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. 2017 Jul 11;199(15):e00872-16.
doi: 10.1128/JB.00872-16. Print 2017 Aug 1.

Cooperative Metabolism in a Three-Partner Insect-Bacterial Symbiosis Revealed by Metabolic Modeling

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Free PMC article

Cooperative Metabolism in a Three-Partner Insect-Bacterial Symbiosis Revealed by Metabolic Modeling

Nana Y D Ankrah et al. J Bacteriol. .
Free PMC article

Abstract

An important factor determining the impact of microbial symbionts on their animal hosts is the balance between the cost of nutrients consumed by the symbionts and the benefit of nutrients released back to the host, but the quantitative significance of nutrient exchange in symbioses involving multiple microbial partners has rarely been addressed. In this study on the association between two intracellular bacterial symbionts, "Candidatus Portiera aleyrodidarum" and "Candidatus Hamiltonella defensa," and their animal host, the whitefly Bemisia tabaci, we apply metabolic modeling to investigate host-symbiont nutrient exchange. Our in silico analysis revealed that >60% of the essential amino acids and related metabolites synthesized by "Candidatus Portiera aleyrodidarum" are utilized by the host, including a substantial contribution of nitrogen recycled from host nitrogenous waste, and that these interactions are required for host growth. In contrast, "Candidatus Hamiltonella defensa" retains most or all of the essential amino acids and B vitamins that it is capable of synthesizing. Furthermore, "Candidatus Hamiltonella defensa" suppresses host growth in silico by competition with "Candidatus Portiera aleyrodidarum" for multiple host nutrients, by suppressing "Candidatus Portiera aleyrodidarum" growth and metabolic function, and also by consumption of host nutrients that would otherwise be allocated to host growth. The interpretation from these modeling outputs that "Candidatus Hamiltonella defensa" is a nutritional parasite could not be inferred reliably from gene content alone but requires consideration of constraints imposed by the structure of the metabolic network. Furthermore, these quantitative models offer precise predictions for future experimental study and the opportunity to compare the functional organization of metabolic networks in different symbioses.IMPORTANCE The metabolic functions of unculturable intracellular bacteria with much reduced genomes are traditionally inferred from gene content without consideration of how the structure of the metabolic network may influence flux through metabolic reactions. The three-compartment model of metabolic flux between two bacterial symbionts and their insect host constructed in this study revealed that one symbiont is structured to overproduce essential amino acids for the benefit of the host, but the essential amino acid production in the second symbiont is quantitatively constrained by the structure of its network, rendering it "selfish" with respect to these nutrients. This study demonstrates the importance of quantitative flux data for elucidation of the metabolic function of symbionts. The in silico methodology can be applied to other symbioses with intracellular bacteria.

Keywords: flux balance analysis; genome reduction; metabolic model; metabolic modeling; nutrient exchange; “Candidatus Hamiltonella defensa”; “Candidatus Portiera aleyrodidarum”.

Figures

FIG 1
FIG 1
Metabolic models of the three-partner symbiosis between the Bemisia whitefly host and two bacterial symbionts, “Candidatus Portiera aleyrodidarum” and “Candidatus Hamiltonella defensa.” (a) Model structure showing species compartments and metabolites exchanged between compartments. The total number of metabolites in each compartment is shown in parentheses, and the numbers of input and output metabolites for each compartment are displayed alongside the arrows. (b to e) Metabolic-network maps of “Candidatus Portiera aleyrodidarum” iNA94 (b), “Candidatus Hamiltonella defensa” iNA348 (c), Bemisia iNA332 (d), and the integrated three-compartment model iNA774 (e) visualized with Cytoscape_v3.4.0. The red circles represent metabolites, and the blue squares represent reactions. (f to h) Genetic robustness of the metabolic networks “Candidatus Portiera aleyrodidarum” iNA94 (f), “Candidatus Hamiltonella defensa” iNA348 (g), and Bemisia iNA332 (h).
FIG 2
FIG 2
In silico predictions of EAA synthesis rates and utilization profiles. (a) Predictions of EAA production by “Candidatus Portiera aleyrodidarum” and host. (b) Predictions of EAA utilization profiles for host and bacteria.
FIG 3
FIG 3
Predicted metabolic interactions between “Candidatus Portiera aleyrodidarum” and “Candidatus Hamiltonella defensa.” The dashed arrows indicate transport reactions between symbionts and hosts. The solid arrows indicate metabolite transformations occurring in the host.
FIG 4
FIG 4
Comparison of metabolites produced and consumed by symbionts. (a) Inputs utilized by symbionts. (b) Outputs produced by symbionts. The circle colors and sizes correspond to metabolite classes and metabolite reaction flux, respectively. The metabolite class “cofactors” includes cofactors, intermediates, and side chains of cofactor biosynthesis.
FIG 5
FIG 5
Relationship between availability of host-derived aspartate and production of the EAAs threonine and lysine in the three-compartment model. (a) Threonine and lysine synthesis from aspartate. “Candidatus Portiera aleyrodidarum” can synthesize threonine from host aspartate, but “Candidatus Portiera aleyrodidarum” and the host mediate complementary reactions in lysine biosynthesis. The metabolic reactions and transport reactions used in the simulations are shown in red and blue, respectively. (b and c) Effects of host synthesis of aspartate (b) and rate of aspartate uptake (c) by “Candidatus Portiera aleyrodidarum” on the synthesis of threonine and the lysine precursor l,l-2,6-diaminoheptanedioate by “Candidatus Portiera aleyrodidarum.” The simulation displays the reaction rates for aspartate aminotransferase (aspartate synthesis), threonine synthase (threonine synthesis), and diaminopimelate decarboxylase (lysine synthesis).
FIG 6
FIG 6
Predicted contributions of “Candidatus Portiera aleyrodidarum” and “Candidatus Hamiltonella defensa” to the supply of lysine and threonine to the host. The reaction rates (solid arrows) and transport rates (dashed arrows) in the three-compartment model (millimoles gram DW−1 hour−1) are shown. (a) “Candidatus Portiera aleyrodidarum”-mediated production of threonine and the lysine precursor l,l-2,6-diaminoheptanedioate from host aspartate (“Candidatus Portiera aleyrodidarum” lacks the genetic capacity to synthesize aspartate). (b) “Candidatus Hamiltonella defensa”-mediated production of threonine and lysine synthesis from endogenously generated aspartate (left) and host aspartate (right).
FIG 7
FIG 7
Bemisia-symbiont-mediated ammonia assimilation and nitrogen recycling. The inferred fluxes for total nitrogen assimilated and released by symbionts were measured in millimoles gram DW−1 hour−1. The dashed arrows represent transport fluxes between hosts and symbionts. The reaction rates are shown as percentages of the total nitrogen entering or leaving the symbiont cell. The solid arrows represent host-mediated reactions.

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