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Genetic and immunologic factors related to Congenital Zika Syndrome in humans

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Author(s):
Lucila Akune Barreiros
Total Authors: 1
Document type: Doctoral Thesis
Press: São Paulo.
Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
Defense date:
Examining board members:
Antonio Condino Neto; Carolina Sanchez Aranda Lago; Michel Satya Naslavsky; Maria Notomi Sato
Advisor: Antonio Condino Neto; Paulo Vítor Soeiro Pereira
Abstract

Zika virus is a flavivirus that re-emerged in the Americas in 2015 and has become an international public health problem. The increase in the prevalence of Zika infections in Brazil coincided with the increase in the occurrence of cases of microcephaly and other neurological complications in neonates, coining the Congenital Zika Syndrome. Despite the severity of certain cases, it is believed that only 20% of those infected children, manifest any symptoms of the disease, which presents with a broad clinical spectrum. Studies with animal models have shown that only strains with deficiencies in components of the type I interferon pathway are susceptible to congenital neurological damage. This, added to studies with dizygotic twins with discordant phenotypes for the syndrome, suggest that genetic factors of the host\'s innate immunity may play a decisive role in the course of the infection and the establishment of the syndrome. Therefore, the present study aimed to investigate the genetic mechanisms of the development of Congenital Zika Syndrome in humans, with special focus on the antiviral immune response. For this purpose, women infected by the virus during pregnancy and their children, with normal development or with Congenital Zika Syndrome, were included in the study. The genetic investigation started with the whole exome sequencing of 75 individuals, divided into two groups: one composed of 20 exposed mothers and 21 affected children and the second composed of 14 exposed mothers and 20 healthy children. Rare variants with prediction of pathogenicity by in silico tools in genes associated with inborn errors of immunity were selected for the primary analysis. Additionally, an exploratory analysis of the association of common and rare variants with the SCZ phenotype was performed, encompassing the whole exome. There was no evidence to pinpoint a causal mechanism, however variants were identified in genes that lead to syndromic phenotypes associated with neurological defects (KMT2A, KMT2D, RTEL1 and NFE2L2 ), genes that encode proteins that interact with components of antiviral immunity (RELA, TNFAIP3 ) and genes associated with the congenital syndrome phenotype that are preferentially expressed in the brain (CNTNAP3, FOXD4L6 ). All of these may be genetic modifying factors that contribute individually on a small scale to the worsening of the phenotype of affected individuals and may also indicate that this is not a single gene or mechanism leading to SCZ, but a multiplicity of factors that may contribute to the final outcome. (AU)

FAPESP's process: 18/09407-0 - Imunnogenetic basis of susceptibility to Zika Virus infection in humans
Grantee:Lucila Akune Barreiros
Support Opportunities: Scholarships in Brazil - Doctorate