year 19, Issue 5 (September - October 2025)
Iran J Med Microbiol 2025, 19(5): 341-353 |
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Maeh R K, AL-Tameemi A I, Mahmood Z S, Fadhil H Y, AL-azawi K. Co-Analysis of TLR7 and CCL2 as Predictive Biomarkers forH1N1 Influenza Infection Severity. Iran J Med Microbiol 2025; 19 (5) :341-353
URL: http://ijmm.ir/article-1-2793-en.html
URL: http://ijmm.ir/article-1-2793-en.html
Raghad KH Maeh1 
, Ahmed Issa AL-Tameemi2 , Zainab S Mahmood3 , Hula Y. Fadhil2 , Khalida.F AL-azawi4
, Ahmed Issa AL-Tameemi2 , Zainab S Mahmood3 , Hula Y. Fadhil2 , Khalida.F AL-azawi4
1- Department of Biotechnology, College of Applied Science, University of Technology, Baghdad, Iraq , raghadnoor79@gmail.com
2- Department of Biology, College of Science, University of Baghdad, Baghdad, Iraq
3- Department of Basic Sciences, College of Dentistry, University of AL-Iraqia, Baghdad, Iraq
4- Department of Biotechnology, College of Applied Science, University of Technology, Baghdad, Iraq
2- Department of Biology, College of Science, University of Baghdad, Baghdad, Iraq
3- Department of Basic Sciences, College of Dentistry, University of AL-Iraqia, Baghdad, Iraq
4- Department of Biotechnology, College of Applied Science, University of Technology, Baghdad, Iraq
Abstract: (368 Views)
Background and Aim: Influenza A virus (H1N1) infection is still a high risk disease that involves inflammatory reactions. Chemokine (C-C motif) ligand 2 (CCL2) and Toll-like receptor 7 (TLR7) are important elements of immune system that regulate antiviral and inflammatory responses. This study aimed to assess the combined diagnostic and prognostic importance of TLR7 and CCL2, and investigate their relationship with clinical parameters and disease severity of H1N1.
Materials and Methods: In this case-control study, 60 influenza patients (divided into influenza-like illness [ILI] and severe acute respiratory infection [SARI] groups) were included along with 30 healthy people that served as control group. Blood samples were used to evaluate the expression of the TLR7 gene using RT-qPCR. The levels of CCL2 were measured using ELISA. ROC curve analysis, multivariate logistic regression, spearman correlation, and nonparametric tests were used to analyze the clinical data.
Results: H1N1 patients showed considerably higher levels of TLR7 expression than controls (median 8.6 vs 1.6; P<0.001). WBC and CRP levels were positively linked with elevated levels of TLR7. On the other hand, CCL2 was significantly lower in SARI group compared to ILI patients (37.5 vs 87.4 pg/mL; P<0.001). Predictive AUCs of 0.75 for TLR7 and 0.79 for CCL2 were found using ROC analysis; the combined model increased AUC to 0.85 (95% CI, 0.73–0.91). The presence of disease severity and diabetes was substantially correlated with both biomarkers.
Conclusion: In severe H1N1 infection, both CCL2 downregulation and TLR7 overexpression indicate increased immunological activity and inflammatory reactions dysregulation. The prognostic accuracy for identifying patients at risk of severe influenza is improved by their combined profiling.
