Avaliação da resposta imune materna contra alvos no cérebro fetal durante a origem de microcefalias derivadas da infecção pelo vírus zika

Abstract

During pregnancy, the mother's immune system undergoes several physiological changes that induce its tolerance to the cells of the embryo. As the embryo has half the genome of its father, the breach of tolerance can induce the production of maternal antibodies against fetal antigens. Among the variables that can induce the breakdown of tolerance are infections by pathogens. Congenital Zika virus (ZIKV) infection leads to malformation of the central nervous system (CNS) in most cases, which has been called congenital Zika virus syndrome (SCZ). In some cases, the patient is born without any clear sequelae and develops postnatal microcephaly, which suggests persistent inflammation of the CNS. Thus, in this project we tested the hypothesis that in addition to the direct damage caused by the viral infection, patients may experience a maternal autoimmune response. Here we show that mothers of children with SCZ have higher levels of antibodies against Engrailed1, a protein expressed by the developing hindbrain. The level of antibodies against Engrailed 1 correlates with the level of ZIKV antibody expression that each mother expresses. However, levels of antibodies against Engrailed 1 do not correlate with the occurrence of epilepsies or hindbrain malformations. We further tested whether serum from mothers of SCZ children reacts with slices of adult hippocampus or telencephalon from rodent embryos, a method employed to detect neural autoantibodies. Serum from these patients does not react against these tissues or even against organoid slices from human brains. Thus, this work suggests that ZIKV infection during pregnancy stimulates the production of maternal antibodies against a target expressed in the embryonic CNS. However, this production does not reflect on the severity of the case, which is probably more dependent on direct infection by the virus.