Multi-dimensional omics approaches to dissect natural immune control mechanisms associated with RNA virus infections

In recent decades, global health has been challenged by emerging and re-emerging viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), human immunodeficiency viruses (HIV-1), and Crimean–Congo hemorrhagic fever virus (CCHFV). Studies have shown dysregulations in the host metabolic processes against SARS-CoV2 and HIV-1 infections, and the research on CCHFV infection is still in the infant stage. Hence, understanding the host metabolic re-programming on the reaction level in infectious disease has therapeutic importance. The thesis uses systems biology methods to investigate the host metabolic alterations in response to SARS-CoV2, HIV-1, and CCHFV infections.

The three distinct viruses induce distinct effects on human metabolism that, nevertheless, show some commonalities. We have identified alterations in various immune cell types in patients during the infections of the three viruses. Further, differential expression analysis identified that COVID-19 causes disruptions in pathways related to antiviral response and metabolism (fructose mannose metabolism, oxidative phosphorylation (OXPHOS), and pentose phosphate pathway). Up-regulation of OXPHOS and ROS pathways with most changes in OXPHOS complexes I, III, and IV were identified in people living with HIV on treatment (PLWHART). The acute phase of CCHFV infection is found to be linked with OXPHOS, glycolysis, N-glycan biosynthesis, and NOD-like receptor signaling pathways. The dynamic nature of the metabolic process and adaptive immune response in CCHFV-pathogenesis are also observed.

Further, we have identified different metabolic flux in reactions transporting TCA cycle intermediates from the cytosol to mitochondria in COVID-19 patients. Genes such as monocarboxylate transporter (SLC16A6) and nucleoside transporter (SLC29A1) and metabolites such as α-ketoglutarate, succinate, and malate were found to be linked with COVID-19 disease response. Metabolic reactions associated with amino acid, carbohydrate, and energy metabolism pathways and various transporter reactions were observed to be uniquely disrupted in PLWHART along with increased production of αketoglutarate (αKG) and ATP molecules. Changes in essential (leucine and threonine) and non-essential (arginine, alanine, and glutamine) amino acid transport were found to be caused by acute CCHFV infection. The altered flux of reactions involving TCA cycle compounds such as pyruvate, isocitrate, and alpha-ketoglutarate was also observed in CCHFV infection.

The research described in the thesis displayed dysregulations in similar metabolic processes against the three viral Infections. But further downstream analysis unveiled unique alterations in several metabolic reactions specific to each virus in the same metabolic pathways showing the importance of increasing the resolution of knowledge about host metabolism in infectious diseases.

List of scientific papers

I. Ambikan, A. T., Yang, H., Krishnan, S., Svensson Akusjärvi, S., Gupta, S., Lourda, M., Sperk, M., Arif, M., Zhang, C., Nordqvist, H., Ponnan, S. M., Sönnerborg, A., Treutiger, C. J., O'Mahony, L., Mardinoglu, A., Benfeitas, R., & Neogi, U. (2022). Multi-omics personalized network analyses highlight progressive disruption of central metabolism associated with COVID-19 severity. Cell systems. 13(8), 665–681.e4.
https://doi.org/10.1016/j.cels.2022.06.006

II. Ambikan, A. T.*, Svensson-Akusjärvi*, S., Krishnan, S., Sperk, M., Nowak, P., Vesterbacka, J., Sönnerborg, A., Benfeitas, R., & Neogi, U. (2022). Genomescale metabolic models for natural and long-term drug-induced viral control in HIV infection. Life science alliance. 5(9), e202201405. *Equal contributions.
https://doi.org/10.26508/lsa.202201405

III. Neogi, U., Elaldi, N., Appelberg, S., Ambikan, A., Kennedy, E., Dowall, S., Bagci, B. K., Gupta, S., Rodriguez, J. E., Svensson-Akusjärvi, S., Monteil, V., Vegvari, A., Benfeitas, R., Banerjea, A., Weber, F., Hewson, R., & Mirazimi, A. (2022). Multi-omics insights into host-viral response and pathogenesis in Crimean-Congo hemorrhagic fever viruses for novel therapeutic target. eLife. 11, e76071.
https://doi.org/10.7554/eLife.76071

IV. Anoop T. Ambikan, Nazif Elaldi, Sara Svensson Akusjärvi, Adil Mardinoglu, Vikas Sood, Ákos Végvári, Rui Benfeitas, Soham Gupta, Ali Mirazimi, Ujjwal Neogi. Transcriptome-based systems-level temporal immune-metabolic profile in Crimean-Congo hemorrhagic fever virus infection. [Manuscript]