Intracellular level of HIF-1α as an indicator of the delayed impact of COVID-19 on peripheral blood lymphocytes metabolism
- Authors: Zubatkina O.V.1, Dobrodeeva L.K.1, Kruglov S.D.1
-
Affiliations:
- Laverov Federal Center for Integrated Arctic Research
- Issue: Vol 30, No 4 (2023)
- Pages: 313-320
- Section: ORIGINAL STUDY ARTICLES
- URL: https://journals.rcsi.science/1728-0869/article/view/254625
- DOI: https://doi.org/10.17816/humeco409527
- ID: 254625
Cite item
Full Text
Abstract
BACKGROUND: COVID-19 infection triggers metabolic alterations that are crucial for both the replication of SARS-CoV-2 and the regulation of the immune response. HIF-1α, which is one of the effectors in the PI3K/Akt/mTOR signal transmission pathway, promotes the reprogramming of metabolism by enhancing aerobic glycolysis.
AIM: To assess whether the intracellular level of HIF-1α can reflect changes in the metabolism of peripheral blood lymphocytes after a COVID-19 infection.
MATERIAL AND METHODS: The sample consisted of 59 volunteers. Thirty eight of them had no history of COVID-19 while 21 reported having COVID-19 infection 2–8 months prior to the study. Serum concentrations of IgG antibodies to SARS-CoV-2 were assessed in both groups. Absolute content of lymphocytes was measured in whole blood, and the concentration of HIF-1α was determined in the lymphocyte lysate by enzyme immunoassay. All data were analyzed using IBM SPSS software (v. 26). Means and standard deviations were calculated for all numeric variables. Normality of the distributions were assessed using Kolmogorov–Smirnov test. Differences between the groups were studied by unpaired Student's t-tests. The differences at p <0.05 were considered statistically significant. Receiver operative characteristic curve was constructed to assess the prognostic value of HIF-1α.
RESULTS: Volunteers with a history of COVID-19 infection had significantly lower concentrations of HIF-1α in peripheral blood lymphocytes compared to their counterparts with no history of COVID-19. Intracellular concentration of HIF-1α was significantly associated with the likelihood of changes in lymphocyte metabolism. HIF-1α concentration of 1.25 ng/106 cells was the most optimal cut-off value.
CONCLUSION: The intracellular level of HIF-1α can serve as an indicator of the potential delayed impact of COVID-19 on the metabolic activity of peripheral lymphocytes. Our research findings hold significant value in monitoring and assessing metabolic alterations in individuals recovering from COVID-19.
Full Text
##article.viewOnOriginalSite##About the authors
Olga V. Zubatkina
Laverov Federal Center for Integrated Arctic Research
Author for correspondence.
Email: ozbiochem@gmail.com
ORCID iD: 0000-0002-5039-2220
SPIN-code: 1581-5178
Dr. Sci. (Biol.), professor, senior research associate
Russian Federation, 249 Lomonosova avenue, 163000 Arhangel'skLilia K. Dobrodeeva
Laverov Federal Center for Integrated Arctic Research
Email: dobrodeevalk@mail.ru
ORCID iD: 0000-0001-5080-6502
SPIN-code: 4518-6925
MD, Dr. Sci. (Med.), professor
Russian Federation, ArkhangelskSergey D. Kruglov
Laverov Federal Center for Integrated Arctic Research
Email: stees67@yandex.ru
ORCID iD: 0000-0002-4085-409X
SPIN-code: 2532-9912
Russian Federation, Arkhangelsk
References
- Sharma A, Ahmad Farouk I, Lal SK. COVID-19: a review on the novel coronavirus disease evolution, transmission, detection, control and prevention. Viruses. 2021;13(2):202. doi: 10.3390/v13020202
- Asselah T, Durantel D, Pasmant E, et al. COVID-19: discovery, diagnostics and drug development. J Hepatol. 2021;74(1):168–184. doi: 10.1016/j.jhep.2020.09.031
- Almas T, Malik J, Alsubai AK, et al. Post-acute COVID-19 syndrome and its prolonged effects: an updated systematic review. Ann Med Surg (Lond). 2022;80:103995. doi: 10.1016/j.amsu.2022.103995
- Mayer KA, Stöckl J, Zlabinger GJ, et al. Hijacking the supplies: metabolism as a novel facet of virus-host interaction. Front Immunol. 2019;10:1533. doi: 10.3389/fimmu.2019.01533
- Appelberg S, Gupta S, Svensson Akusjärvi S, et al. Dysregulation in Akt/mTOR/HIF-1 signaling identified by proteo-transcriptomics of SARS-CoV-2 infected cells. Emerg Microbes Infect. 2020;9(1):1748–1760. doi: 10.1080/22221751.2020.1799723
- Тao JH, Barbi J, Pan F. Hypoxia-inducible factors in T lymphocyte differentiation and function. A review in the theme: cellular responses to hypoxia. Am J Physiol Cell Physiol. 2015;309(9):C580–C589. doi: 10.1152/ajpcell.00204.2015
