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

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

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

About the study

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

To imitate SARS-CoV-2 infection, the team added SARS-CoV-2-specific reactions to whole-body models of human metabolism (WBM). To model the infection in the male and female models, the team investigated the implications of viral replications in the lung. The team noted that the WBM-SARS-COV-2 models were associated with mild infections that required no hospital admissions and had normal levels of CD4+ T-cells. Hence, 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 the changes in the cellular metabolism that were related to the SARS-CoV-2 infection, the availability of CD4+ T-cells, and the increased levels of viral load. This was achieved by using three models for each sex of the healthy WBM-SARS-COV-2 model, WBM-SARS-COV-2 model infected with 1 U virus uptake and normal levels of CD4+ T-cell, and WBM-SARS-COV-2 model with 10 times higher virus uptake and CD4+ T-cells levels.    

Furthermore, the study investigated whether different SARS-CoV-2 variants might have adapted to immune evasion because of the mutation of amino acids present in the SARS-CoV-2 spike protein and metabolic changes in the host. The team collected genomic sequences of five variants of concern (VOCs), two variants of interest (VOIs), and one variant under monitoring (VUM). 

Results

The study results showed that when the COVID-19 virus was taken up from the simulated air, the virus was subsequently replicated in the lung. Viral particles generated after replication were breathed out into the air.

The 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 allowed viral replication in organs with high angiotensin-converting enzyme-2 (ACE-2) receptor expression including the liver, small intestines, and adipocytes. Altogether, a total of 25 virus-specific reactions were added to the WBM, thus yielding 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 the WBM-SARS-COV-2 models of the male and female genders, the maximum possible flux resulting from the virus shedding reaction was 33.0254 U (mmol/day/person) out of 1 U virus inhaled. Moreover, in both models, the uptake of essential amino acids, mainly isoleucine, into the lung from blood circulation limited the maximal flux possible from the virus shedding reaction.      

Simulating the viral load of mild but hospitalized and severe COVID-19 infections showed that SARS-CoV-2 led to 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 necessary for the host-virus WBMs to combat the higher initial SARS-CoV-2 load.       

A comparison of the distribution of flux between the infected and the healthy WBM-SARS-CoV-2 models showed that 15% of the metabolic reactions had altered flux values that differed by at least 10% among both the sexes. Similar results were observed in comparing the WBM-SARS-COV-2-CD4+ model with the healthy and the infected models. Overall, this indicated that the metabolism reactions changed across different organs in both mild and severe infections. Notably, in the female lung, an increase in flux was observed in 12% of the 3,467 lung reactions while a decrease in flux was found in 14.7% of the total lung reactions.

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

Conclusion

The study findings showed a remarkable correlation between isoleucine requirement and the virus shedding rate. Hence, the researchers believe that restricting the availability of isoleucine can lead to the reduction of the SARS-CoV-2 replication rate.

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

*Important notice

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

Written by

Bhavana Kunkalikar

Bhavana Kunkalikar is a medical writer based in Goa, India. Her academic background is in Pharmaceutical sciences and she holds a Bachelor's degree in Pharmacy. Her educational background allowed her to foster an interest in anatomical and physiological sciences. Her college project work based on ‘The manifestations and causes of sickle cell anemia’ formed the stepping stone to a life-long fascination with human pathophysiology.