The maternal system’s exposure to pathogens during pregnancy influences fetal brain development causing a persistent inflammation characterized by elevated pro-inflammatory cytokine levels in offspring. Mycobacterium tuberculosis (Mtb) is a global pathogen that causes tuberculosis, a pandemic responsible for health and economic burdens. Although it is known that maternal infections increase the risk of autism spectrum disorder (ASD), it is not known whether Mtb infection is sufficient to induce ASD associated behaviors, immune dysregulation and altered expression of synaptic regulatory genes. The current study infected pregnant Balb/c mice with Mtb H37Rv and valproic acid (VPA) individually and in combination. Plasma cytokine profiles were measured in offspring using the Bio-plex Th17 pro mouse cytokine panel. Mtb infection increased plasma interleukin (IL)-6 and IL-17A, while tumor necrosis factor alpha (TNF-α), interferon (IFN)-γ and IL-1β were reduced when compared with saline. Mtb-induced maternal immune activation (MIA) offspring displayed increased grooming behavior. The study also revealed dysregulation in gene expression of synaptic molecules in the cerebellum. MIA rescued the VPA-induced effects on self-grooming and social interaction behaviors. Our finding therefore highlights a potential role of Mtb as a MIA agent that can potentially contribute to ASD.
The maternal system's exposure to pathogens influences foetal brain development through the influx of maternal cytokines and activation of the foetal immune status to a persistent inflammatory state characterised by glia cell activation. Neuroinflammation influences the blood‐brain barrier's (BBB) permeability allowing peripheral immune cell trafficking into the brain. Mycobacterium tuberculosis (Mtb) is a pathogen that causes Tuberculosis (TB), a global pandemic responsible for health and economic burdens. Although it is known that maternal infections increase the risk of Autism spectrum disorder (ASD), it is not known whether gestational Mtb infections also contribute to impaired foetal neurodevelopment. Here we infect pregnant Balb/c mice with Mtb H37Rv and Valproic acid (VPA) individually and in combination. Neuroinflammation was measured by assessing microglia and astrocyte population in the prefrontal cortex (PFC) and cerebellum (CER) of pups. Mtb infection increased the microglia population and caused morphological changes to a reactive phenotype in the PFC. Also, the astrocyte population was significantly increased in the PFC of Mtb pups. The BBB permeability was determined by measuring the Evans Blue (EB) dye concentration in the PFC and CER 1 hr post receiving intravenous EB‐dye injection. We found that prenatal Mtb exposure significantly increased the BBB's permeability in the PFC and CER of pups versus saline. Overall, our data demonstrate that prenatal exposure to Mtb predisposes offspring to a higher risk of BBB damage while inducing persistent neuroinflammation, which could lead to impaired neuronal development and function. These findings implicate a potential role of gestational Mtb infections in the aetiology of ASD.
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