Co-factor Influences the Severity of Zika Virus-Associated Microcephaly

Abstract

Microcephaly has been regarded the most remarkable consequence of the Zika virus (ZIKV) epidemic in Brazil 2015. It remains to be determined whether there are factors that contribute to the degree of brain lesion associated with ZIKV infection during pregnancy. Previous studies showed that socioeconomic conditions correlate with ZIKV-associated microcephaly. Certain nutritional deficits display the potential to interfere in the mechanistic target of rapamycin (mTOR) signaling, which plays a major role in the pathophysiology of ZIKV-associated microcephaly. We hypothesize that a nutritional or environmental co-factor that interferes in mTOR signaling correlates with ZIKV-associated birth defects. To assess this hypothesis, we plan to: 1) develop a mouse model of ZIKV-associated microcephaly through intravenous injection of ZIKV and rapamycin for a straightforward interference on mTOR receptor; 2) determine in the experimental model and in cases of ZIKV-associated microcephaly the epigenetic signature (DNA methylation pattern) in neurons and muscle cells harvested by biopsy, and in hematopoietic and mesenchymal stem cells sorted from blood; 3) analyze through mass spectrometry in serum of pregnant female mice submitted to ZIKV and rapamycin injection and in serum of mothers of children with ZIKV-associated microcephaly the metabolomic pattern of cholesterol (a nutritional status marker), vitamin A and its metabolite retinoic acid, folate, and other metabolites related to these three nutritional factors; 4) check whether pregnant female mice submitted to intravenous injection of ZIKV and feed with a deficient diet of the most likely co-factor found in this study give birth to microcephalic mice with features that mimic clinical cases. In summary, our general objective is to develop an experimental model that mimics ZIKV-associated microcephaly cases and to find a co-factor involved in the microcephaly outbreak in Brazil 2015.