COVID-19 hastalarında bağışıklık sistemi üzerinde TLR4 ve TLR7 genlerinin etkisi
Year 2024,
Volume: 49 Issue: 4, 1044 - 1050, 30.12.2024
Nejmiye Akkuş
,
Figen Güzelgül
,
Süheyla Uzun
,
Tuncay Yiğit
,
Kadir Kabahasanoğlu
,
Marwa Abdelmageed
Abstract
Amaç: Bu çalışmada TLR4 ve TLR7 gen polimorfizmlerinin COVID-19 hastalarının bağışıklığı üzerindeki etkilerinin araştırılması amaçlanmıştır..
Gereç ve Yöntem: Toplam 210 COVİD-19 hastalarından iki grup oluşturuldu. Grup 1: Yoğun bakım ünitesine yatışlı ciddi solunum komplikasyonları yaşayan COVİD-19 bölgeleri(n=107). Grup 2: Herhangi bir tedavi veya iyileşme gerektirmeden iyileşen hafif SARS-CoV-2 enfeksiyonu olan COVİD-19 hücreleri(n=103). DNA izolasyonu ve genotipleme için tam kan örnekleri (2 mL) toplandı. Genomik DNA izole edildi. Daha sonra RT-PCR yöntemi kullanılarak SNP analizleri yapıldı. Hastalarda incelenen SNP'ler, TLR4 geni rs4986790 (896A/G, Asp299Gly) ve rs4986791 (1196C/T, Thr399Ile), TLR7 geni rs189681811 (c.2759 G>A Arg920Lys) ve rs149314023 (c.655G>A) Val219Ile).
Bulgular: Çalışmamızda, TLR7 RS189681811 veya TLR7 S149314023 gen polimorfizmleri çalışma gruplarında tespit edilmedi, ancak gen polimorfizmi hem hafif (n=6) hem de şiddetli (n=7) gruplarda anlamlı bir fark dışında gözlendi. TLR4 RS498679 ile TLR4 RS4986791 gen polimorfizmi hem hafif (n=8) hem de şiddetli (n=5) gruplarda iki grup arasında anlamlı bir fark olmaksızın gözlendi.
Sonuç: İncelenen SNP'ler için iki grup arasında genotip dağılımında istatistiksel olarak anlamlı bir fark bulunamadı. Daha büyük örneklem büyüklükleri ve daha geniş bir TLR SNP aralığı ile gelecekteki çok merkezli çalışmalar değerli sonuçlar sağlayabilir ve mevcut literatüre katkıda bulunabilir.
References
- Fan E, Beitler JR, Brochard L, Calfee CS, Ferguson ND, Slutsky AS et al. COVID-19-associated acute respiratory distress syndrome: is a different approach to management warranted? Lancet Respir Med. 2020;8:816–21.
- Wang Q, Zhang Y, Wu L, Niu S, Song C, Guangwen Lu et al. Structural and functional basis of SARS-CoV-2 entry by using human ACE2. Cell. 2020;181:894–904.
- Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese center for disease control and prevention. JAMA. 2020;323:1239-42.
- Adhikari SP, Meng S, Wu YJ, Mao YP, Ye RX, Wang QZ et al. Epidemiology, causes, clinical manifestation and diagnosis, prevention, and control of coronavirus disease (COVID-19) during the early outbreak period: a scoping review. Infect Dis Poverty. 2020;17:29.
- World Health Organization (WHO), 2020. Coronavirus Disease. (COVID-19) Situation Report – 205. Geneva, WHO, 2020.
- Chen R, Liang W, Jiang M, Guan W, Zhan C, Wang T et al. Risk factors of fatal outcome in hospitalized subjects with coronavirus disease 2019 from a nationwide analysis in China. Chest. 2020;158:97‐105.
- Gupta R, Ghosh A, Singh AK, Misra A. Clinical considerations for patients with diabetes in times of COVID-19 epidemic. Diabetes Metab Syndr. 2020;14:211-12.
- Santesmasses D, Castro JP, Zenin AA, Shindyapina AV, Gerashchenk MV, Zhang B et al. COVID-19 is emergent disease of aging. Aging Cell. 2020;19:e13230.
- Brodin P. Immune determinants of COVID-19 disease presentation and severity. Nat Med. 2021;27:28-33.
- Choudhury A, Mukherjee S. In silico studies on the comparative characterization of the interactions of SARS‐CoV‐2 spike glycoprotein with ACE‐2 receptor homologs and human TLRs. J Med Virol. 2020;92:2105‐13.
- Lester SN, Li K. Toll‐like receptors in antiviral innate immunity. J Mol Biol. 2014;426:1246‐64.
