Whole-body metabolic modelling predicts isoleucine dependency of SARS-CoV-2 replication
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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 achieved 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 emphasis 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.
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SciScore for 10.1101/2022.04.13.488249: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources COBRA modelling and flux balance analysis: The sex-specific WBM-SARS-CoV-2 and WBM-SARS-CoV-2-CD4+ models were mathematical representations of the host and virus metabolic transformation and transport reactions that were parameterised as described above. COBRAsuggested: (COBrA, RRID:SCR_005677)We then used Diamond [53] with default parameters to perform blastp for each downloaded sequence against the reference strain (NC_045512.2). Diamondsuggested: (DIAMOND, RRID:SCR_009457)Results from OddPub: Thank you for sharing your code.
Results from LimitationRecognizer: We detected the following …SciScore for 10.1101/2022.04.13.488249: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources COBRA modelling and flux balance analysis: The sex-specific WBM-SARS-CoV-2 and WBM-SARS-CoV-2-CD4+ models were mathematical representations of the host and virus metabolic transformation and transport reactions that were parameterised as described above. COBRAsuggested: (COBrA, RRID:SCR_005677)We then used Diamond [53] with default parameters to perform blastp for each downloaded sequence against the reference strain (NC_045512.2). Diamondsuggested: (DIAMOND, RRID:SCR_009457)Results from OddPub: Thank you for sharing your code.
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Despite these assumptions and limitations, we believe that our modelling approach provides valuable insights and strengths, such as the generation of novel hypotheses in a sex-specific, whole-body yet organ resolved manner during COVID-19 infection. These hypotheses, such as the possibility to reduce the virus replication rate by restricting isoleucine availability in the diet can be translated into clinical research, delivering thereby additional targets for intervention. Notably, the overall computational modelling paradigm could be extended to other viruses, such as influenza and human pathogens.
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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