Original Article

Correlation of Expression of MMP-2, ACE2, and TMPRSS2 Genes with Lymphopenia for Mild and Severity of COVID-19


Some risk causes may be associated with the severity of COVID-19. The central host-pathogen factors might affect infection are human receptor angiotensin-converting enzyme 2 (ACE2), trans-membrane protease serine 2 (TMPRSS2), and SARS-CoV-2 surface spike (S)-protein. The main purpose of this study was to determine the differences in the expression the metalloproteinases-2  (MMP-2), MMP-9, ACE2, and TMPRSS2 genes and their correlation with lymphopenia in the mild and severe types of the COVID-19 patients.
Eighty-eight patients, aged 36 to 60 years old with the mild (n=44) and severe (n=44) types of COVID-19 were enrolled. Total RNA was isolated from the peripheral blood mononuclear cells (PBMCs). The changes of MMP-2, MMP-9, ACE2 and TMPRSS2 gene expression in PBMCs from mild and severe COVID-19 patients were examined by the real time-quantitative polymerase chain reaction (RT-qPCR) assay and, compared between the groups. Data were collected from May 2021 to March 2022.
The mean age of the patients in both groups was 48 (interquartile range, 36–60), and there were no appreciable differences in age or gender distribution between the two groups. The present study showed that a significant increase in the expression of ACE2, TMPRSS2, MMP-2, and MMP-9 genes in the severe type of the COVID-19 patients compared, to the mild type of the COVID-19 patients.
Overall, it suggests the expression levels of these genes on the PBMC surface in the immune system are susceptible to infection by SARS-COV-2 and therefore could potentially predict the patients’ outcome.