- Angelopoulou A, Alexandris N, Konstantinou E, Mesiakaris K, Zanidis C, Farsalinos K et al. Imiquimod—a toll like receptor 7 agonist—is an ideal option for management of COVID 19. Environ Res. 2020;188:109858
- Magro G. SARS‐CoV‐2 and COVID‐19: is interleukin‐6 (IL‐6) the'-culprit lesion'of ARDS onset? What is there besides tocilizumab? SGP130Fc. Cytokine X. 2020;2:100029.
- Su H, Lei CT, Zhang C. Interleukin‐6 signaling pathway and ıts role in kidney disease: an update. Front Immunol. 2017;21:405.
- Bakkari MA, Valiveti CK, Kaushik RS, and Tummala H. Toll-like receptor-4 (TLR4) agonist-based intranasal nanovaccine delivery system for inducing systemic and mucosal immunity. Mol Pharm. 2021;18:2233–41.
- Khadke S, Ahmed N, Ahmed N, Ratts R, Raju S et al. Harnessing the immune system to overcome cytokine storm and reduce viral load in COVID‐19: a review of the phases of illness and therapeutic agents. Virol J. 2020;17:154.
- Onofrio L, Caraglia M, Facchini G, Margherita V, Placido SD, Buonerba C. Toll‐like receptors and COVID‐19: a two‐faced story with an exciting ending. Future Sci OA. 2020;6:FSO605.
- Conti P, Ronconi G, Caraffa A, Gallenga C, Ross R, Frydas I et al. Induction of pro‐inflammatory cytokines (IL‐1 and IL‐6) and lung inflammation by coronavirus‐19(COVI‐19 or SARS‐CoV‐2): anti‐inflammatory strategies. J Biol Regul Homeost Agents. 2020;34:327-31.
- Patra R, Das CN, Mukherjee S. Targeting human TLRs to combat COVID‐19: a solution? J Med Virol. 2021;93:615‐17.
- Takeda K and Akira S. Toll-like receptor signalling. Curr Protoc Immunol. 2015;1:109.
- Akira S, Uematsu S, and Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124:783–801.
- Kuzmich NN, Sivak KV, Chubarev VN, Porozov YB, Savateeva- Lyubimova TN, and Peri F. TLR4 signaling pathway modulators as potential therapeutics in inflammation and sepsis. Vaccines. 2017;5:34.
- O’Neill LA, Golenbock D, and Bowie AG. The history of Toll-like receptors -redefining innate immunity. Nat. Rev. Immunol. 2013;13:453–60.
- Catanzaro M, Fagiani F, Racchi M, Corsini E, Govoni S, Lanni C. Immune response in COVID‐19: addressing a pharmacological challenge by targeting pathways triggered by SARS‐CoV‐2. Signal Transduct Target Ther. 2020;29:84.
- Mustafa MI, Abdelmoneim AH, Mahmoud EM, Makhawi AM. Cytokine storm in COVID‐19 patients, its impact on organs and potential treatment by QTY code‐designed detergent‐free chemokine receptors. Mediators Inflamm. 2020;2020:8198963.
- Vlach J, Bender AT, Przetak M, Pereira A, Deshpande A, Johnson T et al. Discovery of M5049: a novel selective toll‐like receptor 7/8 inhibitor for treatment of autoimmunity. J Pharmacol Exp Ther. 2021;376:397‐409.
- Fallerini C, Daga S, Mantovani S, Benetti E, Picchiotti N, Francisci D et al. Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control study. Elife. 2021;2:e67569.
- Sohn KM, Lee SG, Kim HJ, Cheon S, Jeong H, Lee J et al. COVID-19 Patients upregulate toll-like receptor 4-mediated inflammatory signaling that mimics bacterial sepsis. J Korean Med Sci. 2020;35:e343.
- 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. 2020;395:507–13.
- Chou R, Dana T, Buckley DI, Selph S, Fu R, Totten AM. Epidemiology of and risk factors for coronavirus infection in health care workers: a living rapid review. Ann Intern Med. 2020;173:20‐136.
- Phillips N, Park IW, Robinson JR, Jones HP. The perfect storm: COVID‐19 health disparities in US blacks. J Racial Ethn Health Disparities. 2021;8:1153‐60.
- Shi SM, Bakaev I, Chen H, Travison TG, Berry SD. Risk factors, presentation, and course of coronavirus disease 2019 in a large, academic long‐term care facility. J Am Med Dir Assoc. 2020;21:1378‐1383.e1.
- Tsabouri S, Makis A, Kosmeri C, Siomou E. Risk factors for severity in children with coronavirus disease 2019: a comprehensive literature review. Pediatr Clin. 2021;68:321‐38.
- Zhou Y, Chi J, Lv W, Wang Y. Obesity and diabetes as high‐risk factors for severe coronavirus disease 2019 (Covid‐19). Diabetes Metab Res Rev. 2021;37:e3377.
