Maternal Immune Activation and Interleukin 17A in the Pathogenesis of Autistic Spectrum Disorder and Why It Matters in the COVID-19 Era

Abstract

Autism spectrum disorder (ASD) is the commonest neurodevelopmental disability. It is a highly complex disorder with an increasing prevalence and an unclear etiology. Consensus indicates that ASD arises as a genetically modulated, and environmentally influenced condition. Although pathogenic rare genetic variants are detected in around 20% of cases of ASD, no single factor is responsible for the vast majority of ASD cases or that explains their characteristic clinical heterogeneity. However, a growing body of evidence suggests that ASD susceptibility involves an interplay between genetic factors and environmental exposures. One such environmental exposure which has received significant attention in this regard is maternal immune activation (MIA) resulting from bacterial or viral infection during pregnancy. Reproducible rodent models of ASD are well-established whereby induction of MIA in pregnant dams, leads to offspring displaying neuroanatomical, functional, and behavioral changes analogous to those seen in ASD. Blockade of specific inflammatory cytokines such as interleukin-17A during gestation remediates many of these observed behavioral effects, suggesting a causative or contributory role. Here, we review the growing body of animal and human-based evidence indicating that interleukin-17A may mediate the observed effects of MIA on neurodevelopmental outcomes in the offspring. This is particularly important given the current corona virus disease-2019 (COVID-19) pandemic as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy is a potent stimulator of the maternal immune response, however the long-term effects of maternal SARS-CoV-2 infection on neurodevelopmental outcomes is unclear. This underscores the importance of monitoring neurodevelopmental outcomes in children exposed to SARS-CoV-2-induced MIA during gestation.

Maternal SARS-CoV-2 impacts fetal placental macrophage programs and placenta-derived microglial models of neurodevelopment

“…SARS-CoV-2 exposed HBC-iMGs exhibited reduced synaptosome phagocytosis, an assay that serves as a proxy for synaptic pruning. Notably, reduced synaptic pruning by microglia has been identified as a key mechanism in the pathogenesis of a range of neurodevelopmental disorders including autism [ 61 , 85 ], a neurodevelopmental disease associated with maternal immune activation and viral infection in pregnancy [ 63 , 86 , 87 ]. Thus, the altered resident tissue macrophage programs described here may not be specific to SARS-CoV-2 infection but may reflect more general alterations observed in viral infection in pregnancy.…”

Maternal SARS-CoV-2 impacts fetal placental macrophage programs and placenta-derived microglial models of neurodevelopment

“…SARS-CoV-2 exposed HBC-iMGs were more ameboid in shape and exhibited reduced synaptosome phagocytosis, an assay that serves as a proxy for synaptic pruning. Notably, reduced synaptic pruning by microglia has been identified as a key mechanism in the pathogenesis of autism (57, 83), a neurodevelopmental disease associated with maternal immune activation and viral infection in pregnancy (59, 84, 85). Considering the shared fetal origin between Hofbauer cells and brain microglia (20, 21), this work indicates Hofbauer cells’ potential to serve as a more accessible cell type at birth that could provide information about fetal brain immune programming, which in turn could alter neurodevelopmental trajectories after in utero exposure to maternal SARS-CoV-2 infection.…”

The Outcomes of Maternal Immune Activation Induced with the Viral Mimetic Poly I:C on Microglia in Exposed Rodent Offspring

“…In this review, we will focus on viral infections as immune response triggers because of the drastic increase in risk for neurodevelopmental disorders after a viral infection during pregnancy and considering the relevance to current conditions associated with COVID-19. COVID-19, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has potentially important yet still largely undefined impacts on neurodevelopment [11][12][13][14][15][16]. Additionally, we will describe the current knowledge on the roles of microglia following MIA induced with the viral mimetic polyinosinic-polycytidylic acid (poly I:C) in rodents.…”