Type of Study: Original Research Article |
Subject:
Medical Virology
Received: 2025/07/27 | Accepted: 2025/10/30 | ePublished: 2025/11/11
Received: 2025/07/27 | Accepted: 2025/10/30 | ePublished: 2025/11/11
References
1. Li S, Pan M, Zhao H, Li Y. Role of CCL2/CCR2 axis in pulmonary fibrosis induced by respiratory viruses. J Microbiol Immunol Infect. 2025;58(4):397-405. [DOI:10.1016/j.jmii.2025.02.003] [PMID]
2. Singh S, Anshita D, Ravichandiran V. MCP-1: Function, regulation, and involvement in disease. Int Immunopharmacol. 2021;101:107598. [DOI:10.1016/j.intimp.2021.107598] [PMID] [PMCID]
3. Gschwandtner M, Derler R, Midwood KS. More than just attractive: how CCL2 influences myeloid cell behavior beyond chemotaxis. Front Immunol. 2019;10:2759. [DOI:10.3389/fimmu.2019.02759] [PMID] [PMCID]
4. Maschalidi S, Hässler S, Blanc F, Sepulveda FE, Tohme M, Chignard M, et al. Asparagine endopeptidase controls anti-influenza virus immune responses through TLR7 activation. PLoS Pathog. 2012;8(3):e1002841. [DOI:10.1371/journal.ppat.1002841] [PMID] [PMCID]
5. Ebli FM, Heshmatipour Z, Daneshjou K, Siadat SD. Simultaneous Genetically Detection of Streptococcus pyogenes, Streptococcus pneumoniae and Haemophilus influenzae in Patients with Treatment-Resistant Respiratory Infection. Iran J Pathol. 2023;18(3):356. [DOI:10.30699/ijp.2023.1991067.3075] [PMID] [PMCID]
6. Jeisy-Scott V, Kim JH, Davis WG, Cao W, Katz JM, Sambhara S. TLR7 recognition is dispensable for influenza virus A infection but important for the induction of hemagglutinin-specific antibodies in response to the 2009 pandemic split vaccine in mice. J Virol. 2012;86(20):10988-98. [DOI:10.1128/JVI.01064-12] [PMID] [PMCID]
7. To EE, Erlich J, Liong F, Luong R, Liong S, Bozinovski S, et al. Intranasal and epicutaneous administration of Toll-like receptor 7 (TLR7) agonists provides protection against influenza A virus-induced morbidity in mice. Sci Rep. 2019;9(1):2366. [DOI:10.1038/s41598-019-38864-5] [PMID] [PMCID]
8. Flerlage T, Boyd DF, Meliopoulos V, Thomas PG, Schultz-Cherry S. Influenza virus and SARS-CoV-2: pathogenesis and host responses in the respiratory tract. Nat Rev Microbiol. 2021;19(7):425-41. [DOI:10.1038/s41579-021-00542-7] [PMID] [PMCID]
9. Xue J, Wang X, Wang H, Qiao B, Gao P, Ren B, et al. Unraveled role of TLR7-mediated interferon signaling activation in COVID-19. Front Cell Infect Microbiol. 2025;15:1658249. [DOI:10.3389/fcimb.2025.1658249] [PMID] [PMCID]
10. Ghimire R, Shrestha R, Amaradhi R, Liu L, More S, Ganesh T, et al. Toll-like receptor 7 (TLR7)-mediated antiviral response protects mice from lethal SARS-CoV-2 infection. J Virol. 2025;99(5):e01668-24. [DOI:10.1128/jvi.01668-24] [PMID] [PMCID]
11. Zhou J, Wang D, Gao R, Zhao B, Song J, Qi X, et al. Biological features of novel avian influenza A (H7N9) virus. Nature. 2013;499(7459):500-3. [DOI:10.1038/nature12379] [PMID]
12. Davey Jr RT, Lynfield R, Dwyer DE, Losso MH, Cozzi-Lepri A, Wentworth D, et al. The association between serum biomarkers and disease outcome in influenza A (H1N1) pdm09 virus infection: results of two international observational cohort studies. PLoS One. 2013;8(2):e57121. [DOI:10.1371/journal.pone.0057121] [PMID] [PMCID]
13. Vangeti S, Falck-Jones S, Yu M, Österberg B, Liu S, Asghar M, et al. Human influenza virus infection elicits distinct patterns of monocyte and dendritic cell mobilization in blood and the nasopharynx. Elife. 2023;12:e77345. [DOI:10.7554/eLife.77345] [PMID] [PMCID]
14. Lee N, Wong CK, Chan PK, Chan MC, Wong RY, Lun SW, et al. Cytokine response patterns in severe pandemic 2009 H1N1 and seasonal influenza among hospitalized adults. PLoS One. 2011;6(10):e26050. [DOI:10.1371/journal.pone.0026050] [PMID] [PMCID]