1. Abdelli I, Hassani F, Bekkel Brikci S, Ghalem S. In silico study the inhibition of angiotensin converting enzyme 2 receptor of COVID-19 by Ammoides verticillata components harvested from Western Algeria. J Biomol Struct Dyn. 2021;39(9):3263-76.
2. Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579(7798):270-3.
3. Wang Y, Liu M, Gao J. Enhanced receptor binding of SARS-CoV-2 through networks of hydrogen-bonding and hydrophobic interactions. Proc Natl Acad Sci U S A. 2020;117(25):13967-74.
4. Chakrabarti S, Patel KD. Matrix metalloproteinase-2 (MMP-2) and MMP-9 in pulmonary pathology. Exp Lung Res. 2005;31(6):599-621.
5. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet (London, England). 2020;395(10223):507-13.
6. Gupta R, Ghosh A, Singh AK, Misra A. Clinical considerations for patients with diabetes in times of COVID-19 epidemic. Diabetes Metab Syndr. 2020;14(3):211-2.
7. Wang Q, Zhang Y, Wu L, Niu S, Song C, Zhang Z, et al. Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2. Cell. 2020;181(4):894-904.e9.
8. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020;181(2):271-80.e8.
9. Hulswit RJ, de Haan CA, Bosch BJ. Coronavirus Spike Protein and Tropism Changes. Adv Vir Res. 2016;96:29-57.
10. Djomkam ALZ, Olwal CO, Sala TB, Paemka L. Commentary: SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Fronti Oncology. 2020;10:1448.
11. Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science (New York, NY). 2020;367(6485):1444-8.
12. Lan J, Ge J, Yu J, Shan S, Zhou H, Fan S, et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature. 2020;581(7807):215-20.
13. Devaux CA, Rolain JM, Raoult D. ACE2 receptor polymorphism: Susceptibility to SARS-CoV-2, hypertension, multi-organ failure, and COVID-19 disease outcome. Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi. 2020;53(3):425-35.
14. Gheblawi M, Wang K, Viveiros A, Nguyen Q, Zhong JC, Turner AJ, et al. Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2. Circulation Res. 2020;126(10):1456-74.
15. Li MY, Li L, Zhang Y, Wang XS. Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues. Infect Dis Poverty. 2020;9(1):45.
16. Gemmati D, Bramanti B, Serino ML, Secchiero P, Zauli G, Tisato V. COVID-19 and Individual Genetic Susceptibility/Receptivity: Role of ACE1/ACE2 Genes, Immunity, Inflammation and Coagulation. Might the Double X-chromosome in Females Be Protective against SARS-CoV-2 Compared to the Single X-Chromosome in Males? Int J Mol Sci. 2020;21(10).
17. Asselta R, Paraboschi EM, Mantovani A, Duga S. ACE2 and TMPRSS2 variants and expression as candidates to sex and country differences in COVID-19 severity in Italy. Aging. 2020;12(11):10087-98.
18. Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020;130(5):2620-9.
19. Torre-Fuentes L, Matías-Guiu J, Hernández-Lorenzo L, Montero-Escribano P, Pytel V, Porta-Etessam J, et al. ACE2, TMPRSS2, and Furin variants and SARS-CoV-2 infection in Madrid, Spain. J Med Virol. 2021;93(2):863-9.
20. Davey A, McAuley DF, O'Kane CM. Matrix metalloproteinases in acute lung injury: mediators of injury and drivers of repair. Eur Respir J. 2011;38(4):959-70.
21. Fligiel SE, Standiford T, Fligiel HM, Tashkin D, Strieter RM, Warner RL, et al. Matrix metalloproteinases and matrix metalloproteinase inhibitors in acute lung injury. Human pathology. 2006;37(4):422-30.
22. Beltrán-García J, Osca-Verdegal R, Pallardó FV, Ferreres J, Rodríguez M, Mulet S, et al. Sepsis and Coronavirus Disease 2019: Common Features and Anti-Inflammatory Therapeutic Approaches. Crit Care Med. 2020;48(12):1841-4.
23. Duda I, Krzych Ł, Jędrzejowska-Szypułka H, Lewin-Kowalik J. Plasma Matrix Metalloproteinase-9 and Tissue Inhibitor of Matrix Metalloproteinase-1 as Prognostic Biomarkers in Critically Ill Patients. Open Med (Wars). 2020;15:50-6.
24. Aguirre A, Blázquez-Prieto J, Amado-Rodriguez L, López-Alonso I, Batalla-Solís E, González-López A, et al. Matrix metalloproteinase-14 triggers an anti-inflammatory proteolytic cascade in endotoxemia. J Mol Med. 2017;95(5):487-97.
25. C DA-M, Couto AES, Campos LCB, Vasconcelos TF, Michelon-Barbosa J, Corsi CAC, et al. MMP-2 and MMP-9 levels in plasma are altered and associated with mortality in COVID-19 patients. Biomed Pharmacother. 2021;142:112067.
26. Osman IO, Melenotte C, Brouqui P, Million M, Lagier JC, Parola P, et al. Expression of ACE2, Soluble ACE2, Angiotensin I, Angiotensin II and Angiotensin-(1-7) Is Modulated in COVID-19 Patients. Front Immunol. 2021;12:625732.
27. Miesbach W. Pathological Role of Angiotensin II in Severe COVID-19. TH open. 2020;4(2):e138-e44.
28. Oz M, Lorke DE. Multifunctional angiotensin converting enzyme 2, the SARS-CoV-2 entry receptor, and critical appraisal of its role in acute lung injury. Biomed Pharmacother. 2021;136:111193.
29. Roche N, Crichton ML, Goeminne PC, et al. Update June 2022: management of hospitalised adults with coronavirus disease 2019 (COVID-19): a European Respiratory Society living guideline. Eur Respir J 2022; 60: 2200803
30. Gandhi RT, Lynch JB, Del Rio C. Mild or Moderate Covid-19. N Engl J Med. 2020;383(18):1757-66.
31. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020;382(8):727-33.
32. Chan JF, Yuan S, Kok KH, To KK, Chu H, Yang J, et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet (London, England). 2020;395(10223):514-23.
33. Heurich A, Hofmann-Winkler H, Gierer S, Liepold T, Jahn O, Pöhlmann S. TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein. J Virology. 2014;88(2):1293-307.
34. Chen W, Yuan P, Yang M, Yan Z, Kong S, Yan J, et al. SARS-CoV-2 Entry Factors: ACE2 and TMPRSS2 Are Expressed in Peri-Implantation Embryos and the Maternal-Fetal Interface. Engineering (Beijing, China). 2020;6(10):1162-9.
35. Devaprasad A, Pandit A. Enrichment of SARS-CoV-2 Entry Factors and Interacting Intracellular Genes in Tissue and Circulating Immune Cells. Viruses. 2021;13(9).
36. Kabbani N, Olds JL. Does COVID19 Infect the Brain? If So, Smokers Might Be at a Higher Risk. Mol Pharmacol. 2020;97(5):351-3.
37. Baig AM, Khaleeq A, Ali U, Syeda H. Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanisms. ACS Chem Neurosci. 2020;11(7):995-8.
38. Sadanandam A, Bopp T, Dixit S, Knapp D, Emperumal CP, Vergidis P, et al. A blood transcriptome-based analysis of disease progression, immune regulation, and symptoms in coronavirus-infected patients. Cell Death Discov. 2020;6(1):141.
39. Zhang W, Zhao Y, Zhang F, Wang Q, Li T, Liu Z, et al. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The Perspectives of clinical immunologists from China. Clin Immunol. 2020;214:108393.
40. Wang C, Qian X, Sun X, Chang Q. Angiotensin II increases matrix metalloproteinase 2 expression in human aortic smooth muscle cells via AT1R and ERK1/2. Exp Biol Med (Maywood). 2015;240(12):1564-71.
41. Nasr El-Din A, Ata KAE, Abdel-Gawad AR, Fahmy NF. Impact of High Serum Levels of MMP-7, MMP-9, TGF-β and PDGF Macrophage Activation Markers on Severity of COVID-19 in Obese-Diabetic Patients. Infect Drug Resist. 2021;14:4015-25.
IssueVol 22 No 1 (2023) QRcode
SectionOriginal Article(s)
DOI https://doi.org/10.18502/ijaai.v22i1.12011
ACE2 COVID Gene Lymphopenia Matrix metalloproteinase

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
Ghezelbash B, Rostami M, Heidarvand M, Mafi A, Chegni H, Eskandari N. Correlation of Expression of MMP-2, ACE2, and TMPRSS2 Genes with Lymphopenia for Mild and Severity of COVID-19. Iran J Allergy Asthma Immunol. 2023;22(1):91-98.