Exploring the Genetic Predisposition to Zika Virus Congenital Syndrome

TO THE EDITOR—Santos et al [1] performed the first study to compare, in a case-control setting, the frequencies of specific single-nucleotide polymorphisms (SNPs) affecting the functionality of genes previously linked to proinflammatory response, exploring a possible genetic predisposition to develop microcephaly linked with congenital Zika syndrome. They genotyped SNPs on CD209, tumor necrosis factor (TNF) α, CXCL8, interleukin 6, CCL2, Toll-like receptor (TLR) 3, TLR4, and MHC class I polypeptide-related sequence B (MICB) in 70 mothers who had delivered infants with congenital Zika syndrome, their 71 infants (1 of the mothers had monozygotic twins with the syndrome), and healthy donors (44 mothers and their infants).

The TLR3 polymorphism in women was associated with increased risk of congenital Zika syndrome and the TNFα polymorphism carried by infants with Zika congenital syndrome was related to a more severe microcephaly. In this context it, could be expected that polymorphisms in TNFα would be somehow associated with microcephaly induced by Zika virus (ZIKV), because many studies have shown an inflammatory mechanism involved in fetal brain injury due to viral infection [2-4].

A 2017 study showed that neuronal cultures infected with ZIKV have increased levels or expression of TNF-α, interleukin 1β, glutamate, Glutamate ionotropic receptor NMDA type subunit 2B (GluN2B), and intracellular calcium ions, changes associated with neuronal cell death induced by neurotoxicity [5]. Other study with human brain tissue samples infected by ZIKV demonstrated that microglia activation on viral infection promotes neuroinflammation when associated with viral dissemination [6]. This would be a conceivable mechanism to provoke cell death in the neurons of the developing human brain, once microglial pathogen recognition through Toll-like receptors induces neurotoxicity through the release of cell death signals or activation of inflammasome components [7].

The link between TNFα polymorphisms and severe microcephaly proposed by Santos et al [1], however, is limited, in that this association was found not through case-control comparisons but only in the isolated subgroup of infants with microcephaly. Given that the authors did not find evidence that the gene polymorphism is linked to microcephaly induced by ZIKV)in the global case group of infants with congenital Zika syndrome, it is risky to propose an linkage between this genetic variation and severity microcephaly; the global findings regarding this association are negative.

Other studies have shown that is not an easy task to find genetic predisposition to such complex host-pathogen interactions [8]. Studies comparing controls and affected infants or their mothers have found no specific pathogenic variant associated or weak positive associations between specific SNPs and the adenylate cyclase pathway [9]. However, in a cell culture setting, neurospheres from an affected child, compared with a discordant twin, showed a signature of differential gene expression, especially in the mTOR and Wnt pathway regulators [8].

Taken together, these findings indicate that TNFα polymorphisms have still not been established to be involved in susceptibility to severe microcephaly induced by ZIKV infection, as proposed by Santos et al. To confirm their conclusions, we believe that serial case study methods would have to be applied to provide further to prove that TNFα polymorphisms are indeed a risk factor linked to the severity of microcephaly.

Notes

Acknowledgments. We thank Laura Durão Ferreira for her help with the editing of this text.

Financial support. This work was supported by Pró-Reitoria para Assuntos de Pesquisa e Pós-Graduação (PROPESQ), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (grant 440770/2016-5), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Departamento de Ciência e Tecnologia - Ministério da Saúde (DECIT-MS).

Potential conflicts of interest. Both authors: No reported conflicts. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.