Significance of Catecholamine Biosynthetic/Metabolic Pathway in SARS-CoV-2 Infection and COVID-19 Severity
Abstract
:1. Introduction
2. Materials and Methods
2.1. Human Samples
2.2. Cell and Virus Culture
2.3. Infection Studies
2.4. Total RNA Extraction from Human Samples
2.5. RNA Quantification by Reverse Transcription-Quantitative PCR (RT-qPCR)
2.6. Elisa Assays
2.7. Cytopathic Effect Quantitation (CPE)
2.8. SARS-CoV-2–Human Protein–Protein Interactions (PPIs)
2.9. Chemicals
2.10. Measurement of Cellular ATP Content
2.11. Statistical Analysis
3. Results
3.1. L-Dopa Decarboxylase as a COVID-19 Severity Marker in Nasopharyngeal Swab Samples
3.2. Correlation of the mRNA Levels of DDC with dACE2 in the Nasopharyngeal Swabs of Severe CoV-2 Group
3.3. Reduced DDC and dACE2 Expression in Whole Blood Samples of Hospitalized COVID-19 Patients
3.4. Decreased Dopamine Levels in the Serum of Hospitalized COVID-19 Patients
3.5. Alteration of Catecholamine Pathway-Related Genes Expression in Whole Blood Samples of SARS-CoV-2-Infected Hospitalized Individuals
3.6. Correlation between the Expression of DDC with dACE2 and MAOs in Whole Blood Samples of Hospitalized COVID-19 Patients
3.7. The effect of SARS-CoV-2 Infection on Catecholamine Pathway-Related Gene Expression in Cultured Epithelial Cells
3.8. Effect of SARS-CoV-2 Infection on the Expression of Hypoxia-Response Genes That Are Correlated with the Catecholamine Pathway, in the Blood of Hospitalized COVID-19 Patients and in Cultured Epithelial Cells
3.9. Meta-Analysis of the Direct Protein-Protein Interactions of the Catecholamine Biosynthesis/Metabolism and Hypoxia Pathways with Specific SARS-CoV-2 Proteins
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Gene. | Orientation | Sequence (5′-3′) | Reference |
---|---|---|---|
DDC | Forward | AGAGGGAAGGAGATGGTGGATTA | [33] |
Reverse | GGGGCTGTGCCAGTGCGT | ||
DDC | Forward | ACGCACTGGCACAGCCCC | |
Reverse | CACTCCTCCCCCTTCTCC | ||
EPO | Forward | GCCCCACCACGCCTCATCTGT | [59] |
Reverse | CTTCCAGGCATAGAAATTAAC | ||
ISG56 | Forward | GGACAGGAAGCTGAAGGAG | [61] |
Reverse | AGTGGGTGTTTCCTGCAA | ||
ACE2 | Forward | CGAAGCCGAAGACCTGTTCTA | [60] |
Reverse | GGGCAAGTGTGGACTGTTCC | ||
dACE2 | Forward | GTGAGAGCCTTAGGTTGGATTC | [18] |
Reverse | TAAGGATCCTCCCTCCTTTGT | ||
MAOA | Forward | GGGCTGCTACACGGCCTACT | |
Reverse | GACCTCCCTAGCTGCTCGTTCT | ||
MAOB | Forward | GGAGCCAGTGCATTATGAAGA | |
Reverse | GCCTGCAAAGTAAATCCTGTC | ||
VMAT2 | Forward | CGGATGTGGCATTTTGTATGG | |
Reverse | TTCTTCTTTGGCAGGTGGACTTC | ||
DBH | Forward | GCCATCCATTTCCAGCTCCT | |
Reverse | TCCAGGCGTCCGCAAAATAG | ||
HIF-1α | Forward | CATAAAGTCTCAACATGGAAGGT | |
Reverse | ATTTGATGGGTGAGGAATGGGTT | ||
GLUT1 | Forward | CAGTTTGGCTACAACACTGGAGT | |
Reverse | ATAGCGGTGGACCCATGTCT | ||
LDHA | Forward | TTCACCCATTAAGCTGTCATGG | |
Reverse | GACACCAGCAACATTCATTCCA | ||
EPCAM | Forward | CGCAGCTCAGGAAGAATGTG | |
Reverse | TGAAGTACACTGGCATTGACG | ||
CD45 | Forward | AAAAGTGCTCCTCCAAGCCA | |
Reverse | TGGGAGGCCTACACTTGACA | ||
CD74 | Forward | CCGGCTGGACAAACTGACA | |
Reverse | GGTGCATCACATGGTCCTCTG | ||
LYN | Forward | TTCTGGTCTCCGAGTCACTCA | |
Reverse | GCCGTCCACTTAATAGGGAACT | ||
YWHAZ | Forward | GCTGGTGATGACAAGAAAGG | |
Reverse | GGATGTGTTGGTTGCATTTCCT |
SARS-CoV-2 | ||||
---|---|---|---|---|
Characteristics | Negative | Mild CoV-2 | Severe CoV-2 | p Value |
Total Number | 38 | 37 | 21 | |
Median age in years (IQR) | 47 (34–68) | 38 (31–52) | 64 (61–75) | 0.001 a |
Sex | ||||
Male | 14 (36.8%) | 14 (37.8%) | 17 (81%) | 0.0065 b |
Female | 23 (60.6%) | 14 (37.8%) | 4 (19%) | |
NR | 1 (2.6%) | 9 (24.4%) | 0 |
SARS-CoV-2 | ||||
