A New Model of SARS-CoV-2 Infection Based on (Hydroxy)Chloroquine Activity
Chloroquine and hydroxychloroquine (H)CQ are well known anti-malarial drugs, while their use against COVID-19 is more controversial. (H)CQ activity was examined in tissue culture cells to determine if their anti-viral benefits or adverse effects might be due to altering host cell pathways. Metabolic analysis revealed (H)CQ inhibit oxidative phosphorylation in mitochondria, likely by sequestering protons needed to drive ATP synthase. This activity could cause cardiotoxicity because heart muscle relies on beta oxidation of fatty acids. However, it might also explain their therapeutic benefit against COVID-19. A new model of SARS-CoV-2 infection postulates virus enters host cell mitochondria and uses its protons for genome release. Oxidative phosphorylation is eventually compromised, so glycolysis is upregulated to maintain ATP levels. (H)CQ could prevent viral infection and/or slow its replication by sequestering these protons. In support of this model other potential COVID-19 therapeutics also targeted mitochondria, as did tobacco smoke, which may underlie smokers' protection. The mitochondria of young people are naturally more adaptable and resilient, providing a rationale for their resistance to disease progression. Conversely, obesity and diabetes could exacerbate disease severity by providing extra glucose to infected cells dependent on glycolysis. The description of (H)CQ function presented here, together with its implications for understanding SARS-CO-V2 infection, makes testable predictions about disease progression and identifies new approaches for treating COVID-19. .
Smoke exposure Four p60mm plates of attached A549 lung carcinoma cells were aspirated, washed with PBS, and aspirated again. Control plates were untreated and exposed to breath exhalation in the absence of smoke. Cigar smoke was blown into two experimental plates followed by rapid lid closure to trap the smoke. After 3min. at room temperature the lid was removed from one plate and smoke allowed to dissipate (labeled 1 smoke in Figure 4G ). The other plate was exposed to another aliquot of cigar smoke followed by rapid lid closure (labeled 2 smoke). After 6 min. total incubation time cells were removed with trypsin, pelleted, and re-suspended in 500L of the indicated media. 100l aliquots were distributed in a white 96 well assay plate and incubated at 37 o C in the CO2 incubator for 1hr. ATP levels were then analyzed using CellTiterGlo as described previously.
Competing interests The author declares no competing interests.
Materials & Correspondence
Robert J. Sheaff Associate Professor The University of Tulsa Department of Chemistry and Biochemistry Keplinger M2215 800 South Tucker Drive Tulsa, OK 74104 Office 918-631-2319 E-mail: email@example.com Sheaff, 2020 Supl. Fig. 4 Supl. Fig. 5 : Red blood cells were pre-incubated with 1mM CQ for 1hr (orange line). After washing an aliquot was withdrawn to determine ATP levels using CTG (inset graph). Remaining cells were lysed by re-suspending in H2O and vortexing, followed by UV/Vis analysis of the..
Dowd, Andriano, Brazel, Rotondi, Block et al., Demographic science aids in understanding the spread and fatality rates of COVID-19, Proceedings of the National Academy of Sciences, doi:10.1073/pnas.2004911117
Fitch, Involvement of heme in the antimalarial action of chloroquine, Trans Am Clin Climatol Assoc
Guzik, COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options, Cardiovasc Res, doi:10.1093/cvr/cvaa106
Janowitz, Gablenz, Pattinson, Wang, Conigliaro et al., Famotidine use and quantitative symptom tracking for COVID-19 in non-hospitalised patients: a case series, Gut, doi:10.1136/gutjnl-2020-321852
Kase, Nikolić, Bakke, Bogen, Aas et al., Remodeling of Oxidative Energy Metabolism by Galactose Improves Glucose Handling and Metabolic Switching in Human Skeletal Muscle Cells, PLoS One, doi:10.1371/journal.pone.0059972
Kolwicz, Purohit, Tian, Cardiac Metabolism and its Interactions with Contraction, Growth, and Survival of Cardiomyocytes, Circulation Research, doi:10.1161/CIRCRESAHA.113.302095
Magagnoli, Narendran, Pereira, Cummings, Hardin et al., Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19, MedRxiv, doi:.10.1101/2020.04.16.20065920
Malik, Properties of Coronavirus and SARS-CoV-2, Malays J Pathol
Osellame, Blacker, Duchen, Cellular and molecular mechanisms of mitochondrial function, Best Pract Res Clin Endocrinol Metab, doi:10.1016/j.beem.2012.05.003
Pajak, Siwiak, Sołtyka, Priebe, Zieliński et al., 2-Deoxy-d-Glucose and Its Analogs: From Diagnostic to Therapeutic Agents, Int J Mol Sci, doi:10.3390/ijms21010234
Park, Epidemiology, Virology, and Clinical Features of Severe Acute Respiratory Syndromecoronavirus-2 (SARS-CoV-2
Schrezenmeier, Dörner, Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology, Nat Rev Rheumatol, doi:10.1038/s41584-020-0372-x
Vardavas, Nikitara, COVID-19 and smoking: A systematic review of the evidence, Tob Induc Dis, doi:10.18332/tid/119324
Walls, Park, Tortorici, Wall, Mcguire et al., Structure, Function, and Antigenicity of the SARS-CoV-2 Glycoprotein, Cell, doi:10.1016/j.cell.2020.02.058