Tn-Core: A Toolbox for Integrating Tn-seq Gene Essentiality Data and Constraint-Based Metabolic Modeling

diCenzo, George C.; Mengoni, Alessio; Fondi, Marco

doi:10.1021/acssynbio.8b00432

Cited by 14 publications

(9 citation statements)

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“…Context-specific core metabolic models, containing a minimal set of reactions for biomass production in a given environment, were extracted from the iGD1348 and iGD1575 metabolic models through the integration of Tn-seq data 34 using Tn-Core 48 . The accuracy of the resulting core metabolic models was determined through comparison with iGD726, a manually prepared core metabolic model of S. meliloti 34 .…”

Section: Resultsmentioning

confidence: 99%

“…Metabolic modeling procedures. Model integration, model manipulations, and FBA simulations were performed in MATLAB R2016b (mathworks.com) using the SBMLToolbox version 4.1.0 110 , libSBML version 5.13.0 111 , and scripts from the COBRA Toolbox commit 9b10fa1 112 , the TIGER Toolbox version 1.2.0-beta 113 , FASTCORE version 1.0 114 , and the Tn-Core Toolbox version 2.2 48 . The iLOG CPLEX Studio 12.7.1 solver (ibm.com) was used for nearly all FBA simulations; the exception was for the preparation of iGD1348, during which the Gurobi version 7.0.1 solver (gurobi.com) was used.…”

Section: Methodsmentioning

confidence: 99%

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Genome-scale metabolic reconstruction of the symbiosis between a leguminous plant and a nitrogen-fixing bacterium

et al. 2020

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The mutualistic association between leguminous plants and endosymbiotic rhizobial bacteria is a paradigmatic example of a symbiosis driven by metabolic exchanges. Here, we report the reconstruction and modelling of a genome-scale metabolic network of Medicago truncatula (plant) nodulated by Sinorhizobium meliloti (bacterium). The reconstructed nodule tissue contains five spatially distinct developmental zones and encompasses the metabolism of both the plant and the bacterium. Flux balance analysis (FBA) suggests that the metabolic costs associated with symbiotic nitrogen fixation are primarily related to supporting nitrogenase activity, and increasing N 2-fixation efficiency is associated with diminishing returns in terms of plant growth. Our analyses support that differentiating bacteroids have access to sugars as major carbon sources, ammonium is the main nitrogen export product of N 2-fixing bacteria, and N 2 fixation depends on proton transfer from the plant cytoplasm to the bacteria through acidification of the peribacteroid space. We expect that our model, called 'Virtual Nodule Environment' (ViNE), will contribute to a better understanding of the functioning of legume nodules, and may guide experimental studies and engineering of symbiotic nitrogen fixation.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Genome-scale metabolic reconstruction of the symbiosis between a leguminous plant and a nitrogen-fixing bacterium

et al. 2020

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“…One metric commonly used for model validation is the comparison of gene essentiality predictions generated with metabolic reconstructions with those that are identified as essential through transposon mutagenesis (40). We compared gene essentiality predictions yielded by iNgo_557 on GCB to a published dataset that is comprised of essential genes, which were identified through the growth of strain MS11 transposon insertion mutants on GC agar ( Dataset S3 ) (41).…”

Section: Resultsmentioning

confidence: 99%

Transcriptome guided metabolic network analysis reveals rearrangements of carbon flux distribution inNeisseria gonorrhoeaeduring neutrophil co-culture

Potter

Baiocco

Papin

et al. 2022

Preprint

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The ability of bacterial pathogens to metabolically adapt to the environmental conditions of their hosts is critical to both colonization and invasive disease. Infection withNeisseria gonorrhoeae(the gonococcus, Gc) is characterized by the influx of neutrophils (PMNs), which fail to clear the bacteria and make antimicrobial products that can exacerbate tissue damage. The inability of the human host to clear Gc infection is particularly concerning in light of the emergence of strains that are resistant to all clinically recommended antibiotics. Bacterial metabolism represents a promising target for the development of new therapeutics against Gc. Here, we generated a curated genome-scale metabolic network reconstruction (GENRE) of Gc strain FA1090. This GENRE links genetic information to metabolic phenotypes and predicts Gc biomass synthesis and energy consumption. We validated this model with published data and in new results reported here. Contextualization of this model using the transcriptional profile of Gc exposed to PMNs revealed substantial rearrangements of Gc central metabolism and induction of Gc nutrient acquisition strategies for alternate carbon source use. These features enhanced the growth of Gc in the presence of neutrophils. From these results we conclude that the metabolic interplay between Gc and PMNs helps define infection outcomes. The use of transcriptional profiling and metabolic modeling to reveal new mechanisms by which Gc persists in the presence of PMNs uncovers unique aspects of metabolism in this fastidious bacterium, which could be targeted to block infection and thereby reduce the burden of gonorrhea in the human population.

