Polymorphism of TNFα with measurement of IL-18, IL-37 and Glutathione in Iraqi patents with Leishmaniasis

• Rabia Ali Aboud

  Al- Farahidi University, Baghdad

General Background: Leishmaniasis remains a significant public health issue, particularly affecting immunocompromised populations and children in endemic regions. Specific Background: The immunopathogenesis involves complex cytokine responses and antioxidant mechanisms, yet limited data exists on the interaction of TNFα polymorphisms and interleukin expression in visceral leishmaniasis. Knowledge Gap: There is a paucity of studies linking genetic variants of TNFα with cytokine profiles and glutathione dynamics in Iraqi patients with L. donovani infections. Aims: This study aimed to assess serum levels of IL-18, IL-37, TNFα, glutathione, and the rs767455 SNP in TNFα among infected individuals. Results: Patients exhibited significantly elevated IL-18, IL-37, TNFα, and IgG levels alongside markedly reduced glutathione compared to controls (P≤0.001). A direct correlation was observed between glutathione and both TNFα (r=0.224, P=0.006) and IL-37 (r=0.155, P=0.05). A SNP variation (AA to GG) in rs767455 was noted in multiple infected individuals. Novelty: This is the first study to report a significant elevation of IL-37 and a defined correlation of glutathione with inflammatory cytokines in visceral leishmaniasis. Implications: These findings underscore the potential of cytokine and glutathione profiling, alongside genetic markers, as diagnostic or prognostic tools in managing leishmaniasis.

Highlights:

• Significant Increase in Cytokines: Patients with visceral leishmaniasis exhibited markedly higher levels of IL-18, IL-37, TNFα, and Glutathione compared to controls.

• Genetic Variation Identified: A SNP (rs767455) mutation in the TNFα gene was observed in several infected individuals, changing genotype from AA to GG.

• Correlative Biomarker Insight: Strong correlation found between Glutathione and TNFα/IL-37 levels, suggesting possible biomarker or therapeutic implications.

Keywords: Leishmaniasis, TNFα, IL-18, IL-37, Glutathione

[1] S. Scarpini, A. Dondi, C. Totaro, C. Biagi, and F. Melchionda, “Visceral Leishmaniasis: Epidemiology, Diagnosis, and Treatment Regimens in Different Geographical Areas with a Focus on Pediatrics,” Microorganisms, vol. 10, no. 10, p. 1887, Sep. 2022.

[2] Y. Rassi, S. Z. Parkhideh, S. Rafizadeh, and M. R. Jalil-Navaz, “A Comprehensive Review of the Situation of Visceral Leishmaniasis Vectors in Iran,” J. Arthropod-Borne Dis., vol. 18, no. 1, pp. 1–11, Mar. 2024.

[3] E. K. Elmahallawy, A. A. M. Alkhaldi, and A. A. Saleh, “Host Immune Response Against Leishmaniasis and Parasite Persistence Strategies: A Review and Assessment of Recent Research,” Biomed. Pharmacother., vol. 139, p. 111671, Jul. 2021.

[4] H. Ding, G. Wang, Z. Yu, H. Sun, and L. Wang, “Role of Interferon-Gamma (IFN-γ) and IFN-γ Receptor 1/2 (IFNγR1/2) in Regulation of Immunity, Infection, and Cancer Development,” Biomed. Pharmacother., vol. 155, p. 113683, Nov. 2022.

[5] F. S. Almeida, S. E. R. V. Vanderley, F. C. Comberlang, A. G. de Andrade, and L. H. C. Cavalcante-Silva, “Leishmaniasis: Immune Cells Crosstalk in Macrophage Polarization,” Trop. Med. Infect. Dis., vol. 8, no. 5, p. 276, May 2023.

[6] D. Jang, A-H. Lee, H-Y. Shin, H-R. Song, and J-H. Park, “The Role of Tumor Necrosis Factor Alpha (TNF-α) in Autoimmune Disease and Current TNF-α Inhibitors in Therapeutics,” Int. J. Mol. Sci., vol. 22, no. 5, p. 2719, Mar. 2021.

[7] V. Andretto, S. Dusi, S. Zilio, M. Repellin, D. Kryza, S. Ugel, and G. Lollo, “Tackling TNF-α in Autoinflammatory Disorders and Autoimmune Diseases: From Conventional to Cutting Edge in Biologics and RNA-Based Nanomedicines,” Adv. Drug Deliv. Rev., vol. 201, p. 115080, Oct. 2023.

[8] H. Zhang, N. Shi, Z. Diao, Y. Chen, and Y. Zhang, “Therapeutic Potential of TNFα Inhibitors in Chronic Inflammatory Disorders: Past and Future,” Genes Dis., vol. 8, no. 1, pp. 38–47, Mar. 2020.

[9] J-M. Yuk, J. K. Kim, I. S. Kim, and E-K. Jo, “TNF in Human Tuberculosis: A Double-Edged Sword,” Immune Netw., vol. 24, no. 1, p. e4, Feb. 2024.

[10] E. V. Ryabokon, T. E. Onishchenko, E. O. Furyk, and A. B. Khelemendyk, Vector-Borne Infectious Diseases, Zaporozhye State Medical University, Ukraine, 2020.

