Prevalence of Toxoplasma gondii During Pregnancy and the Function of the IL6-174 G>C Mutation
Abstract
Toxoplasma gondii is an intracellular parasite that leads to congenital toxoplasmosis and to neuro-ocular sequelae in newborns, some of which are severe, stillbirth and miscarriage. Polymorphisms in cytokine genes is one factor of the host genome that might be involved in the susceptibility to infection during prenatal period. In this study, the susceptibility of pregnant women to Toxoplasma gondii infection was investigated in relation to IL6 174 G>C (rs1800795) polymorphism.
Methods: The Women's and Children's Hospital in Babylon, Iraq, undertook a case control study from November 2024 to February 2024. Fifty pregnant women were included in the study; 20 of them were cases with proven T. gondii infection (anti IgG positive) and 30 were healthy controls who tested negative for the parasite. Allele Specific PCR for the IL6 174 G>C polymorphism was used for genotyping. A computerised VIDAS Toxo IgG II (ELFA) developed by bioMérieux in France was used to screen the sera for anti-T. gondii IgG antibodies. Logistic regression was used for estimation of odds ratio (OR) under the codominant, dominant and recessive genetic model, and Fisher's exact test was used to compare the frequencies of geno/alleles.
Results: In the cases, the GC heterozygote was significantly more common (50%) than in the controls (16.7%). There was a significant in the overall genotype distribution between the two groups (Fisher's exact test; P = 0.041). Under the codominant model, with GG as the reference, logistic regression analysis showed association of the GC genotype with an increased risk of infection (OR = 5.667, 95% CI: 1.369–23.462, P = 0.017). The model with overdominant high risk for heterozygotes (GC vs. GG+CC) was confirmed with strong and statistically significant increased risk (OR = 5.000, 95% CI: 1.363–18.348, P = 0.015). There was no significant found between the CC homozygote (OR = 1.417, P = 0.653). The control group was not in Hardy Weinberg equilibrium (χ² = 12.05, df = 1, P < 0.001), which was due to the small sample size.
Conclusion: The IL6 174 G>C polymorphism and specially the heterozygote GC is more susceptible to the Toxoplasma gondii during pregnancy. This could be due to an over-dominant effect, in which one copy of the C allele changes the regulation of interleukin 6, which could upset the Th1/Th2 balance that is necessary for parasite control and foetal immune tolerance. Prior to clinical translation, bigger multicenter prospective trials with direct measurement of blood IL 6 levels are necessary to assess the polymorphism's potential as a genetic marker for risk stratification in prenatal treatment.
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References
Rabaan AA, Uzairue LI, Alfaraj AH, et al. Seroprevalence, Risk Factors and Maternal-Fetal Outcomes of Toxoplasma gondii in Pregnant Women from WHO Eastern Mediterranean Region: Systematic Review and Meta-Analysis. Pathogens. 2023;12(9):1157.
Al-Saud NS, Al-Jaser MH, Al-Shammari MB, et al. The Prevalence of Toxoplasma gondii in Saudi Arabia (1994–2023): A Systematic Review and Meta-Analysis. J Epidemiol Glob Health. 2024;14(4):1413 1452.
Sarkar M, Anuradha B, Sharma N, Roy R. Seropositivity of Toxoplasmosis in antenatal women with bad obstetric history in a tertiary-care Hospital of Andhra Pradesh, India. J Health Popul Nutr. 2012;30(1):87–92.
Al-Hamdani M, Mahdi N. Toxoplasmosis among women with habitual abortion. East Mediterr Health J. 1996;3(2):310–315.
Montoya JG. Laboratory diagnosis of Toxoplasma gondii infection and toxoplasmosis. J Infect Dis. 2002;185(Suppl 1):S73–S82.
Jin S, Chang ZY, Ming X. Fast dipstick dye immunoassay for detection of immunoglobulin G (IgG) and IgM antibodies of human toxoplasmosis. Clin Diagn Lab Immunol. 2005;12:198–201.
Brown K, Blader I. The role of DNA microarrays in Toxoplasma gondii research, the causative agent of ocular toxoplasmosis. J Ocul Biol Dis Infor. 2009;2(4):214–222.
Ebadi P, Solhjoo K, Bagheri K, Eftekhar F. Seroprevalence of toxoplasmosis among the women with recurrent spontaneous abortion in comparison with the women with uncomplicated delivery. J Jahrom Univ Med Sci. 2011;9:1.
Sher A, Denkers E, Gazzinelli R. Induction and regulation of host cell-mediated immunity by Toxoplasma gondii. Ciba Found Symp. 1995;195:95–104.