15. Jiang Q, Zhang Y, Duan D, Retout S, Upmanyu R, Glavini K, et al. Using exploratory pharmacokinetic and pharmacodynamic analyses to predict the probability of flu‐like symptoms in healthy volunteers and patients with chronic hepatitis B treated with the toll‐like receptor 7 agonist ruzotolimod. Clin Transl Sci. 2024;17(8):e13896. [DOI:10.1111/cts.13896] [PMID] [PMCID]
16. Rappe JC, Finsterbusch K, Crotta S, Mack M, Priestnall SL, Wack A. A TLR7 antagonist restricts interferon-dependent and-independent immunopathology in a mouse model of severe influenza. J Exp Med. 2021;218(11):e20201631. [DOI:10.1084/jem.20201631] [PMID] [PMCID]
17. Dong Y, Dong Y, Zhu C, Yang L, Wang H, Li J, et al. Targeting CCL2-CCR2 signaling pathway alleviates macrophage dysfunction in COPD via PI3K-AKT axis. Cell Commun Signal. 2024;22(1):364. [DOI:10.1186/s12964-024-01746-z] [PMID] [PMCID]
18. Guo S, Zhang Q, Guo Y, Yin X, Zhang P, Mao T, et al. The role and therapeutic targeting of the CCL2/CCR2 signaling axis in inflammatory and fibrotic diseases. Front Immunol. 2025;15:1497026. [DOI:10.3389/fimmu.2024.1497026] [PMID] [PMCID]
19. Maeh RK, Fadhil HY. Downregulation of CCL20 in Severe COVID-19 Infections and its Association with NLRP3 Gene Polymorphisms. Iraqi J Sci. 2025;66(5):9. [DOI:10.24996/ijs.2025.66.5.9]
20. Forouhi NG, Harding AH, Allison M, Sandhu MS, Welch A, Luben R, et al. Elevated serum ferritin levels predict new-onset type 2 diabetes: results from the EPIC-Norfolk prospective study. Diabetologia. 2007;50(5):949-56. [DOI:10.1007/s00125-007-0604-5] [PMID]
21. Sun L, Franco OH, Hu FB, Cai L, Yu Z, Li H, et al. Ferritin concentrations, metabolic syndrome, and type 2 diabetes in middle-aged and elderly Chinese. J Clin Endocrinol Metab. 2008;93(12):4690-6. [DOI:10.1210/jc.2008-1159] [PMID]
22. Files JK, Boppana S, Perez MD, Sarkar S, Lowman KE, Qin K, et al. Sustained cellular immune dysregulation in individuals recovering from SARS-CoV-2 infection. J Clin Invest. 2021;131(1):e140491. [DOI:10.1172/JCI140491] [PMID] [PMCID]
23. Zou Y, Ding M, Zheng Y, Dai G, Wang T, Zhu C, et al. Peripheral blood cytokine expression levels and their clinical significance in children with influenza. Transl Pediatr. 2025;14(2):286. [DOI:10.21037/tp-2024-534] [PMID] [PMCID]
24. Bober A, Mika J, Piotrowska A. A Missing Puzzle in Preclinical Studies-Are CCR2, CCR5, and Their Ligands' Roles Similar in Obesity-Induced Hypersensitivity and Diabetic Neuropathy?-Evidence from Rodent Models and Clinical Studies. Int J Mol Sci. 2024;25(20):11323. [DOI:10.3390/ijms252011323] [PMID] [PMCID]
25. Wang YL, Koh WP, Yuan JM, Pan A. Plasma ferritin, C-reactive protein, and risk of incident type 2 diabetes in Singapore Chinese men and women. Diabetes Res Clin Pract. 2017;128:109-18. [DOI:10.1016/j.diabres.2017.04.012] [PMID]
26. Ali N. Elevated level of C‐reactive protein may be an early marker to predict risk for severity of COVID‐19. J Med Virol. 2020;92(11):2409. [DOI:10.1002/jmv.26097] [PMID] [PMCID]
27. Aufi IM, Fadhil HY, Ali AW, Alhamdani FG, Owaid FM. Epidemiology of seasonal influenza outbreak among Iraqi population: 2018. Iraqi J Agric Sci. 2020;51(1):454-61. [DOI:10.36103/ijas.v51i1.944]
28. Klein SL, Passaretti C, Anker M, Olukoya P, Pekosz A. The impact of sex, gender and pregnancy on 2009 H1N1 disease. Biol Sex Differ. 2010;1(1):5. [DOI:10.1186/2042-6410-1-5] [PMID] [PMCID]
29. Varghese M, Clemente J, Lerner A, Abrishami S, Islam M, Subbaiah P, et al. Monocyte trafficking and polarization contribute to sex differences in meta-inflammation. Front Endocrinol. 2022;13:826320. [DOI:10.3389/fendo.2022.826320] [PMID] [PMCID]
30. Wang M, Chen X, Shang Y, Chen B, Chen H, Zhou L, et al. Oligopeptide-strategy of targeting at adipose tissue macrophages using ATS-9R/siCcl2 complex for ameliorating insulin resistance in GDM. Biomed Pharmacother. 2024;175:116775. [DOI:10.1016/j.biopha.2024.116775] [PMID]
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