Elsevier

Acta Tropica

Volume 211, November 2020, 105594
Acta Tropica

Genetic polymorphism in IL17RA induces susceptibility to Toxoplasma gondii infection in Brazilian pregnant women

https://doi.org/10.1016/j.actatropica.2020.105594Get rights and content

Highlights

  • The GG and AG genotypes were the most frequents in reactive pregnant women.

  • The rs2275913 polymorphism seems to modulate the expression of IL-17.

  • There is evidence of susceptibility to T. gondii infection driven by the rs4819554 (IL17RA) SNP G allele.

  • AA and A-allele patterns were associated with the absence of hypertension /abortion.

Abstract

Congenital toxoplasmosis is a parasitic disease caused by Toxoplasma gondii, an obligate intracellular parasite which can cause fetal death/abortion and can induce damage in the brain and eyes of the infected babies. The environmental and genetic factors associated with T. gondii and the maternal immune response, drive part of the pathogenesis of congenital toxoplasmosis. Thus, in this study, we aimed to investigate the allelic and genotypic frequencies of specific single nucleotide polymorphisms (SNPs) in the IL17A and IL17RA genes, as well as the production of IL-17A, IL-33, and CCL2 in pregnant women, from the State of Rio Grande do Norte, Brazil, further relating these along with the clinical parameters, to the toxoplasmosis infection. Through PCR-RFLP techniques, two SNPs implicated in Th17 immune response, IL17A rs2275913 (G> A) and IL17RA rs4819554 (A> G) modulation were evaluated in pregnant women, either infected or not infected by T. gondii. These women were also evaluated in terms of plasma release of CCL2, IL-33, and IL-17A which relate to hypertension, number of abortions, and ethnic pattern. The results showed that the G-allele of the SNP rs2275913 (IL17A) appeared to be protective in this population, while the rs4819554 (IL17RA) SNP G allele was associated with greater susceptibility to T. gondii infection [ρ value = 0.025; OR = 2.815 (1.118–7.089); CI = 95%]. None of the cytokines had any influence on the analyzed parameters (abortion and hypertension). In conclusion, our data suggest an immunogenic evidence of susceptibility to T. gondii infection driven by the rs4819554 (IL17RA) SNP G allele in Brazilian pregnant women. Further studies are needed to reinforce this trial marker in populations from distinct geographical areas as well as to confirm the protective pattern related to the G-allele of the SNP rs2275913 (IL17A) in pregnant women.

Introduction

Toxoplasma gondii is an intracellular parasite with tropism to the human placenta, eyes, and the central nervous system (Carruthers et al. 2007; Wohlfert et al., 2017). The disease, toxoplasmosis, when affecting immunocompetent individuals triggers nonspecific symptoms such as muscle pain, swollen lymph nodes, fever, and headache (Khan et al. 2006; Mendes et al. 2014; Silva et al. 2014), whereas in immunosuppressed individuals, it can be fatal (Liu et al. 2019; Van Bilsen et al. 2017).

The most severe clinical manifestation of T. gondii infection is congenital toxoplasmosis, which usually does not cause considerable damage to the pregnant mother, but it does to the fetus, in the short or long term, causing spontaneous abortion, stillbirth, hydrocephalus, macro or microcephalus, cerebral calcifications, retinochoroiditis, and ocular or central nervous system alterations (Gómez-Chávez et al. 2019; Olariu et al. 2011).

The induction of a panel of Th1-profile inflammatory mediators, such as IL-1, IFN-gamma, TNF, IL-6, IL-12, CCL2, CCL5, IL-17A and others, is defined as a key event to elicit the anti-T. gondii response (Neves et al. 2012; Dutra et al. 2013). Clinical manifestations can also be triggered by the host inflammatory response, such as the active ocular toxoplasmosis related to the decreased production of CCL-2 and increased levels of IL-17A and IL-33, respectively (Rey et al. 2013; Jones et al. 2010; Tong and Lu, 2015; Zhang et al. 2019). In addition, the genetic modification from the single nucleotide polymorphisms (SNPs) of inflammatory and regulatory cytokine genes have also been associated to the T. gondii susceptibility and its related pathogenesis (Wujcika et al. 2018).

