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- EFFECTS OF PLACENTAL LISTERIA MONOCYTOGENES INFECTION ON FETAL NEURODEVELOPMENT
- Lee, Kun Ho
- Electronic Theses & Dissertations
Maternal infection can lead to adverse pregnancy outcomes. Numerous epidemiological studies have demonstrated an association between prenatal infection and neuropsychiatric disorders, including autism spectrum disorder (ASD). Different prenatal infections are associated with distinct neurological pathologies, necessitating studies of the diversity of prenatal pathogens and their consequences. Listeria monocytogenes (Lm) is a foodborne pathogen that causes listeriosis, which typically affects...
Show moreMaternal infection can lead to adverse pregnancy outcomes. Numerous epidemiological studies have demonstrated an association between prenatal infection and neuropsychiatric disorders, including autism spectrum disorder (ASD). Different prenatal infections are associated with distinct neurological pathologies, necessitating studies of the diversity of prenatal pathogens and their consequences. Listeria monocytogenes (Lm) is a foodborne pathogen that causes listeriosis, which typically affects immunocompromised individuals, including pregnant mothers. Prenatal infection with Lm can cause detrimental pregnancy outcomes, such as miscarriages, stillbirths, preterm labor, and death in newborns. However, neurological outcomes of maternal listeriosis have not been characterized. Here, I sought to investigate whether placental infection with Lm is associated with altered neurodevelopment by using a bioluminescence strain of Lm and a murine model of pregnancy-associated listeriosis. I show that placental infection affects neurodevelopment during pregnancy and behavior in the offspring.To investigate how placental infection with Lm dysregulates fetal brain development, I performed RNA-seq on fetal brains to quantify the enrichment of genes that were associated with the infection during gestation. The findings of RNA-seq analysis illustrated that placental infection with Lm altered fetal brain transcriptome and showed sexually dichotomous gene expression profiles. I further assessed the effects of different traits, including Lm exposure, the intensity of placental infection, and sex on the fetal transcriptome using systems biology. The genes were grouped into co-expression modules. Notably, maternal infection and its intensity measured by bioluminescence imaging signal were significantly associated with specific modules, suggesting these traits are the main factors driving these transcriptional changes. Lastly, I showed that placental Listeria infection enriched ASD-associated genes. These results demonstrate that maternal listeriosis dysregulates fetal brain transcriptome during gestation. Neurodevelopment is a complex process influenced by various environmental factors during pregnancy. To examine whether prenatal infection with Lm affects cortical lamination and neural activity, I performed hematoxylin and eosin staining and immunohistochemistry. Gross anatomy of the brain structure analysis showed that placental infection with Lm affected cortical lamination in a localized manner. Furthermore, increased neural activity was observed in Lm- exposed male offspring. These results illustrate that placental infection with Lm induces morphological changes in brain tissue during neurodevelopment. Behavioral symptoms of neuropsychiatric disorders are an important component of the diagnosis. Animal behavioral assays and tools have been developed to examine animal behavior such as social interactions, anxiety, and repetitive behaviors. I examined behavior tests that resembled ASD to determine if mouse offspring born following placental infection displayed abnormal behavior. Lm-exposed offspring exhibited altered behaviors and showed sex-dependent behavioral changes. Overall, my work highlights the impact of maternal listeriosis on brain development during pregnancy and its effects on offspring’s behavior and contributes to the understanding of the spectrum of fetal neurodevelopment.