Mycobacterium tuberculosis causes a leaky blood‐brain barrier and neuroinflammation in the prefrontal cortex and cerebellum regions of infected mice offspring

Abstract

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.

Stress, depression, and hippocampus: from biochemistry to electrophysiology

“…Preclinical models provide evidence that inflammatory factors influence the development of fetal neurotransmitter systems critical for behavioral regulation, including serotonergic (Hsueh et al 2017), dopaminergic (Bronson and Bale 2014;Luchicchi et al 2016), and glutamatergic (Rahman et al 2017) systems. In addition to directly affecting fetal brain development, exposure to inflammation in utero is thought to trigger an inflammatory process in the fetal brain (Manjeese et al 2021;Singh et al 2021), which can alter brain development through the activation of glial cells (Reus et al 2015), increased oxidative stress (Hassan et al 2016), and aberrant neuronal development.…”

Leukoencephalopathy due to inhalational and trans-conjunctival heroin abuse: First case report from Pakistan

“…Features particular to this case include presentation in a state of stupor with cerebral edema and supratentorial leukoencephalopathy after a single instance of sniffing, with a recent history of its administration via conjunctival route. Our patient also had a recent history of tuberculosis, which has been shown to increase the permeability of blood brain barrier [ 11 ]. The increased permeability might have played some role in augmenting the toxic effects of heroin on brain but the absence of ADA on CSF analysis and paucity of literature to support this argument makes it a questionable inference.…”