Bacterial immunomodulatory structures as determinants of the maternal immune response and autism risk

Autism is a group of neurodevelopmental conditions that have shown increasing prevalence over the last several decades. Despite being largely idiopathic in origin, numerous genetic and environmental risk factors have been identified. One of the leading environmental risk factors for autism is maternal immune activation (MIA) following infection. The impact of bacterial infection on MIA and neurodevelopmental outcomes has been widely studied though the specific causal underpinnings that directly influence autism risk remains elusive. In preclinical research, bacterial-derived lipopolysaccharide (LPS) is most often used to model bacterial infection and drive immune responses and autism-like outcomes. However, pathogenic structural determinants of the specific MIA response are rarely considered. Male and female fetuses also have distinct immune responses to MIA, which have been linked to sex-specific alterations in mitochondrial dysfunction and placental barrier disruption resulting in distinct behavioural characteristics. This review will discuss the known clinical and preclinical research on the impact of infection on MIA and neurodevelopmental outcomes, emphasizing the key role of bacterial structural factors. Here, we put forth that it is not only the severity, timing, and physical location of a bacterial infection that is important. Rather it is more nuanced, involving variations in key pathogenic immunostimulatory structures that, in turn, lead to a diversity of immune response phenotypes in both the mother and offspring, and distinct alterations in placental barrier integrity.