011) [86], (7) Takahashi et al. (2015) [124], (8) Gunesekere et al. [71], (9) Criss and Seifert (2012) [38], (10) Seib et al. (2006) [84], (11) Schmitt et al. (2009) [83], (12) Stevanin et al. (2007) [52], (13) Kobsar et al. (2011) [51], (14) Coureuil et al. (2014) [125], (15) Virji (2009) [49], (16) Hellerud et al. (2015) [48]
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Fig8: Graphical summary and hypothesis relating major findings of this work and published data. The figure is not intended to give a comprehensive overview of the entire metabolism and stress responses in N. meningitidis but to illustrate pathways that link metabolism, protein sequence and gene expression differences of selected (virulence-associated) genes and the pathogenesis of IMD as described in the main text. Accordingly, genes and pathways that were highly expressed in MC58 in blood and/or that are strongly upregulated between saliva and blood in MC58 are depicted in red, and genes and pathways that are highly expressed in α522 or that are strongly upregulated between saliva and blood in α522 are depicted in green. Asterisks next to enzyme or protein names indicate that the corresponding proteins have a less than average sequence similarity (BSRP < 0.958) or are entirely missing in strain α522. Arrows with plus signs indicate (predominantly) activating regulatory interactions, and arrows with minus signs (predominantly) inhibitory regulatory interactions. For further details and abbreviations see main text. The literature cited in the figure is indicated by bracketed numerals next to the respective arrows: (1) Newcombe et al. (2005) [33], (2) Delany et al. (2006) [70], (3) Fantappie et al. (2009) [74], (4) Monaco et al. (2006) [87], (5) Huis in’t Veld et al. (2011) [72], (6) Tala et al. (2011) [86], (7) Takahashi et al. (2015) [124], (8) Gunesekere et al. [71], (9) Criss and Seifert (2012) [38], (10) Seib et al. (2006) [84], (11) Schmitt et al. (2009) [83], (12) Stevanin et al. (2007) [52], (13) Kobsar et al. (2011) [51], (14) Coureuil et al. (2014) [125], (15) Virji (2009) [49], (16) Hellerud et al. (2015) [48]
Mentions: Despite the substantial genetic differences between both strains affecting surface antigens as well as metabolic genes likely affecting Cys and Gln biosynthesis (summarized in Fig. 8), both were surprisingly similar in a variety of in vitro virulence assays and in their growth behavior under infection mimicking conditions (Table 1 and Fig. 5). In particular, the finding that both strains have the same fitness in human blood and CSF despite the large differences in the disease/carriage ratios between CC ST-32 and CC ST-35 strains further indicates that the ability to grow under infection mimicking conditions might be necessary but not sufficient for explaining the invasive property of certain meningococcal lineages. Virulence, i.e. host damage, might rather be related to the way how meningococci accomplish growth in this environment. In line with this hypothesis, the large transcriptome differences observed particularly in human blood (Fig. 1) indicate that different transcriptional programs probably compensate for the differences in the genetic backgrounds of both strains in response to host components. This so called phenotypic buffering is a general property of complex gene-regulatory networks [25, 36].Fig. 8

View Article: PubMed Central - PubMed

ABSTRACT

Background: Commensal bacteria like Neisseria meningitidis sometimes cause serious disease. However, genomic comparison of hyperinvasive and apathogenic lineages did not reveal unambiguous hints towards indispensable virulence factors. Here, in a systems biological approach we compared gene expression of the invasive strain MC58 and the carriage strain &alpha;522 under different ex vivo conditions mimicking commensal and virulence compartments to assess the strain-specific impact of gene regulation on meningococcal virulence.

Results: Despite indistinguishable ex vivo phenotypes, both strains differed in the expression of over 500 genes under infection mimicking conditions. These differences comprised in particular metabolic and information processing genes as well as genes known to be involved in host-damage such as the nitrite reductase and numerous LOS biosynthesis genes. A model based analysis of the transcriptomic differences in human blood suggested ensuing metabolic flux differences in energy, glutamine and cysteine metabolic pathways along with differences in the activation of the stringent response in both strains. In support of the computational findings, experimental analyses revealed differences in cysteine and glutamine auxotrophy in both strains as well as a strain and condition dependent essentiality of the (p)ppGpp synthetase gene relA and of a short non-coding AT-rich repeat element in its promoter region.

Conclusions: Our data suggest that meningococcal virulence is linked to transcriptional buffering of cryptic genetic variation in metabolic genes including global stress responses. They further highlight the role of regulatory elements for bacterial virulence and the limitations of model strain approaches when studying such genetically diverse species as N. meningitidis.

Electronic supplementary material: The online version of this article (doi:10.1186/s12864-017-3616-7) contains supplementary material, which is available to authorized users.

No MeSH data available.


Related in: MedlinePlus