Del Rio L, Bennouna S, Salinas J, Denkers E. CXCR2 deficiency confers impaired neutrophil recruitment and increased susceptibility during Toxoplasma gondii infection. J Immunol. 2001;167:6503–6509.
Khan A, Murphy P, Casciotti L, et al. Mice lacking the chemokine receptor CCRl show increased susceptibility to Toxoplasma gondii infection. J Immunol. 2001;166:1930–1937.
Bennouna S, Bliss S, Curiel T, Denkers E. Cross-talk in the innate immune system: neutrophils instruct recruitment and activation of dendritic cells during microbial infection. J Immunol. 2003;171:6052–6058.
Aliberti J, Valenzuela J, Carruthers V, et al. Molecular mimicry of a CCR5 binding-domain in the microbial activation of dendritic cells. Nat Immunol. 2003;4:485–490.
Ocana-Morgner C, Mota M, Rodriguez A. Malaria blood stage suppression of liver stage immunity by dendritic cells. J Exp Med. 2003;197:143–151.
Yap G, Pesin M, Sher A. Cutting edge: IL-12 is required for the maintenance of IFN-γ production in T cells mediating chronic resistance to the intracellular pathogen, Toxoplasma gondii. J Immunol. 2000;165:628–631.
Entrican G. Immune regulation during pregnancy and host–pathogen interactions in infectious abortion. J Comp Pathol. 2002;126:79–94.
Wegmann TG. Foetal protection against abortion: is it immunosuppression or immunostimulation? Ann Immunol (Paris). 1984;135D:309–312.
Wegmann TG, Lin H, Guilbert L, Mosmann TR. Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a Th2 phenomenon? Immunol Today. 1993;14(7):353–356.
Mor G. Pregnancy reconceived. Nat Hist. 2007;116:36–41.
Mor G, Koga K. Macrophages and pregnancy. Reprod Sci. 2008;15:435–436.
Barbosa BF, Silva DA, Costa IN, Mineo JR, Ferro EA. BeWo trophoblast cell susceptibility to Toxoplasma gondii is increased by interferon-gamma, interleukin-10 and transforming growth factor-beta1. Clin Exp Immunol. 2008;151(3):536–545.
Das H, Koizumi T, Sugimoto T, et al. Quantitation of Fas and Fas ligand gene expression in human ovarian, cervical and endometrial carcinoma using real-time quantitative RT-PCR. Br J Cancer. 2000;82:1682–1688.
Shiono Y, Mun HS, He N, et al. Maternal-foetal transmission of Toxoplasma gondii in IFN-γ deficient pregnant mice. Parasitol Int. 2007;56:141–148.
Clark DA, Chaouat G, Wong K, Gorczynski RM, Kinsky R. Tolerance mechanisms in pregnancy: a reappraisal of the role of Class I paternal MHC antigens. Am J Reprod Immunol. 2010;63:93-103.
Bidwell J, Keen L, Gallagher G, et al. Cytokine gene polymorphism in human disease: online databases. Genes Immun. 2001;1:3-19.
Bobe P, Kannellopoulus-Langevin C, Bleux C, Voison GA. Modulation of mouse anti-SRBC antibody response by placental extracts II. Antigen specificity and regulatory role of B and T cell populations affected by two distinct placental fractions. J Immunol. 1986;136:574-581.
Saini V, Arora S, Yadav A, Bhattacharjee J. Cytokines in recurrent pregnancy loss. Clin Chim Acta. 2011;412:702-708.
Bansal AS. Joining the immunological dots in recurrent miscarriage. Am J Reprod Immunol. 2010;64:307-315.
Suzuki T, Higgins P, Crawford D. Control selection for RNA quantitation. Biotechniques. 2000;29:332–337.
De Paschale M, Agrappi C, Belvisi L. Revision of the positive predictive value of IgM anti-Toxoplasma antibodies as an index of recent infection. New Microbiol. 2008;31:105–111.
Raghupathy R. Pregnancy: success and failure within the Th1/Th2/Th3 paradigm. Semin Immunol. 2001;13:219-228.
Daher S, Shulzhenko N, Morgun A, et al. Associations between cytokine gene polymorphisms and recurrent pregnancy loss. J Reprod Immunol. 2003;58:69-77.
Deng H, Devleesschauwer B. Seroprevalence of Toxoplasma gondii in pregnant women and livestock in the mainland of China: a systematic review and hierarchical meta-analysis. Sci Rep. 2020;8(1):6218.
Giakoumelou S, Wheelhouse N, Cuschieri K, et al. The role of infection in miscarriage. Hum Reprod Update. 2016;22(1):116–33. PMID: 26386469
Nayeri T, Sarvi S, Moosazadeh M, et al. The global seroprevalence of anti-Toxoplasma gondii antibodies in women who had spontaneous abortion: A systematic review and meta-analysis. PLoS Negl Trop Dis. 2020;14(3):e0008103.
