Molecular Insights into the impact of Deleterious Missense nsSNPs in IL-2 structure and function on Antifungal Immune Responses: An In Silico analysis

Abstract

Background and Aims: To evaluate the functional and structural impact of deleterious missense single-nucleotide polymorphisms (nsSNPs) on human Interleukin-2 (IL-2), a key cytokine in antifungal immunity. Methods: In silico analysis of nsSNPs using bioinformatics tools (MAPP, PhD-SNP, PolyPhen-1/2, SIFT, SNAP, PredictSNP, I-Mutant 2.0, ConSurf, Project HOPE) to predict their effects on protein function and structure. MusiteDEEP was used for post-translational modification analysis. Results: Novel deleterious missense nsSNPs were identified in IL-2 (M1T, F62C, 73P, S107I, G118E, and W141R). Computational analyses predicted significant alterations in IL-2’s surface properties, such as altered (signal peptide, transmembrane protein, disordered interface, metal binding, coiled coil, stability, disordered interface), or loss of (N-terminal acetylation, acetylation, strand, loop, transmembrane protein), or gain of (intrinsic disorder, of helix, allosteric site or of relative solvent accessibility), change is hydrophobicity and size were observed. Thus, potentially disrupt interactions with other immune molecules and function. Dramatic changes were obsevered in post-translational modifications for mutations T71I and S107I, resulted in the loss of phosphorylation sites, while the mutations M1T and L92S led to a gain of phosphorylation. Conclusion: These findings represents a foundational step in identifying potentially pathogenic IL-2 mutations, suggest the nsSNPs in IL-2 may contribute to impaired antifungal immunity by altering protein function and structure. Further research is warranted to explore the clinical implications of these findings for personalized medicine approaches to fungal infections.

References

1. 1.Sharfe N, Dadi HK, Shahar M, Roifman 12. Benard G, Romano CC, Cacere CM. Human immune disorder arising CR, Juvenale M, Mendes-Gianniinterleukin-2 receptor. Proc Natl Acad 2, IFN-gamma and IL-10 secretion from mutation of the alpha chain of the Sci U S A. 1997;94(7):3168-71.
2. 2.Boyman O, Surh CD, Sprent J. Potential use of IL-2/anti-IL-2 antibody imni MJ, Duarte AJ. Imbalance of ILin the immunosuppression associated with human paracoccidioidomycosis. Cytokine. 2001;13(4):248-52. mune complexes for the treatment of 13. Tayyaba Sadaf FD. Identification of cancer and autoimmune disease. Expert Deleterious Nssnps of Interleukin-2
3. 3.Zhou P, Chen J, He J, Zheng T, Yunis J, bility Using Computational Meth- Opin Biol Ther. 2006;6(12):1323-31. Makota V, et al. Low-dose IL-2 therapy invigorates CD8+ T cells for viral con- (IL-2) Gene and Its Structural Staods International Journal of Research 2018;Volume 05 Issue 04 trol in systemic lupus erythematosus. 14. Arshad M, Noor N, Iqbal Z, Jaleel H. PLoS Pathog. 2021;17(10):e1009858. In silico analysis of missense SNPs in Biological activity of interleukin-2 or pathogenic role in immune diseases.
4. 4.Treseler CB, Maziarz RT, Levitz SM. bound to Candida albicans. Infect Immun. 1992;60(1):183-8.
5. 5.Zheng XF, Hong YX, Feng GJ, Zhang GF, Rogers H, Lewis MA, et al. Lipopolysaccharide-induced M2 to M1 macrophage transformation for IL12p70 production is blocked by Candida albicans mediated up-regula- TNFR1a and their possible therapeutic Hum Immunol. 2023;84(11):609-17.
6. 6.Ittisoponpisan S, Islam SA, Khanna T, Alhuzimi E, David A, Sternberg MJE. Can Predicted Protein 3D Structures Provide Reliable Insights into whether Missense Variants Are Disease Associated? J Mol Biol. 2019;431(11):2197212. tion of EBI3 expression. PLoS One. 16. Pejaver V, Urresti J, Lugo-Martinez 2013;8(5):e63967. J, Pagel KA, Lin GN, Nam HJ, et Bistoni F, Romani L. Early T cell unnotypic impact of amino acid vari-
7. 7.Spaccapelo R, Del Sero G, Mosci P, responsiveness in mice with candidiasis and reversal by IL-2: effect on T 66 al. Inferring the molecular and pheants with MutPred2. Nat Commun. 2020;11(1):5918. Molecular Insights into the impact of Deleterious Missense nsSNPs in IL-2 structure and function on Antifungal Immune Responses: An In Silico analysis Majmaah Journal of Health Sciences ,Vol. 14, Issue 1, January - 2026, Rajabi - 1447
8. 8.Thompson A, Orr SJ. Emerging IL-12 family cytokines in the fight nodeficiency. J Allergy Clin Immunol. 2008;122(6):1082-6. against fungal infections. Cytokine. 23. Ege M, Ma Y, Manfras B, Kalwak K, 2018;111:398-407. Lu H, Lieber MR, et al. Omenn syn- Hitchens K, Butcher S, Murray RZ, et Blood. 2005;105(11):4179-86.
9. 9.Wells CA, Salvage-Jones JA, Li X, al. The macrophage-inducible C-type drome due to ARTEMIS mutations. lectin, mincle, is an essential component of the innate immune response to Candida albicans. J Immunol. 2008;180(11):7404-13.
10. 10.Granucci F, Vizzardelli C, Pavelka N, Feau S, Persico M, Virzi E, et al. Inducible IL-2 production by dendritic cells revealed by global gene expression analysis. Nat Immunol. 2001;2(9):882-8.
11. 11.Gafa V, Lande R, Gagliardi MC, Severa M, Giacomini E, Remoli ME, et al. Human dendritic cells following Aspergillus fumigatus infection express the CCR7 receptor and a differential pattern of interleukin-12 (IL-12), IL-23, and IL-27 cytokines, which lead to a Th1 response. Infect Immun. 2006;74(3):1480-9.
12. 12.Zelante T, Wong AY, Ping TJ, Chen J, Sumatoh HR, Vigano E, et al. CD103(+) Dendritic Cells Control Th17 Cell Function in the Lung. Cell Rep. 2015;12(11):1789-801.
13. 13.Villa A, Notarangelo LD, Roifman CM. Omenn syndrome: inflammation in leaky severe combined immuMolecular Insights into the impact of Deleterious Missense nsSNPs in IL-2 structure and function on Antifungal Immune Responses: An In Silico analysis 67