- Taha SI, Shata AK, Baioumy SA, Fouad SH, Anis SG, Mossad IM et al. Toll-Like Receptor 4 polymorphisms (896A/G and 1196C/T) as an ındicator of COVID-19 severity in a convenience sample of egyptian patients. J Inflamm Res. 2021;27:14:6293-303.
Effects of TLR4 and TLR7 genes on the immune system in COVID-19 patients
Year 2024,
Volume: 49 Issue: 4, 1044 - 1050, 30.12.2024
Nejmiye Akkuş
,
Figen Güzelgül
,
Süheyla Uzun
,
Tuncay Yiğit
,
Kadir Kabahasanoğlu
,
Marwa Abdelmageed
Abstract
Purpose: This study aimed to investigate the effects of TLR4 and TLR7 gene polymorphisms on the immunity of COVID-19 patients.
Materials and Methods: A total of 210 COVID-19 patients were divided into two groups. Group 1: COVID-19 patients experiencing severe respiratory complications requiring intensive care unit admission (n=107). Group 2: COVID-19 patients with mild SARS-CoV-2 infection who have been recovered without requiring any treatment or hospitalization (n=103). Whole blood samples (2 mL) were collected for DNA isolation and genotyping. Genotyping analyses were then conducted using the RT-PCR method to investigate the following single nucleotide polymorphisms (SNPs): TLR4 gene rs4986790 (896A/G, Asp299Gly) and rs4986791 (1196C/T, Thr399Ile), TLR7 gene rs189681811 (c.2759 G>A Arg920 Lys ) and rs149314023 (c.655G>A Val219Ile).
Results: TLR7 RS189681811 and TLR7 RS149314023 gene polymorphisms were not observed in any of the study groups. However, TLR4 RS4986790 and TLR4 RS4986791 gene polymorphisms were observed in both mild and severe groups with no significant differences.
Conclusion: No statistically significant differences in genotype distribution were found between the two groups for the SNPs examined. Future multicentered studies with larger sample sizes and a broader range of TLR SNPs could provide valuable insights and contribute to the existing literature.
References
- Fan E, Beitler JR, Brochard L, Calfee CS, Ferguson ND, Slutsky AS et al. COVID-19-associated acute respiratory distress syndrome: is a different approach to management warranted? Lancet Respir Med. 2020;8:816–21.
- Wang Q, Zhang Y, Wu L, Niu S, Song C, Guangwen Lu et al. Structural and functional basis of SARS-CoV-2 entry by using human ACE2. Cell. 2020;181:894–904.
- Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese center for disease control and prevention. JAMA. 2020;323:1239-42.
- Adhikari SP, Meng S, Wu YJ, Mao YP, Ye RX, Wang QZ et al. Epidemiology, causes, clinical manifestation and diagnosis, prevention, and control of coronavirus disease (COVID-19) during the early outbreak period: a scoping review. Infect Dis Poverty. 2020;17:29.
- World Health Organization (WHO), 2020. Coronavirus Disease. (COVID-19) Situation Report – 205. Geneva, WHO, 2020.
- Chen R, Liang W, Jiang M, Guan W, Zhan C, Wang T et al. Risk factors of fatal outcome in hospitalized subjects with coronavirus disease 2019 from a nationwide analysis in China. Chest. 2020;158:97‐105.
- Gupta R, Ghosh A, Singh AK, Misra A. Clinical considerations for patients with diabetes in times of COVID-19 epidemic. Diabetes Metab Syndr. 2020;14:211-12.
- Santesmasses D, Castro JP, Zenin AA, Shindyapina AV, Gerashchenk MV, Zhang B et al. COVID-19 is emergent disease of aging. Aging Cell. 2020;19:e13230.
- Brodin P. Immune determinants of COVID-19 disease presentation and severity. Nat Med. 2021;27:28-33.
- Choudhury A, Mukherjee S. In silico studies on the comparative characterization of the interactions of SARS‐CoV‐2 spike glycoprotein with ACE‐2 receptor homologs and human TLRs. J Med Virol. 2020;92:2105‐13.
- Lester SN, Li K. Toll‐like receptors in antiviral innate immunity. J Mol Biol. 2014;426:1246‐64.
- Angelopoulou A, Alexandris N, Konstantinou E, Mesiakaris K, Zanidis C, Farsalinos K et al. Imiquimod—a toll like receptor 7 agonist—is an ideal option for management of COVID 19. Environ Res. 2020;188:109858
- Magro G. SARS‐CoV‐2 and COVID‐19: is interleukin‐6 (IL‐6) the'-culprit lesion'of ARDS onset? What is there besides tocilizumab? SGP130Fc. Cytokine X. 2020;2:100029.
