Variations in maternal adenylate cyclase genes are associated with congenital Zika syndrome in a cohort from Northeast, Brazil

Rossi, Átila Duque; Faucz, Fábio R.; Melo, Adriana; Pezzuto, Paula; Azevedo, Girlene S.; Schamber-Reis, Bruno Luiz Fonseca; Tavares, Jousilene de Sales; Mattapallil, Joseph J.; Tanuri, Amílcar; Aguiar, Renato Santana; Cardoso, Cynthia Chester; Stratakis, Constantine A.

doi:10.1111/joim.12829

Cited by 17 publications

(13 citation statements)

References 48 publications

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“…Genetic variation in the human population contributes to disease progression for WNV (Bigham et al, 2011; Rios et al, 2010), DENV (Pabalan et al, 2017; Xavier-Carvalho et al, 2017), and ZIKV (Rossi et al, 2018). WNV causes symptoms in only 20% of infected individuals, (Hadler et al, 2014), with two-thirds of those cases becoming neuroinvasive (Centers for Disease Control and Prevention, 2018), DENV manifests in approximately 25% of individuals (Bhatt et al, 2013), and ZIKV is symptomatic in 18% of individuals (Duffy et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Insulin Potentiates JAK/STAT Signaling to Broadly Inhibit Flavivirus Replication in Insect Vectors

et al. 2019

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Section: Introductionmentioning

confidence: 99%

Insulin Potentiates JAK/STAT Signaling to Broadly Inhibit Flavivirus Replication in Insect Vectors

et al. 2019

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“…Host genetics is a rather new approach in congenital virology and, especially during the recent ZIKV epidemics in Brazil, host genetic factors were identified. A case-control study of a Brazilian cohort identified a statistically significant association of maternal adenylate cyclase genes with the development of CZS [85]. Comparable to the identification of the TLR2 2258 G>A SNP, the T allele in SNP rs3775291 of the TLR3 gene is associated with a risk of CZS [86].…”

Section: The Advent Of Induced Pluripotent Stem Cells and The Associamentioning

confidence: 99%

Pluripotent Stem Cell-Based Models: A Peephole into Virus Infections during Early Pregnancy

Claus

Jung

Hübschen

2020

Cells

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The rubella virus (RV) was the first virus shown to be teratogenic in humans. The wealth of data on the clinical symptoms associated with congenital rubella syndrome is in stark contrast to an incomplete understanding of the forces leading to the teratogenic alterations in humans. This applies not only to RV, but also to congenital viral infections in general and includes (1) the mode of vertical transmission, even at early gestation, (2) the possible involvement of inflammation as a consequence of an activated innate immune response, and (3) the underlying molecular and cellular alterations. With the progress made in the development of pluripotent stem cell-based models including organoids and embryoids, it is now possible to assess congenital virus infections on a mechanistic level. Moreover, antiviral treatment options can be validated, and newly emerging viruses with a potential impact on human embryonal development, such as that recently reflected by the Zika virus (ZIKV), can be characterized. Here, we discuss human cytomegalovirus (HCMV) and ZIKV in comparison to RV as viruses with well-known congenital pathologies and highlight their analysis on current models for the early phase of human development. This includes the implications of their genetic variability and, as such, virus strain-specific properties for their use as archetype models for congenital virus infections. In this review, we will discuss the use of induced pluripotent stem cells (iPSC) and derived organoid systems for the study of congenital virus infections with a focus on their prominent aetiologies, HCMV, ZIKV, and RV. Their assessment on these models will provide valuable information on how human development is impaired by virus infections; it will also add new insights into the normal progression of human development through the analysis of developmental pathways in the context of virus-induced alterations. These are exciting perspectives for both developmental biology and congenital virology.

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“…both genes are part of key pathways in programming neural embryology (Caires-Junior et al 2018). Case-control studies have shown the influence of maternal adenocyclase (ADCY) SNVs (Rossi et al 2019) and of TOL3 (maternal)/TNFα (infants) SNVs ) in susceptibility of CZS and/or microcephaly. In turn, Azamor et al (2018) indicated that a Type III interferon maternal SNV promotes protection against the development of CZS.…”

Section: Introductionmentioning

confidence: 99%

Hypothetical Human Immune Genome Complex Gradient May Help to Explain the Congenital Zika Symdrome Catastrophe in Brazil: A New Theory

Oliveira

Bresani-Salvi

Morais

et al. 2020

Preprint

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There are few data considering human genetics as an important risk factor for birth abnormalities related to ZIKV infection during pregnancy, even though sub-Saharan African populations are apparently more resistant to CZS as compared to populations in the Americas.We hypothesized that single nucleotide variants (SNVs), especially in innate immune genes, could make some populations more susceptible to Zika congenital complications than others.Differences in the SNV frequencies among continental populations provide great potential for Machine Learning techniques. We explored a key immune genomic gradient between individuals from Africa, Asia and Latin America, working with complex signatures, using 297SNVs. We employed a two-step approach. In the first step, decision trees (DTs) were used to extract the most discriminating SNVs among populations. In the second step, machine learning algorithms were used to evaluate the quality of the SNV pool identified in step one for discriminating between individuals from sub-Saharan African and Latin-American populations.Our results suggest that 10 SNVs from 10 genes (CLEC4M, CD58, OAS2, CD80, VEPH1, CTLA4, CD274, CD209, PLAAT4, CREB3L1) were able to discriminate sub-Saharan Africans from Latin American populations using only immune genome data, with an accuracy close to 100%.Moreover, we found that these SNVs form a genome gradient across the three main continental populations. These SNVs are important elements of the innate immune system and in the response against viruses. Our data support the Human Immune Genome Complex Gradient hypothesis as a new theory that may help to explain the CZS catastrophe in Brazil.

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Variations in maternal adenylate cyclase genes are associated with congenital Zika syndrome in a cohort from Northeast, Brazil

Abstract: These results suggest that maternal ADCY genes contribute to ZIKV pathogenicity and influence the outcome of CZS, being promising candidates for further replication studies and functional analysis.

Cited by 17 publications

References 48 publications

Insulin Potentiates JAK/STAT Signaling to Broadly Inhibit Flavivirus Replication in Insect Vectors

Insulin Potentiates JAK/STAT Signaling to Broadly Inhibit Flavivirus Replication in Insect Vectors

Pluripotent Stem Cell-Based Models: A Peephole into Virus Infections during Early Pregnancy

Hypothetical Human Immune Genome Complex Gradient May Help to Explain the Congenital Zika Symdrome Catastrophe in Brazil: A New Theory

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