[11] E. Yizengaw, Y. Takele, S. Franssen, B. Gashaw, and M. Yimer, “Investigation of Parasite Genetic Variation and Systemic Immune Responses in Patients with Cutaneous Leishmaniasis,” Infect. Dis. Poverty, vol. 13, p. 76, 2024.

[12] M. Alishvandi, S. Bahrami, S. Rashidi, and G. Hatam, “Isoenzyme Characterization of Leishmania infantum: Antioxidant Activity of Superoxide Dismutase and Glutathione Peroxidase,” BMC Infect. Dis., vol. 24, p. 208, 2024.

[13] M. H. Flaih, E. R. Alwaily, A. A. Hafedh, and K. R. Hussein, “Six-Year Study on Cutaneous Leishmaniasis in Al-Muthanna, Iraq,” Infect. Chemother., vol. 56, no. 2, pp. 213–221, Jun. 2024.

[14] L. ALTAIE and M. A. J. ALQAYIM, “Hematological Features of Visceral Leishmaniasis of Infected Children in Baghdad, Iraq,” Ann. Parasitol., vol. 67, no. 3, pp. 515–521, 2021.

[15] A. J. Alyasiri and H. H. Ali, “A Clinicoepidemiological Study on Kala-Azar in Al-Muthanna Province, Iraq,” J. Appl. Health Sci. Med., vol. 4, no. 2, pp. 14–28, 2024.

[16] X. Z. Han, H. B. Li, J. H. Wei, X. Y. Xu, Y. Li, and Y. Q. Che, “Serological Characteristics and Clinical Implications of IgG Subclasses in Visceral Leishmaniasis,” Trop. Med. Int. Health, Dec. 2023.

[17] Z. B. Mehrangiz, R. Oskoei, M. H. Kohansal, A. Barac, and E. Ahmadpour, “Serum Profile of IL-1β and IL-17 Cytokines in Visceral Leishmaniasis,” Comp. Immunol. Microbiol. Infect. Dis., vol. 69, p. 101431, Apr. 2020.

[18] D. Tadesse, A. Abdissa, M. Mekonnen, T. Belay, and A. Hailu, “Antibody and Cytokine Levels in Visceral Leishmaniasis Patients,” PLoS Negl. Trop. Dis., vol. 15, no. 8, p. e0009632, Aug. 2021.

[19] A. M. Hussein and H. Z. Ali, “Detection of TNF-Alpha Level as Biomarker in Different Stages of Cutaneous Leishmaniasis,” Iraqi J. Sci., vol. 63, no. 8, pp. 3313–3321, 2022.

[20] Sh. Kumar, Sh. B. Chauhan, Sh. Upadhyay, S. S. Singh, and V. Verma, “Altered IL-7 Signaling in CD4+ T Cells from Patients with Visceral Leishmaniasis,” PLoS Negl. Trop. Dis., Feb. 2024.

[21] L. A. Rostan, O. Dion, S. A. A. Jan, and H. Guegan, “IL-33/ST2 Axis in Disease Progression in the Spleen During Leishmania donovani Infection,” Parasites Vectors, vol. 13, p. 320, 2020.

[22] N. Amiri-Dashatan, M. Koushki, M. Rezaei-Tavirani, and N. Ahmadi, “Stage-Specific Differential Gene Expression of Glutathione Peroxidase,” Rep. Biochem. Mol. Biol., vol. 9, no. 3, Oct. 2020.

[23] M. Alishvandi, S. Bahrami, S. Rashidi, and G. Hatam, “Isoenzyme Characterization of Leishmania infantum,” BMC Infect. Dis., vol. 24, p. 208, 2024.

[24] N. Pinho, N. C. Bombaça, J. R. Wiśniewski, and G. Dias-Lopes, “Nitric Oxide Resistance in Leishmania braziliensis Involves Glutathione Metabolism,” Antioxidants, vol. 11, no. 2, p. 277, 2022.

[25] M. C. González-Montero, M. J. Andrés-Rodríguez, N. García-Fernández, Y. Pérez-Pertejo, and R. M. Reguera, “Targeting Trypanothione Metabolism in Trypanosomatids,” Molecules, vol. 29, no. 10, p. 2214, 2024.

[26] D. Tadesse, A. Abdissa, M. Mekonnen, T. Belay, and A. Hailu, “Antibody and Cytokine Levels in Visceral Leishmaniasis Patients,” PLoS Negl. Trop. Dis., vol. 15, no. 8, p. e0009632, Aug. 2021.

[27] Sh. S. Khudhur and S. M. H. Alosami, “The Impact of rs767455 and rs1061622 Polymorphisms on Treatment Outcomes in Iraqi Ankylosing Spondylitis Patients,” Egypt. J. Hosp. Med., vol. 89, no. 2, pp. 3488–3494, Oct. 2022.

[28] D. Alhilali and S. I. Mohammed, “Genetic Polymorphisms at TNF-Alpha Receptors Associated with Autoimmune Diseases and Anti-TNF Biologic Response,” Iraqi J. Pharm. Sci., vol. 33, no. 4, pp. 49–58, 2024.