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Study examines co-metabolism during SARS-CoV-2 infection

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In a recent study published on bioRxiv* preprint server, researchers investigated host-virus co-metabolism during infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Study: Whole-body metabolic modeling predicts isoleucine dependence of SARS-CoV-2 replication. Image Credit: CROCOTHERIE / Shutterstock

Various studies have reported that viral infections, such as coronavirus disease 2019 (COVID-19), influence the metabolism of infected cells. However, it is still unclear whether the metabolic alterations occur at the cellular or whole-body level.

About the study

In the present study, researchers developed sex-specific whole-body organ-resolved models representing human metabolism to replicate the metabolic responses of SARS-CoV-2 infected lungs and peripheral organs.

To mimic SARS-CoV-2 infection, the team added SARS-CoV-2-specific responses to whole-body models of human metabolism (WBM). To model the infection in male and female models, the team studied the implications of viral replications in the lungs. The team noted that WBM-SARS-COV-2 patterns were associated with mild infections that did not require hospitalization and had normal levels of CD4+ T cells. Therefore, to simulate higher viral loads observed in mild but hospitalized infections and patients with severe infections, the viral uptake flux was increased to 10 U.

The team explored changes in cellular metabolism linked to SARS-CoV-2 infection, availability of CD4+ T cells, and increased viral load levels. This was achieved using three models for each sex of the healthy WBM-SARS-COV-2 model, the infected WBM-SARS-COV-2 model with 1 U virus uptake and normal levels of CD4+ T cells, and WBM-SARS- COV-2 model with 10 times higher virus uptake and CD4+ T cell levels.

Additionally, the study investigated whether different SARS-CoV-2 variants could have adapted for immune evasion due to the mutation of amino acids present in the SARS-CoV-2 spike protein and changes metabolism in the host. The team collected the genomic sequences of five variants of concern (VOC), two variants of interest (VOI) and one variant under surveillance (VUM).

Results

The study results showed that when the COVID-19 virus was sampled from the simulated air, the virus was subsequently replicated in the lungs. Virus particles generated after replication were exhaled into the air.

WBMs consisted of reactions involved in the metabolism of immuno-metabolites and could detect any changes occurring in this pathway. The setup used in the study also enabled viral replication in organs with high angiotensin-converting enzyme-2 (ACE-2) receptor expression, including the liver, small intestine, and adipocytes. In total, a total of 25 virus-specific reactions were added to the WBM, thus producing models with 83,082 and 85,568 metabolic reactions occurring in 28 and 30 organs of the male and female models, respectively.

Flux balance analysis showed that in male and female WBM-SARS-COV-2 models, the maximum possible flux resulting from the virus shedding response was 33.0254 U (mmol/day/ person) on 1 U of inhaled virus. Additionally, in both models, uptake of essential amino acids, primarily isoleucine, into the lungs from the bloodstream limited the maximum possible flux of the virus shedding response.

Viral load simulation of mild but hospitalized and severe COVID-19 infections showed that SARS-CoV-2 caused a six-fold increase in CD8+ T cells and a three-fold increase in CD4+ T cells. This indicated that increased levels of T cells are required for host virus WBMs to combat the higher initial load of SARS-CoV-2.

A comparison of flux distribution between infected and healthy WBM-SARS-CoV-2 models showed that 15% of metabolic responses had altered flux values ​​that differed by at least 10% in both sexes. Similar results were observed when comparing the WBM-SARS-COV-2-CD4+ model with the healthy and infected models. Taken together, this indicates that metabolic responses changed in different organs in mild and severe infections. Notably, in the female lung, increased flow was observed in 12% of 3,467 lung reactions, while decreased flow was observed in 14.7% of total lung reactions.

Among the SARS-CoV-2 variants, Delta VOC showed the highest viral shedding rate, followed by B.1.640 VUM. Interestingly, the maximum virus shedding rate was lower for Omicron COV than for the parent strain. The team also found a linear increase in virus exhalation flux with increasing threonine requirement in all SARS-CoV-2 variants except the Omicron BA.1 and BA subvariants. 2.

Conclusion

The results of the study showed a remarkable correlation between isoleucine requirements and virus shedding rate. Therefore, researchers believe that restricting the availability of isoleucine may lead to a reduction in the replication rate of SARS-CoV-2.

Moreover, the new WBN modeling paradigm used in the present study can be further used for other viruses.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be considered conclusive, guide clinical practice/health-related behaviors, or treated as established information.