Megli CJ, Coyne CB. Infections at the maternal-fetal interface: an overview of pathogenesis and defence. Nat Rev Microbiol. 2022;20(2):67–82.
Liu Q, Wang ZD, Huang SY, Zhu XQ. Diagnosis of toxoplasmosis and typing of Toxoplasma gondii. Parasit Vectors. 2015;8:292. DOI: 10.1186/s13071-015-0902-6
Pereira KS, Franco RM, Leal DA. Transmission of toxoplasmosis (Toxoplasma gondii) by foods. Adv Food Nutr Res. 2010;60:1–19.
Dubey JP, Jones JL. Toxoplasma gondii infection in humans and animals in the United States. Int J Parasitol. 2008;38(11):1257–78.
Matin S, Shahbazi G, Namin ST, et al. Comparison of Placenta PCR and Maternal Serology of Aborted Women for Detection of Toxoplasma gondii in Ardabil, Iran. Korean J Parasitol. 2017;55(6):607–11.
Kieffer F, Wallon M. Congenital toxoplasmosis. Handb Clin Neurol. 2013;112:1099–101.
McAuley JB. Congenital Toxoplasmosis. J Pediatric Infect Dis Soc. 2014;3 Suppl 1(Suppl 1):S30–5.
Foroutan-Rad M, Khademvatan S, Majidiani H, et al. Seroprevalence of Toxoplasma gondii in the Iranian pregnant women: A systematic review and meta-analysis. Acta Trop. 2016;158:160–9.
Nowakowska D, Stray-Pedersen B, Spiewak E, et al. Prevalence and estimated incidence of Toxoplasma infection among pregnant women in Poland: a decreasing trend in the younger population. Clin Microbiol Infect. 2006;12(9):913–7.
Saki J, Mohammadpour N, Moramezi F, Khademvatan S. Seroprevalence of Toxoplasma gondii in women who have aborted in comparison with the women with normal delivery in Ahvaz, southwest of Iran. Scientific World Journal. 2015;2015:764369.
Abdul-Ghani R. Polymerase chain reaction in the diagnosis of congenital toxoplasmosis: more than two decades of development and evaluation. Parasitol Res. 2011;108(3):505–12.
Robert-Gangneux F, Darde ML. Epidemiology of and diagnostic strategies for toxoplasmosis. Clin Microbiol Rev. 2012;25(2):264–96.
Chaichan P, Mercier A, Galal L, et al. Geographical distribution of Toxoplasma gondii genotypes in Asia: A link with neighboring continents. Infect Genet Evol. 2017;53:227–38.
Rico-Torres CP, Vargas-Villavicencio JA, Correa D. Is Toxoplasma gondii type related to clinical outcome in human congenital infection? Systematic and critical review. Eur J Clin Microbiol Infect Dis. 2016;35(7):1079–88.
Rahimi Esboei B, Kazemi B, Zarei M, et al. Evaluation of RE and B1 Genes as Targets for Detection of Toxoplasma gondii by Nested PCR in Blood Samples of Patients with Ocular Toxoplasmosis. Acta Parasitol. 2019;64(2):384–9.
Eshratkhah Mohammadnejad A, Eslami G, Shamsi F, et al. Prevalence of food-borne Toxoplasma in pregnant women population of Urmia, Iran. J Food Qual Hazards Control. 2018;5(1):17–23.
Marshall ES, Elsheikha HM, Hakimi MA, Flynn RJ. Toxoplasma gondii peroxiredoxin promotes altered macrophage function, caspase-1-dependent IL-1beta secretion enhances parasite replication. Vet Res. 2011;42:80.
Prada J, Liekfeld A, Bergmann F, Grobusch MP. Expression of interleukin-6, tumour necrosis factor-alpha and nitric oxides during episodes of ocular toxoplasmosis in an HIV patient. Acta Ophthalmol Scand. 2007;85(8):911–913.
Matowicka-Karna J, Dymicka-Piekarska V, Kemona H. Does Toxoplasma gondii infection affect the levels of IgE and cytokines (IL-5, IL-6, IL-10, IL-12, and TNF-alpha)? Clin Dev Immunol. 2009;2009:37469.
Wujcicka W, Wilczyński J, Nowakowska D. Contribution of IL6 −174 G>C and IL1B +3954 C>T polymorphisms to congenital infection with Toxoplasma gondii. Eur J Clin Microbiol Infect Dis. 2015;34(12):2287 2294.
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