AbstractBackgroundHost 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.MethodsWe accessed samples from Zika pregnancies, 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 newborn outcome and we characterized placenta gene expression profile at term.FindingsNewborns carrying CG/CC genotypes of rs2257167 inIFNAR1presented higher risk of developing CZS (OR=3.73; IC=1.36-10.21;Pcorrected=0.02646). No association betweenIFNLSNPs and CZS was observed. Placenta from CZS cases displayed lower levels ofIFNL2andISG15along with higherIFIT5.The rs2257167 CG/CC placentas also demonstrated high levels ofIFIT5and inflammation-related genes.InterpretationWe 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 theIFNAR1rs2257167 genotype. These 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.FundingThis work was supported by the Instituto Oswaldo Cruz (Rio de Janeiro, Brazil) and by the Instituto de Tecnologia em Imunobiológicos (Rio de Janeiro, Brazil).Research in contextEvidence before this studyLevels of type I and type III interferons are genetically controlled and decisively regulate outcome of spontaneous viral infections or response to antiviral treatment. Hepatitis C virus, Yellow Fever and Zika virus belong to the Flaviviridae family and elicit similar host immune responses. Congenital Zika Syndrome presents well-known risk factors, mainly the first trimester of pregnancy as well as social and nutritional factors, however, these do not entirely explain abnormal outcomes.Added value of this studyWe conducted a case-control study to evaluate SNPs in type I and III interferon genes using samples from newborns and mothers who had zika infection during pregnancy. We have shown that newborn interferon type I background contributes to the development of abnormal CSZ. This specific genetic makeup regulates placental immunological responses and prevents an exacerbated type I, and lack of type III, interferon response in syndromic cases.Implications of all the available evidenceOur study suggests an important factor regulating the host-pathogen interaction during Zika virus (ZIKV) infections in humans. During pregnancy, genetic variations play a role in balancing tissue-specific type I and III interferons during ZIKV congenital infection influencing fetal neurological damage. Custom pharmacological interventions could be used to modulate immunity and inflammation towards protective responses.Graphical abstract