---|---|---|---|---|
Characteristics | Healthy | Ward/CoV-2 | ICU/CoV-2 | p Value |
Total number | n = 35 | n = 35 | n = 32 | |
Median age in years (IQR) | 49 (42–55) | 59 (38–70) | 62 (56–70) | p < 0.0001 a |
Sex | ||||
Male | 20 (57.2%) | 25 (71.4%) | 25 (78.1%) | 0.2231 b |
Female | 15 (42.8%) | 10 (28.6%) | 7 (21.9%) | |
Comorbidities | ||||
Hypertension (%) | - | 5.71 (25.71 *) | 9.38 (43.75 *) | |
Diabetes (%) | - | 2.86 (5.71 *) | 0 (9.38 *) | |
Other Comorbidities (%) | - | 20 | 9.38 | |
>1 comorbidity (%) | - | 31.43 | 43.75 | |
None (%) | 100 | 40 | 37.5 | |
Clinical Measurements Median (IQR) | ||||
Creatinine (mg/dL) | 0.700–1.300 | 0.900 (0.700–1.300) | 1.000 (0.800–1.200) | |
CRP (mg/L) | 8–10 | 5.300 (1.475–31.250) | 14.400 (6.750–26.250) | |
Urea (mg/dL) | 6–24 | 25.500 (21.250–33.750) | 31 (24–47.500) | |
White blood cell count (per µL) | 4500–11,000 | 5185 (4265–6565) | 10,300 (5250–11,170) * | 0.008 c |
Neutrophils (%) | 70 | 67.500 (53.130–81.880) | 83 (78–88) * | <0.0001 c |
Lymphocytes (%) | 20–40 | 28.400 (16.500–37.450) | 12.600 (8–18.500) * | 0.0002 c |
Platelets (per µL) | 150,000–450,000 | 184,500 (147,250–246,000) | 206,000 (139,500–255,500) | |
D-dimer (pg/mL) | <0.5 | 0.915 (0.505–8.750) | 0.540 (0.210–1.590) | |
AST (IU/L) | 8–33 | 29.500 (20.500–50.500) | 46 (36.500–61) | 0.0029 c |
ALT (IU/L) | 4–36 | 27 (18.250–41.500) | 38 (26.500–49.500) | 0.0179 c |
LDH (U/L) | 105–333 | 266.500 (199–322.500) | 489 (355.500–682.300) | <0.0001 c |
Fibrinogen (mg/dL) | 200–400 | 480 (383.200–548) | 627 (550.500–709) | <0.0001 c |
SARS-CoV-2 | ||||||
---|---|---|---|---|---|---|
Characteristics | Healthy | Ward/CoV-2 | ICU/CoV-2 | ICU/non-CoV-2 | ICU/CoV-2 + Dexa | p Value |
Total number, N | 33 | 28 | 33 | 27 | 29 | |
Dopamine levels | ||||||
Median (IQR) (pg/mL) | 197.8 (138.2–316.2) | 62.22 (43.44–182.4) | 76.43 (63.76–107.4) | 146.3 (107.9–202.4) | 93.06 (71.3–127.6) | <0.0001 a |
Median age in years (IQR) | 57 (52–60) | 55 (42–75) | 62 (54–71) | 67 (50–75) | 61 (55–72) | 0.041 b |
Sex | ||||||
Male | 22 | 21 | 27 | 17 | 21 | 0.514 c |
Female | 11 | 7 | 6 | 10 | 8 | |
Comorbidities | ||||||
Hypertension (%) | 0 (17.86 *) | 12.12 (45.45 *) | 7.40 (14.81 *) | 3.45 (37.93 *) | ||
Diabetes (%) | - | 7.14 (10.71 *) | 3.03 (18.18 *) | - | 0 (10.34 *) | |
Lipids (%) | - | 0 (7.14 *) | 6.06 (15.15 *) | 0 (14.81 *) | 3.45 (13.79 *) | |
Other comorbidities (%) | - | 10.71 | 6.06 | 7.41 | 10.34 | |
>1 comorbidity (%) | - | 39.29 | 45.45 | 25.93 | 65.52 | |
None (%) | 100% | 42.86 | 27.28 | 59.26 | 17.24 |
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Mpekoulis, G.; Kalliampakou, K.I.; Milona, R.S.; Lagou, D.; Ioannidis, A.; Jahaj, E.; Chasapis, C.T.; Kefallinos, D.; Karakasiliotis, I.; Kotanidou, A.; et al. Significance of Catecholamine Biosynthetic/Metabolic Pathway in SARS-CoV-2 Infection and COVID-19 Severity. Cells 2023, 12, 12. https://doi.org/10.3390/cells12010012
Mpekoulis G, Kalliampakou KI, Milona RS, Lagou D, Ioannidis A, Jahaj E, Chasapis CT, Kefallinos D, Karakasiliotis I, Kotanidou A, et al. Significance of Catecholamine Biosynthetic/Metabolic Pathway in SARS-CoV-2 Infection and COVID-19 Severity. Cells. 2023; 12(1):12. https://doi.org/10.3390/cells12010012
Chicago/Turabian StyleMpekoulis, George, Katerina I. Kalliampakou, Raphaela S. Milona, Despoina Lagou, Anastasios Ioannidis, Edison Jahaj, Christos T. Chasapis, Dionysis Kefallinos, Ioannis Karakasiliotis, Anastasia Kotanidou, and et al. 2023. "Significance of Catecholamine Biosynthetic/Metabolic Pathway in SARS-CoV-2 Infection and COVID-19 Severity" Cells 12, no. 1: 12. https://doi.org/10.3390/cells12010012