12- Novel Targets of SARS-CoV-2 Spike Protein in Human Fetal Brain Development Suggest Early Pregnancy Vulnerability

Primary Author

Mariah C. Antopia

Additional Author(s)

Parul Varma, Zane R. Lybrand, and Jenny Hsieh

Faculty Mentor

Jenny Hsieh

Additional Mentor(s)

Parul Varma

Abstract

A new global health concern, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions of people worldwide. Despite fast-tracked intensive research on various aspects of SARS-CoV-2, the impact of infection in pregnant mothers and their developing fetuses is relatively unexplored. Emerging studies of placenta, embryos, and cerebral organoids suggest vulnerability of fetal organs including the brain to coronavirus disease 2019. Additionally, a recent case study from Paris has reported transient neurological complications in neonates born to infected mothers. However, whether the fetal brain expresses cellular components that could lead to SARS-CoV-2 infection remains poorly understood. Spike protein (S) of coronaviruses is the primary protein involved in viral entry by facilitating fusion of virus and host cell membrane. A recent interactome analysis using mass spectrometry has identified 332 SARS-CoV-2 human protein-protein interactions. Out of the entire interactome, three proteins namely ZDHHC5, GOLGA7, and ATP1A1 showed specific interaction with the S protein of SARS-CoV-2. The purpose of this study is to analyze fetal brain expression of known S protein interactors (ACE2, TMPRSS2, and FURIN) and novel S protein interactors (ZDHHC5, ATP1A1, and GOLGA7) that we hypothesize could play a role in SARS-CoV-2 neuroinvasion during fetal brain development. Excel mining techniques were used to search and compile the genes of interest from publicly available fetal brain bulk RNA sequencing dataset (BrainSpan). Graphpad Prism was used to plot temporal patterns for the genes of interest and median values for each time point was compared to draw conclusions about the temporal expression pattern. Lastly, heatmaps were created for spatial expression of genes using R studio. Our analysis revealed that known S protein interactors ACE2 and TMPRSS2 have low levels of expression during fetal brain development, but FURIN is modestly expressed. Moreover, novel S protein interactors ZDHHC5, GOLGA7 and ATP1A1 are highly expressed throughout the fetal brain development with peaks of expression around the 2nd and 3rd trimester of pregnancy. Our study is the first comprehensive bioinformatic study exploring the expression of known and newly identified S protein interactors in the human fetal brain. It provides significant clues for further cellular and molecular analysis of these genes with potential for neuroinvasion of SARS-CoV-2 to disrupt fetal brain development.

Presentation

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