- Su H, Lei CT, Zhang C. Interleukin‐6 signaling pathway and ıts role in kidney disease: an update. Front Immunol. 2017;21:405.
- Bakkari MA, Valiveti CK, Kaushik RS, and Tummala H. Toll-like receptor-4 (TLR4) agonist-based intranasal nanovaccine delivery system for inducing systemic and mucosal immunity. Mol Pharm. 2021;18:2233–41.
- Khadke S, Ahmed N, Ahmed N, Ratts R, Raju S et al. Harnessing the immune system to overcome cytokine storm and reduce viral load in COVID‐19: a review of the phases of illness and therapeutic agents. Virol J. 2020;17:154.
- Onofrio L, Caraglia M, Facchini G, Margherita V, Placido SD, Buonerba C. Toll‐like receptors and COVID‐19: a two‐faced story with an exciting ending. Future Sci OA. 2020;6:FSO605.
- Conti P, Ronconi G, Caraffa A, Gallenga C, Ross R, Frydas I et al. Induction of pro‐inflammatory cytokines (IL‐1 and IL‐6) and lung inflammation by coronavirus‐19(COVI‐19 or SARS‐CoV‐2): anti‐inflammatory strategies. J Biol Regul Homeost Agents. 2020;34:327-31.
- Patra R, Das CN, Mukherjee S. Targeting human TLRs to combat COVID‐19: a solution? J Med Virol. 2021;93:615‐17.
- Takeda K and Akira S. Toll-like receptor signalling. Curr Protoc Immunol. 2015;1:109.
- Akira S, Uematsu S, and Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124:783–801.
- Kuzmich NN, Sivak KV, Chubarev VN, Porozov YB, Savateeva- Lyubimova TN, and Peri F. TLR4 signaling pathway modulators as potential therapeutics in inflammation and sepsis. Vaccines. 2017;5:34.
- O’Neill LA, Golenbock D, and Bowie AG. The history of Toll-like receptors -redefining innate immunity. Nat. Rev. Immunol. 2013;13:453–60.
- Catanzaro M, Fagiani F, Racchi M, Corsini E, Govoni S, Lanni C. Immune response in COVID‐19: addressing a pharmacological challenge by targeting pathways triggered by SARS‐CoV‐2. Signal Transduct Target Ther. 2020;29:84.
- Mustafa MI, Abdelmoneim AH, Mahmoud EM, Makhawi AM. Cytokine storm in COVID‐19 patients, its impact on organs and potential treatment by QTY code‐designed detergent‐free chemokine receptors. Mediators Inflamm. 2020;2020:8198963.
- Vlach J, Bender AT, Przetak M, Pereira A, Deshpande A, Johnson T et al. Discovery of M5049: a novel selective toll‐like receptor 7/8 inhibitor for treatment of autoimmunity. J Pharmacol Exp Ther. 2021;376:397‐409.
- Fallerini C, Daga S, Mantovani S, Benetti E, Picchiotti N, Francisci D et al. Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control study. Elife. 2021;2:e67569.
- Sohn KM, Lee SG, Kim HJ, Cheon S, Jeong H, Lee J et al. COVID-19 Patients upregulate toll-like receptor 4-mediated inflammatory signaling that mimics bacterial sepsis. J Korean Med Sci. 2020;35:e343.
- 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. 2020;395:507–13.
- Chou R, Dana T, Buckley DI, Selph S, Fu R, Totten AM. Epidemiology of and risk factors for coronavirus infection in health care workers: a living rapid review. Ann Intern Med. 2020;173:20‐136.
- Phillips N, Park IW, Robinson JR, Jones HP. The perfect storm: COVID‐19 health disparities in US blacks. J Racial Ethn Health Disparities. 2021;8:1153‐60.
- Shi SM, Bakaev I, Chen H, Travison TG, Berry SD. Risk factors, presentation, and course of coronavirus disease 2019 in a large, academic long‐term care facility. J Am Med Dir Assoc. 2020;21:1378‐1383.e1.
- Tsabouri S, Makis A, Kosmeri C, Siomou E. Risk factors for severity in children with coronavirus disease 2019: a comprehensive literature review. Pediatr Clin. 2021;68:321‐38.
- Zhou Y, Chi J, Lv W, Wang Y. Obesity and diabetes as high‐risk factors for severe coronavirus disease 2019 (Covid‐19). Diabetes Metab Res Rev. 2021;37:e3377.
- Taha SI, Shata AK, Baioumy SA, Fouad SH, Anis SG, Mossad IM et al. Toll-Like Receptor 4 polymorphisms (896A/G and 1196C/T) as an ındicator of COVID-19 severity in a convenience sample of egyptian patients. J Inflamm Res. 2021;27:14:6293-303.