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      Virus-Induced Maternal Immune Activation as an Environmental Factor in the Etiology of Autism and Schizophrenia

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          Abstract

          Maternal immune activation (MIA) is mediated by activation of inflammatory pathways resulting in increased levels of cytokines and chemokines that cross the placental and blood-brain barriers altering fetal neural development. Maternal viral infection is one of the most well-known causes for immune activation in pregnant women. MIA and immune abnormalities are key players in the etiology of developmental conditions such as autism, schizophrenia, ADHD, and depression. Experimental evidence implicating MIA in with different effects in the offspring is complex. For decades, scientists have relied on either MIA models or human epidemiological data or a combination of both. MIA models are generated using infection/pathogenic agents to induce an immunological reaction in rodents and monitor the effects. Human epidemiological studies investigate a link between maternal infection and/or high levels of cytokines in pregnant mothers and the likelihood of developing conditions. In this review, we discuss the importance of understanding the relationship between virus-mediated MIA and neurodevelopmental conditions, focusing on autism and schizophrenia. We further discuss the different methods of studying MIA and their limitations and focus on the different factors contributing to MIA heterogeneity.

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          Most cited references104

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          Host microbiota constantly control maturation and function of microglia in the CNS.

          As the tissue macrophages of the CNS, microglia are critically involved in diseases of the CNS. However, it remains unknown what controls their maturation and activation under homeostatic conditions. We observed substantial contributions of the host microbiota to microglia homeostasis, as germ-free (GF) mice displayed global defects in microglia with altered cell proportions and an immature phenotype, leading to impaired innate immune responses. Temporal eradication of host microbiota severely changed microglia properties. Limited microbiota complexity also resulted in defective microglia. In contrast, recolonization with a complex microbiota partially restored microglia features. We determined that short-chain fatty acids (SCFA), microbiota-derived bacterial fermentation products, regulated microglia homeostasis. Accordingly, mice deficient for the SCFA receptor FFAR2 mirrored microglia defects found under GF conditions. These findings suggest that host bacteria vitally regulate microglia maturation and function, whereas microglia impairment can be rectified to some extent by complex microbiota.
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            SARS-CoV-2: A Storm is Raging

            The pandemic coronavirus infectious disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is rapidly spreading across the globe. In this issue of the JCI, Chen and colleagues compared the clinical and immunological characteristics between moderate and severe COVID-19. The authors found that respiratory distress on admission is associated with unfavorable outcomes. Increased cytokine levels (IL-6, IL-10, and TNF-α), lymphopenia (in CD4+ and CD8+ T cells), and decreased IFN-γ expression in CD4+ T cells are associated with severe COVID-19. Overall, this study characterized the cytokine storm in severe COVID-19 and provides insights into immune therapeutics and vaccine design.
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              Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders.

              Neurodevelopmental disorders, including autism spectrum disorder (ASD), are defined by core behavioral impairments; however, subsets of individuals display a spectrum of gastrointestinal (GI) abnormalities. We demonstrate GI barrier defects and microbiota alterations in the maternal immune activation (MIA) mouse model that is known to display features of ASD. Oral treatment of MIA offspring with the human commensal Bacteroides fragilis corrects gut permeability, alters microbial composition, and ameliorates defects in communicative, stereotypic, anxiety-like and sensorimotor behaviors. MIA offspring display an altered serum metabolomic profile, and B. fragilis modulates levels of several metabolites. Treating naive mice with a metabolite that is increased by MIA and restored by B. fragilis causes certain behavioral abnormalities, suggesting that gut bacterial effects on the host metabolome impact behavior. Taken together, these findings support a gut-microbiome-brain connection in a mouse model of ASD and identify a potential probiotic therapy for GI and particular behavioral symptoms in human neurodevelopmental disorders. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Front Neurosci
                Front Neurosci
                Front. Neurosci.
                Frontiers in Neuroscience
                Frontiers Media S.A.
                1662-4548
                1662-453X
                12 April 2022
                2022
                12 April 2022
                : 16
                : 834058
                Affiliations
                [1] 1Department of Clinical Neurosciences, University of Cambridge , Cambridge, United Kingdom
                [2] 2Autism Research Centre, Department of Psychiatry, University of Cambridge , Cambridge, United Kingdom
                [3] 3Department of Basic and Clinical Neuroscience, King’s College London , London, United Kingdom
                Author notes

                Edited by: Yasir Ahmed Syed, Cardiff University, United Kingdom

                Reviewed by: Brian Kalish, University of Toronto, Canada; Stefano Sotgiu, University of Sassari, Italy

                *Correspondence: Aïcha Massarali, a.massrali@ 123456gmail.com

                This article was submitted to Neurodevelopment, a section of the journal Frontiers in Neuroscience

                Article
                10.3389/fnins.2022.834058
                9039720
                35495047
                fd688b2b-a1f4-45b6-980c-415b5d6e7e52
                Copyright © 2022 Massarali, Adhya, Srivastava, Baron-Cohen and Kotter.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 12 December 2021
                : 01 March 2022
                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 104, Pages: 8, Words: 6811
                Categories
                Neuroscience
                Mini Review

                Neurosciences
                autism spectrum conditions,autism,maternal immune activation (mia),sars-cov-2,schizophrenia,lps,poly(i:c)

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