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. 2022:20:4098-4109.
doi: 10.1016/j.csbj.2022.07.019. Epub 2022 Jul 20.

Whole-body metabolic modelling predicts isoleucine dependency of SARS-CoV-2 replication

Ines Thiele  1   2   3   4 , Ronan M T Fleming  1   5
Affiliations

Whole-body metabolic modelling predicts isoleucine dependency of SARS-CoV-2 replication

Ines Thiele et al. Comput Struct Biotechnol J. 2022.

Abstract

We aimed at investigating host-virus co-metabolism during SARS-CoV-2 infection. Therefore, we extended comprehensive sex-specific, whole-body organ resolved models of human metabolism with the necessary reactions to replicate SARS-CoV-2 in the lung as well as selected peripheral organs. Using this comprehensive host-virus model, we obtained the following key results: 1. The predicted maximal possible virus shedding rate was limited by isoleucine availability. 2. The supported initial viral load depended on the increase in CD4+ T-cells, consistent with the literature. 3. During viral infection, the whole-body metabolism changed including the blood metabolome, which agreed well with metabolomic studies from COVID-19 patients and healthy controls. 4. The virus shedding rate could be reduced by either inhibition of the guanylate kinase 1 or availability of amino acids, e.g., in the diet. 5. The virus variants differed in their maximal possible virus shedding rates, which could be inversely linked to isoleucine occurrences in the sequences. Taken together, this study presents the metabolic crosstalk between host and virus and emphasises the role of amino acid metabolism during SARS-CoV-2 infection, in particular of isoleucine. As such, it provides an example of how computational modelling can complement more canonical approaches to gain insight into host-virus crosstalk and to identify potential therapeutic strategies.

Keywords: Constraint-based modelling; Covid-19; Isoleucine; Metabolic modelling; SARS-CoV-2 infection; Variants of concerns.

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Conflict of interest statement

The authors declare that they have no known competing financial interests that could have appeared to influence the work reported in this paper.

Figures

None
Graphical abstract
Fig. 1
Fig. 1
Overview of the sex-specific host-virus metabolic whole-body models. A. Schematic overview of the host-virus model. B. Schematic overview of the virus metabolic reactions added to the sex-specific, organ-resolved whole-body human metabolic models. B. Statistics on reaction and metabolite content of the host-virus models. D. Structural viral proteins, their copy numbers used for modelling the viral infection, and their protein modifications (see Methods for more details).
Fig. 2
Fig. 2
Metabolite changes occurring during mild and severe virus infection. A. Overall changes in reaction flux values in the WBM models in mild (WBM-SARS-COV-2) and severe (WBM-SARS-COV-2-CD4+) infection models compared with the healthy WBM models. B. Biochemical network visualisation of predicted metabolic changes occurring in the female lung during mild infection. Flux values that increased (red) or decreased (blue) by more than 10% when comparing the female WBM-SARS-COV-2 with the healthy WBM model. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 3
Fig. 3
Predicted effect of drug treatment (A) and different dietary regimes on the maximally possible virus shedding rates in the different organs (B). All fluxes are given in mmol/day/person.
Fig. 4
Fig. 4
Analysis of SARS-CoV-2 variants in the context of the host-virus whole-body models. A. List of considered variants and their classifications. A total of 12,233 variant sequences were analysed. B. Predicted maximal possible virus shedding flux using the variant-specific WBM-SARS-COV-2 models. C. Mean amino acid requirements per virus particle were determined by multiplying the number of amino acids in the structural and non-structural proteins by the protein copy numbers (Fig. 1D).
Fig. 5
Fig. 5
Predicted dependency of the maximal possible virus shedding flux on isoleucine and threonine requirements of the nascent virus particle. Predicted anticorrelation of the maximal possible virus shedding flux in the variant-specific female WBM-SARS-COV-2 models on isoleucine (A) and threonine (B). C. Sequence alignment of randomly chosen sequences of three variants and the parental virus for the M protein. See also Fig. S2-4 for more examples.
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