Additionally, the diagnosis of a T. gondii infection in pregnant women can be confusing due to false positives when only immunoglobulins are detected to analyze the mother's immune response (Simon et al. 2020). We emphasize that in prenatal screenings, a false-positive IgG test result in a pregnant woman can lead to stopping preventive measures, leading to the risk of an acute infection during pregnancy. On the other hand, no immunologic or genetic marker exists to apply in a clinical trial of pregnant women in the potential risk of T. gondii infection. This marker would support clinicians in the management of pregnant women living in areas of high risk of toxoplasmosis and, consequently, minimize the consequences by increasing the surviving rate of the fetus and health of the baby.

Since the city of Santa Cruz, in the Rio Grande do Norte state in Brazil presents 66.2% of toxoplasmosis among all pregnant women (Freitas et al. 2017), the aim of this cross-sectional study was to investigate the allele and genotypic frequencies of the IL17A and IL17RA polymorphisms and the plasma markers (IL-17A, IL-33, and CCL2) in pregnant women infected with T. gondii, with a clinical record of abortion and hypertension, in the state of Rio Grande do Norte, Brazil.

Section snippets

Population, sample collection, and processing

A total of 204 pregnant women visiting the “Maternidade Escola Januário Cicco” in Natal, Rio Grande do Norte state, Brazil, between 2015 and 2017, were enrolled in the survey, with each providing written Informed Consent Term. The population sample in this study was classified according to their ethnic characteristics as white, black and "pardo". The Brazilian census categories have always included the term "pardo" or "parda" for the admixed population; miscegenation is a pattern in Brazilian

Results

In the studied population (204 women), 138 (67.64%) were positive to T. gondii infection. Of these, 26 (12.74%) were reactive only for IgM, of which 3 (1.47%) women had low avidity to IgG and 109 (53.43%) women had high avidity to IgG. The mean age of the reactive group of women was 30.5 ± 7.1 years, with a majority of them being “pardas” (term given to racial miscegenation; a pattern in Brazilian population), with no reports of symptoms related to T. gondii infection (Table 2).

We also

Discussion

This study allowed us to determine that the prevalence of human toxoplasmosis in pregnant women in the Northeast region of Brazil remained homogeneous over the last decade, in accordance with previous studies (Barbosa et al., 2009; Freitas et al. 2017). Besides, using a single nucleotide polymorphism (SNP), we pointed out a novelty with this study, showing that, for the SNP rs4819554 (IL17RA), the allele G (AG + GG) was more prevalent on the T. gondii reactive women, suggesting higher

Ethical approval

The samples used in this study, as well as the relevant information about the research subjects, were authorized for publication after approval by the Research Ethics Committee of the Federal University of Rio Grande do Norte, which occurred with the number 1314,667.

Authors’ contributions

JMAA and CBSO performed to the data analysis, immunogenic analyses and manuscript writing; YSRM conducted the data analysis, manuscript production and statistical analysis; JES and YGBA performed the phlebotomy and initial sample processing; PVS, DMSS, GPC and AT contributed to the immunological analysis, manuscript production and text review; GMP and JCOCF contributed to genetic analysis; VFAN responsible for conceptualization, funding acquisition, writing-review & editing, contributed to data

Funding

This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG), Universidade Federal do Rio Grande do Norte (UFRN) and Universidade Federal de Ouro Preto (UFOP), Brazil. VFAN (Process # 306,036/2019–3) and AT (Process # 305,634/2017–8) are CNPq Research Productivity Scholarship and GPC is a CNPq PDJ scholarship.

Credit author statement

Joelma Maria de Araujo Andrade and Claudio Bruno Silva de Oliveira: performed to the data analysis, immunogenic analyses and manuscript writing; Ywlliane da Silva Rodrigues Meurer: conducted the data analysis, manuscript production and statistical analysis; Jéssica Emanuella Santana and Yngrid Gleyter Barbosa de Almeida: performed the phlebotomy and initial sample processing; Priscilla Vilela dos Santos Débora Maria Soares de Souza Guilherme de Paula Costa and André Talvani: contributed to the

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

We are grateful to the Department of Pharmacology, Paulista School of Medicine, USP, the Laboratory of Immunobiology of Inflammation, DECBI/ICEB/UFOP and the Department of Clinical Analysis, School of Pharmacy/UFRN for all support during experimental procedures. We would like to thank Editage (www.editage.com) for English language editing. The authors would like to thank the Brazilian Research Support Agencies (CNPq, CAPES and FAPEMIG)

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