Serum GRP-78 Düzeyleri Tedaviden 3 Ay Sonrasında Halen Yüksek Seyretmektedir: Bir Kohort Çalışması

Yıl 2021, Cilt: 47 Sayı: 1, 17 - 22, 01.04.2021

Ramazan Sabırlı Aylin Köseler Tarık Gören Aykut Kemancı Neslihan Türkçüer İbrahim Türkçüer Özgür Kurt

https://doi.org/10.32708/uutfd.858821

Öz

GRP-78 proteininin bat koronavirüs, Mers-Cov, ebola virüs, deng virüsü, japon ensefalit virüsü, influenza virüs ve zika virüs gibi birçok virüsün hücreye girişinde rol oynadığı bilinmektedir. Bu çalışmada COVID-19 enfeksiyonu geçirmiş ve tedavi almış ve tamamen iyileşmiş olan hastalarda tedavi başlangıcından üç ay sonrasındaki Glucose Regulated Protein-78 (GRP-78) düzeylerini incelemeyi amaçladık. Daha öncesinde Sabırlı ve ark. tarafından yapılan çalışma grubunda yer alan, COVID-19 hastalığı tanısı almış ve hastalığı geçirip tamamen iyileşmiş olan 20 hasta prospektif kohorta dahil edildi. Hastaların acil servise ilk tanıda başvurusu ve 3 ay sonra kontrole çağrıldığında alınan kanlardan enzyme-linked immunosorbent assay (ELISA) metodu ile GRP-78 düzeyi çalışıldı. Acil servise ilk başvuruda alınan kanda serum GRP-78 düzeyi 1393,31 ± 306,33 pg/ml; tedavi başlangıcından 90 gün sonra bakılan serum GRP-78 düzeyi ise 1451,73 ± 336,65 pg/ml olarak saptandı. İlk başvuru ve 3 ay sonraki kontrolde ölçülen GRP-78 düzeyleri açısından istatistiksel olarak anlamlı farklılık saptanmadı (p=0,451). Sonuç olarak bu çalışmada COVID-19 infeksiyonunda tedavi başlangıcından 3 ay sonrasında dahi yüksek seyrettiğini ortaya koyduk. GRP-78 düzeyinin yüksek kalmasının kişinin Sars-CoV-2 virüsüne karşı immunitesi konusunda fikir verdirici olabilir fakat bu hususun gerek hücre kültürü çalışması ve gerekse daha uzun süreli kohort çalışması yapılarak incelenmesine ihtiyaç vardır.

Anahtar Kelimeler

Endoplazmik Retikulum Stresi, GRP-78, Covid19 enfeksiyonu, pnömoni.

Serum GRP-78 Levels Still Remain High 3 Months Later After the Treatment: A Cohort Study

Öz

Glucose Regulated Protein (GRP-78) plays a role in the intrusion of many viruses such as bat coronavirus, MERS-CoV, ebola virus, dengue virus, Japanese encephalitis virus, influenza virus, and Zika virus. This study, however, aims to examine the GRP-78 levels in patients who were infected with COVID-19, treated and recovered completely three months after the initiation of treatment. A total of 20 patients who were diagnosed with the COVID-19 disease and fully recovered, and who had participated in a previous study conducted by Sabırlı et al., were included in this prospective cohort study. Using the enzyme-linked immunosorbent assay (ELISA) method, the GRP-78 levels were examined in the blood samples. The mean serum GRP-78 level was found to be 1393.31 ± 306.33 pg / ml in the blood samples drawn from the patients when they were first admitted to the emergency department while the mean serum GRP-78 level measured 90 days after the initiation of treatment was 1451.73 ± 336.65 pg / ml. No statistically significant differences were found between the GRP-78 levels measured during the first admission and the follow-up control 3 months later (p = 0.451). In conclusion, this study revealed that the GRP-78 levels remained high in patients with COVID-19 infections even after 3 months following the initiation of treatment. This high GRP-78 level may provide insight into the immunity of the person against the Sars-CoV-2 virus; however, this issue should be further examined both in a cell culture study and in a longer-term cohort study.

