In vitro functional study of interleukin IL-17a associated with maternal immune activation in human neurodevelopment and Autism

• Grant number: 24/10059-7
• Support Opportunities: Regular Research Grants
• Start date: August 01, 2025
• End date: July 31, 2028
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Andréa Laurato Sertié
• Grantee: Andréa Laurato Sertié
• Host Institution: Instituto Israelita de Ensino e Pesquisa Albert Einstein (IIEPAE). Sociedade Beneficente Israelita Brasileira Albert Einstein (SBIBAE). São Paulo , SP, Brazil
• Associated researchers: Amanda Braga de Figueiredo ; Caroline Lourenço Alves ; Fabio Papes ; Helder Takashi Imoto Nakaya ; Kenneth John Gollob ; Luciana Cavalheiro Marti ; Maria Rita dos Santos e Passos Bueno

Abstract

Autism Spectrum Disorder (ASD) is a heterogeneous group of neuropsychiatric conditions caused by genetic and environmental risk factors. The genetic etiology of ASD is complex, involving different genes and inheritance patterns, while the pathophysiological mechanisms remain only partially understood. Among the known environmental risk factors, maternal immune activation (MIA) has increasingly been recognized as a significant contributor to ASD in offspring. Animal models of MIA have shown that maternal infection during pregnancy triggers an increase in proinflammatory cytokines, which can cross the placental barrier and disrupt fetal brain development. One such cytokine, interleukin IL-17a, plays a pivotal role in mediating MIA-induced behavioral abnormalities that resemble those seen in ASD. However, the specific cell types most affected in the developing human brain and the downstream molecular pathways involved remain poorly characterized. Furthermore, it remains unclear whether the brain changes triggered by IL-17a are truly comparable to those observed in individuals with ASD. In this context, this project aims to provide a deeper understanding of the pathomechanisms underlying ASD and explore how IL-17a contributes to neurodevelopmental abnormalities associated with the disorder. To achieve this, we will use cortical organoids derived from induced pluripotent stem cells of neurotypical control individuals and individuals with ASD without cognitive impairment and macrocephaly as experimental models. These organoids, both with and without IL-17a treatment, will be extensively characterized using different approaches, including single-cell RNA sequencing. Additionally, we will develop and test a brain organoid model that includes microglia, aiming at determine whether this complementary model can provide further insights into the impact of neuroinflammation on brain development. This project holds significant potential to yield valuable information about the pathological mechanisms of ASD and open new avenues for understanding the role of neuroinflammation in the pathogenesis of ASD and other complex neurodevelopmental disorders. (AU)