- Dang EV, Barbi J, Yang HY, et al. Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell. 2011;146(5):772–784. doi: 10.1016/j.cell.2011.07.033
- Loftus RM, Finlay DK. Immunometabolism: cellular metabolism turns immune regulator. J Biol Chem. 2016;291(1):1–10. doi: 10.1074/jbc.R115.693903
- Saravia J, Raynor JL, Chapman NM, et al. Signaling networks in immunometabolism. Cell Res. 2020;30(4):328–342. doi: 10.1038/s41422-020-0301-1
- Fattahi S, Khalifehzadeh-Esfahani Z, Mohammad-Rezaei M, et al. PI3K/Akt/mTOR pathway: a potential target for anti-SARS-CoV-2 therapy. Immunol Res. 2022;70(3):269–275. doi: 10.1007/s12026-022-09268-x
- Korneenkov AA, Ryazantsev SV, Vyazemskaya EE. Calculation and interpretation of indicators of informativeness of diagnostic medical technologies. Medical Council. 2019;20:41–47. (In Russ). doi: 10.21518/2079-701X-2019-20-45-51
- Shen XR, Geng R, Li Q, et al. ACE2-independent infection of T lymphocytes by SARS-CoV-2. Signal Transduct Target Ther. 2022;7(1):83. doi: 10.1038/s41392-022-00919-x
- Helal MA, Shouman S, Abdelwaly A, et al. Molecular basis of the potential interaction of SARS-CoV-2 spike protein to CD147 in COVID-19 associated-lymphopenia. J Biomol Struct Dyn. 2022;40(3):1109–1119. doi: 10.1080/07391102.2020.1822208
- Wang S, Qiu Z, Hou Y, et al. AXL is a candidate receptor for SARS-CoV-2 that promotes infection of pulmonary and bronchial epithelial cells. Cell Res. 2021;31(2):126–140. doi: 10.1038/s41422-020-00460-y
- So L, Lee J, Palafox M, et al. The 4E-BP-eIF4E axis promotes rapamycin-sensitive growth and proliferation in lymphocytes. Sci Signal. 2016;9(430):ra57. doi: 10.1126/scisignal.aad8463
- Lionetto L, Ulivieri M, Capi M, et al. Increased kynurenine-to-tryptophan ratio in the serum of patients infected with SARS-CoV2: an observational cohort study. Biochim Biophys Acta Mol Basis Dis. 2021;1867(3):166042. doi: 10.1016/j.bbadis.2020.166042
- Rees CA, Rostad CA, Mantus G, et al. Altered amino acid profile in patients with SARS-CoV-2 infection. Proc Natl Acad Sci U S A. 2021;118(25):e2101708118. doi: 10.1073/pnas.2101708118
- Tanner JE, Alfieri C. The fatty acid lipid metabolism nexus in COVID-19. Viruses. 2021;13(1):90. doi: 10.3390/v13010090
- Chapman NM, Boothby MR, Chi H. Metabolic coordination of T cell quiescence and activation. Nat Rev Immunol. 2020;20(1):55–70. doi: 10.1038/s41577-019-0203-y
- Jia H, Liu C, Li D, et al. Metabolomic analyses reveals new stage-specific features of the COVID-19. Eur Respir J. 2021;59(2):2100284. doi: 10.1183/13993003.00284-2021
- Bojkova D, Klann K, Koch B, et al. Proteomics of SARS-CoV-2-infected host cells reveals therapy targets. Nature. 2020;583(7816):469–472. doi: 10.1038/s41586-020-2332-7
- Bharadwaj S, Singh M, Kirtipal N, et al. SARS-CoV-2 and glutamine: SARS-CoV-2 triggered pathogenesis metabolic reprograming of glutamine in host cells. Front Mol Biosci. 2020;7:627842. doi: 10.3389/fmolb.2020.627842
- Wang R, Dillon CP, Shi LZ, et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity. 2011;35(6):871–882. doi: 10.1016/j.immuni.2011.09.021
- Kierans SJ, Taylor CT. Regulation of glycolysis by the hypoxia-inducible factor (HIF): implications for cellular physiology. J Physiol. 2021;599(1):23–37. doi: 10.1113/JP280572
- Coutaz M, Hurrell BP, Auderset F, et al. Notch regulates Th17 differentiation and controls trafficking of IL-17 and metabolic regulators within Th17 cells in a context-dependent manner. Sci Rep. 2016;6:39117. doi: 10.1038/srep39117
- Zhao C, Chen J, Cheng L, et al. Deficiency of HIF-1alpha enhances influenza A virus replication by promoting autophagy in alveolar type II epithelial cells. Emerg Microbes Infect. 2020;9(1):691–706. doi: 10.1080/22221751.2020.1742585
- Shen T, Wang T. Metabolic reprogramming in COVID-19. Int J Mol Sci. 2021;22(21):11475. doi: 10.3390/ijms222111475
- Koyasu S, Kobayashi M, Goto Y, et al. Regulatory mechanisms of hypoxia-inducible factor 1 activity: two decades of knowledge. Cancer Science. 2018;109(3):560–571. doi: 10.1111/cas.13483
- Man K, Kallies A. Synchronizing transcriptional control of T cell metabolism and function. Nat Rev Immunol. 2015;15(9):574–584. doi: 10.1038/nri3874
- Gnanaprakasam JNR., Sherman JW, Wang R. MYC and HIF in shaping immune response and immune metabolism. Cytokine Growth Factor Rev. 2017;35:63–67. doi: 10.1016/j.cytogfr.2017.03.004