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. 2021 Nov 25:12:764746.
doi: 10.3389/fimmu.2021.764746. eCollection 2021.

Congenital Zika Syndrome Is Associated With Interferon Alfa Receptor 1

Tamiris Azamor  1   2 , Daniela Prado Cunha  3 , Andréa Marques Vieira da Silva  2 , Ohanna Cavalcanti de Lima Bezerra  1 , Marcelo Ribeiro-Alves  4 , Thyago Leal Calvo  1 , Fernanda de Souza Gomes Kehdy  1 , Fernanda Saloum de Neves Manta  1 , Thiago Gomes de Toledo Pinto  1 , Laís Pereira Ferreira  1 , Elyzabeth Avvad Portari  3 , Letícia da Cunha Guida  3 , Leonardo Gomes  3 , Maria Elisabeth Lopes Moreira  3 , Elizeu Fagundes de Carvalho  5 , Cynthia Chester Cardoso  6 , Marcelo Muller  2 , Ana Paula Dinis Ano Bom  2 , Patrícia Cristina da Costa Neves  2 , Zilton Vasconcelos  3 , Milton Ozório Moraes  1
Affiliations

Congenital Zika Syndrome Is Associated With Interferon Alfa Receptor 1

Tamiris Azamor et al. Front Immunol. .

Abstract

Host factors that influence Congenital Zika Syndrome (CZS) outcome remain elusive. Interferons have been reported as the main antiviral factor in Zika and other flavivirus infections. Here, we accessed samples from 153 pregnant women (77 without and 76 with CZS) and 143 newborns (77 without and 66 with CZS) exposed to ZIKV conducted a case-control study to verify whether interferon alfa receptor 1 (IFNAR1) and interferon lambda 2 and 4 (IFNL2/4) single nucleotide polymorphisms (SNPs) contribute to CZS outcome, and characterized placenta gene expression profile at term. Newborns carrying CG/CC genotypes of rs2257167 in IFNAR1 presented higher risk of developing CZS (OR=3.41; IC=1.35-8.60; Pcorrected=0.032). No association between IFNL SNPs and CZS was observed. Placenta from CZS cases displayed lower levels of IFNL2 and ISG15 along with higher IFIT5. The rs2257167 CG/CC placentas also demonstrated high levels of IFIT5 and inflammation-related genes. We found CZS to be related with exacerbated type I IFN and insufficient type III IFN in placenta at term, forming an unbalanced response modulated by the IFNAR1 rs2257167 genotype. Despite of the low sample size se findings shed light on the host-pathogen interaction focusing on the genetically regulated type I/type III IFN axis that could lead to better management of Zika and other TORCH (Toxoplasma, Others, Rubella, Cytomegalovirus, Herpes) congenital infections.

Keywords: Congenital Zika Syndrome; placenta; rs2257167; type I interferon; type III interferon.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Event-based flowchart of CZS occurrence. The trimester of pregnancy in which first Zika symptoms occur and newborn genotypes of rs2257167 were used as independent variables to determine the association with CZS outcome. Total number of newborns with full information of both trimesters of infection and rs2257167 genotypes (n=125) was used to calculate the absolute number of newborns per group (n) and CZS percentage. Concerning infections in the first trimester of pregnancy, we found that irrespective of rs2257167 genotypes, 66% of the cases developed CZS, in contrast with second and third trimesters. Considering rs2257167, newborn CG/CC genotype seems to be associated with CZS risk in the second and third trimesters.
Figure 2
Figure 2
ZIKV infection leads to an immunological imbalance in placenta. Placental gene expression profile in healthy (N = 10) versus ZIKV-infected women (N = 74). Each dot corresponds to one placenta analyzed. The number of dots varies according to gene analyzed due to failed amplifications. Median and standard deviation of gene expression values are normalized by the housekeeping genes selected by the geNorm and NormFinder as well as 18S ribosomal RNA and RLP13 ribosomal protein L13 (grey boxes). Values are adjusted by mothers’ age (below or equal to/above 40 years of age) and trimester of infection (the trimester of pregnancy in which the first Zika symptoms occur or asymptomatic ZIKV infections). P-values ** ≤ 0.01, * ≤ 0.05 and ≤ 0.1.
Figure 3
Figure 3
Placental gene expression associated with CZS. Detailed graphs of differentially expressed genes in placenta without CZS (No CZS; N = 45) or with CZS (CZS; N = 29). Each dot corresponds to one placenta analyzed. The number of dots varies according to gene analyzed due to failed amplifications. Median and standard deviation of gene expression values are normalized by housekeeping genes selected by geNorm and NormFinder as well as 18S ribosomal RNA and RLP13 ribosomal protein L13 (grey boxes). Values are adjusted by mothers’ age (below or equal to/above 40 years of age) and infection trimester (trimester of pregnancy in which the first Zika symptoms occur or asymptomatic ZIKV infections). P-values ** ≤ 0.01, * ≤ 0.05, and ≤0.1.
Figure 4
Figure 4
Placental gene expression is modulated by newborn rs2257167 genotypes in ZIKV-infected pregnancy. Detailed graphs of differentially expressed genes in placenta from rs2257167 GG (N = 20) and CG/CC (N = 13) newborns. Each dot corresponds to one placenta analyzed. The number of dots varies according to gene analyzed due to failed amplifications. Median and standard deviation of gene expression values are normalized by housekeeping genes selected by geNorm and NormFinder as well as 18S ribosomal RNA and RLP13 ribosomal protein L13 (grey boxes). Values are adjusted by mothers’ age (below or equal to/above 40 years of age) and infection trimester (trimester of pregnancy in which first Zika symptoms or asymptomatic ZIKV infections occur) P-values**≤ 0.01, * ≤ 0.05, and ≤ 0.1.
Figure 5
Figure 5
Schematic representation of functional relation between Type I and III IFN in congenital ZIKV infections regarding CZS, showing that lower risk of developing CZS is related to higher levels of IFNL and balanced levels of Type-I IFN.
Figure 6
Figure 6
Schematic model showing the main findings of this study. The ZIKV infection during pregnancy faces placenta as an immunological barrier. In newborns with IFNAR1 rs2257167 CG/CC genotype the high levels of type I IFN and low type III IFN in placenta, culminating with CZS.
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