Anahtar Kelimeler

Endoplasmic Reticulum Stress, GRP-78, Covid19 infection, pneumonia

Kaynakça

• 1- CDC. 2019 Novel Coronavirus, Wuhan, China. CDC. Available at https://www.cdc.gov/coronavirus/2019-ncov/about/index.html. January 26, 2020; Accessed: January 27, 2020. Gallegos A. WHO Declares Public Health Emergency for Novel Coronavirus. Medscape Medical News. Available at https://www.medscape.com/viewarticle/924596. January 30, 2020; Son Erişim Tarihi:1 Aralık, 2020.)
• 2- Cascella M, Rajnik M, Cuomo A, et al. Features, Evaluation, and Treatment of Coronavirus (COVID-19) [Updated 2020 Aug 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554776/
• 3- Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The species Severe acute respiratory syndrome-related coronavirus: Classifying 2019-nCoV and naming it SARS-CoV-2. Nat. Microbiol. 2020;5: 536–44.
• 4- Huang Y, Yang C, Xu XF, Xu W, Liu SW. Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19. Acta Pharmacol Sin. 2020;41:1141-9.
• 5- Kuo L, Godeke GJ, Raamsman MJ, Masters PS, Rottier PJ. Retargeting of coronavirus by substitution of the spike glycoprotein ectodomain: crossing the host cell species barrier. J Virol 2000;74: 1393-1406.
• 6- Yamada Y, Liu XB, Fang SG, Tay FP, Liu DX. Acquisition of cell-cell fusion activity by amino acid substitutions in spike protein determines the infectivity of a coronavirus in cultured cells. PLoS One 2009;4:e6130.
• 7- Zhang Y, Liu R, Ni M, Gill P, Lee AS. Cell surface relocalization of the endoplasmic reticulum chaperone and unfolded protein response regulator GRP78/BiP. J Biol Chem. 2010;14;285:15065-75.
• 8- Ibrahim IM, Abdelmalek DH, Elfiky AA. GRP78: A cell's response to stress. Life Sci. 2019;226:156-63.
• 9- Chu H, Chan CM, Zhang X, et al. Middle East respiratory syndrome coronavirus and bat coronavirus HKU9 both can utilize GRP78 for attachment onto host cells. J J Biol Chem. 2018;293:11709-26.
• 10- Köseler A, Sabirli R, Gören T, Türkçüer I, Kurt Ö. Endoplasmic Reticulum Stress Markers in SARS-COV-2 Infection and Pneumonia: Case-Control Study. In Vivo. 2020;34:1645-50.
• 11- Palmeira A, Sousa E, Köseler A, et al. Preliminary Virtual Screening Studies to Identify GRP78 Inhibitors Which May Interfere with SARS-CoV-2 Infection. Pharmaceuticals (Basel). 2020;13:132.
• 12- Sabirli R, Koseler A, Goren T, Turkcuer I, Kurt O. High GRP78 levels in Covid-19 infection: A case-control study. Life Sci. 2021;265:118781.
• 13- https://covid19.saglik.gov.tr/Eklenti/39061/0/covid19rehberieriskinhastatedavisipdf.pdf. (Son Erişim Tarihi:11.12.2020)
• 14- Chan CP, Siu KL, Chin KT, Yuen KY, Zheng B, Jin DY. Modulation of the unfolded protein response by the severe acute respiratory syndrome coronavirus spike protein. J Virol. 2006;80:9279-87.
• 15- Versteeg GA, van de Nes PS, Bredenbeek PJ, Spaan WJ. The Coronavirus Spike Protein Induces Endoplasmic Reticulum Stress and Upregulation of Intracellular Chemokine mRNA Concentrations. J Virol. 2007; 81: 10981-90.
• 16- Doerflinger M, Reljic B, Menassa J, et al. Circulating BiP/Grp78 is a novel prognostic marker for sepsis-mediated immune cell death. FEBS J. 2020 Sep 7. doi: 10.1111/febs.15552. Epub ahead of print. PMID: 32894892.
• 17- Stan RC, Pinto Bonin C, Porto R, Soriano FG, de Camargo MM. Increased grp78 transcription is correlated to reduced tlr4 transcription in patients surviving sepsis. Clin Exp Immunol. 2019;198:273-80.
• 18- Ma Y, Yu J, Chan HL, et al. Glucose-regulated protein 78 is an intracellular antiviral factor against hepatitis B virus. Mol Cell Proteomics. 2009;8:2582-94.