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“…Model integration, model manipulations, and FBA simulations were performed in MATLAB R2016b (mathworks.com) using the SBMLToolbox version 4.1.0 (66), libSBML version 5.13.0 (67), and scripts from the COBRA Toolbox commit 9b10fa1 (68), the TIGER Toolbox version 1.2.0-beta (60), FASTCORE version 1.0 (69), and the Tn-Core Toolbox version 2.2 (70). The iLOG CPLEX Studio 12.7.1 solver (ibm.com) was used for nearly all FBA simulations; the exception was for preparation of iGD1348, during which the Gurobi version 7.0.1 solver (gurobi.com) was used.…”

Section: Methodsmentioning

confidence: 99%

A Virtual Nodule Environment (ViNE) for modelling the inter-kingdom metabolic integration during symbiotic nitrogen fixation

diCenzo

Tesi

Pfau

et al. 2019

Preprint

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16Biological associations are often premised upon metabolic cross-talk between the organisms, 17with the N2-fixing endosymbiotic relationship between rhizobia and leguminous plants being 18 a prime example. Here, we report the in silico reconstruction of a metabolic network of a 19Medicago truncatula plant nodulated by the bacterium Sinorhizobium meliloti. The nodule 20 tissue of the model contains five spatially distinct developmental zones and encompasses the 21 metabolism of both the plant and the bacterium. Flux balance analysis (FBA) suggested that 22 the majority of the metabolic costs associated with symbiotic nitrogen fixation are directly 23 related to supporting nitrogenase activity, while a minority is related to the formation and 24 maintenance of nodule and bacteroid tissue. Interestingly, FBA simulations suggested there 25 was a non-linear relationship between the rate of N2-fixation per gram of nodule and the rate 26 of plant growth; increasing the N2-fixation efficiency was associated with diminishing returns 27 in terms of plant growth. Evaluating the metabolic exchange between the symbiotic partners 28 provided support for: i) differentiating bacteroids having access to sugars (e.g., sucrose) as a 29 major carbon source, ii) ammonium being the major nitrogen export product of N2-fixing 30 bacteria, and iii) N2-fixation being dependent on the transfer of protons from the plant 31 cytoplasm to the bacteria through acidification of the peribacteroid space. Our simulations 32 further suggested that the use of C4-dicarboxylates by N2-fixing bacteroids may be, in part, a 33 consequence of the low concentration of free oxygen in the nodule limiting the activity of the 34 plant mitochondria. These results demonstrate the power of this integrated model to advance 35 our understanding of the functioning of legume nodules, and its potential for hypothesis 36 generation to guide experimental studies and engineering of symbiotic nitrogen fixation. 37 38Macroorganisms are colonized by a staggering diversity of microorganisms, collectively 39 referred to as a 'holobiont' (1, 2). The intimate association between organisms is often driven 40 by metabolic exchanges: many insects obtain essential nutrients from obligate bacterial 41 symbionts (3), most plants can obtain phosphorus from arbuscular mycorrhiza in exchange for 42 carbon (4), and the gut microbiota is thought to contribute to animal nutrition (5, 6). Complex 43 global patterns often emerge during these intimate biological associations (7), especially when 44 nutritional inter-dependencies are involved (8-10). The communication between the two 45 metabolic networks of the interacting organisms may give rise to unpredicted phenotypic traits 46 and unexpected emergent properties. Metabolic relationships can span over a large taxonomic 47 range and have profound biological relevance (11)(12)(13)(14). For example, the interactions between 48 bacteria and multicellular organisms have been suggested to be key drivers of evolutionary 49transitions, leading to ...

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Tn-Core: A Toolbox for Integrating Tn-seq Gene Essentiality Data and Constraint-Based Metabolic Modeling

Cited by 14 publications

References 77 publications

Genome-scale metabolic reconstruction of the symbiosis between a leguminous plant and a nitrogen-fixing bacterium

Genome-scale metabolic reconstruction of the symbiosis between a leguminous plant and a nitrogen-fixing bacterium

Transcriptome guided metabolic network analysis reveals rearrangements of carbon flux distribution inNeisseria gonorrhoeaeduring neutrophil co-culture

A Virtual Nodule Environment (ViNE) for modelling the inter-kingdom metabolic integration during symbiotic nitrogen fixation

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