Maternal immune activation and role of placenta in the prenatal programming of neurodevelopmental disorders

Neuronal Signaling, Journal Year: 2023, Volume and Issue: 7(2)

Published: May 17, 2023

Maternal infection during pregnancy, leading to maternal immune activation (mIA) and cytokine release, increases the offspring risk of developing a variety neurodevelopmental disorders (NDDs), including schizophrenia. Animal models have provided evidence support these mechanistic links, with placental inflammatory responses dysregulation function implicated. This leads changes in fetal brain balance altered epigenetic regulation key pathways. The prenatal timing such mIA-evoked changes, accompanying developmental an

Language: Английский

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Role of microglia in brain development after viral infection

Frontiers in Cell and Developmental Biology, Journal Year: 2024, Volume and Issue: 12

Published: Jan. 16, 2024

Microglia are immune cells in the brain that originate from yolk sac and enter developing before birth. They play critical roles development by supporting neural precursor proliferation, synaptic pruning, circuit formation. However, microglia also vulnerable to environmental factors, such as infection stress may alter their phenotype function. Viral activates produce inflammatory cytokines anti-viral responses protect damage. excessive or prolonged microglial activation impairs leads long-term consequences autism spectrum disorder schizophrenia disorder. Moreover, certain viruses attack deploy them “Trojan horses” infiltrate brain. In this brief review, we describe function of during examine after through microglia-neural crosstalk. We identify limitations for current studies highlight future investigated questions.

Language: Английский

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Maternal SARS-CoV-2 impacts fetal placental macrophage programs and placenta-derived microglial models of neurodevelopment

Journal of Neuroinflammation, Journal Year: 2024, Volume and Issue: 21(1)

Published: June 25, 2024

Abstract Background The SARS-CoV-2 virus activates maternal and placental immune responses. Such activation in the setting of other infections during pregnancy is known to impact fetal brain development. effects on neurodevelopment are mediated at least part by microglia. However, microglia inaccessible for direct analysis, there no validated non-invasive surrogate models evaluate utero microglial priming function. We have previously demonstrated shared transcriptional programs between Hofbauer cells (HBCs, or macrophages) mouse models. Methods results assessed HBCs isolated from 24 term placentas ( N = 10 positive cases, 14 negative controls). Using single-cell RNA-sequencing, we that HBC subpopulations exhibit distinct cellular programs, with specific differentially impacted SARS-CoV-2. Assessment expressed genes implied impaired phagocytosis, a key function both microglia, some subclusters. Leveraging synaptic pruning, showed pregnancies can be transdifferentiated into microglia-like (HBC-iMGs), pruning behavior compared controls. Conclusion These findings suggest birth used create personalized offspring programming.

Language: Английский

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At the crux of maternal immune activation: Viruses, microglia, microbes, and IL‐17A

Immunological Reviews, Journal Year: 2022, Volume and Issue: 311(1), P. 205 - 223

Published: Aug. 18, 2022

Summary Inflammation during prenatal development can be detrimental to neurodevelopmental processes, increasing the risk of neuropsychiatric disorders. Prenatal exposure maternal viral infection pregnancy is a leading environmental factor for manifestation these Preclinical animal models immune activation (MIA), established investigate this link, have revealed common and microbial signaling pathways that link mother fetus set tone neurodevelopment. In particular, intestinal T helper 17 cells, educated by endogenous microbes, appear key drivers effector IL‐17A signals capable reaching fetal brain causing neuropathologies. Fetal microglial cells are particularly sensitive maternally derived inflammatory signals, they shift their functional phenotype in response MIA. Resulting cortical malformations miswired interneuron circuits cause aberrant offspring behaviors recapitulate core symptoms human Still, popular use “sterile” immunostimulants initiate MIA has limited translation clinic, as stimulants fail capture biologically relevant innate adaptive sequelae induced live pathogen infection. Thus, there need more translatable models, with focus on pathogens like seasonal influenza viruses.

Language: Английский

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Understanding the Potential Impact of Trimester-Specific Maternal Immune Activation due to SARS-CoV-2 on Early Human Neurodevelopment and the Role of Cytokine Balance

Brain Behavior & Immunity - Health, Journal Year: 2025, Volume and Issue: unknown, P. 100956 - 100956

Published: Jan. 1, 2025

Language: Английский

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Infections during pregnancy: An ongoing threat

Seminars in Perinatology, Journal Year: 2025, Volume and Issue: unknown, P. 152075 - 152075

Published: April 1, 2025

Language: Английский

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Characterization of human cytomegalovirus infection dynamics in human microglia

Journal of General Virology, Journal Year: 2025, Volume and Issue: 106(4)

Published: April 29, 2025

Human cytomegalovirus (HCMV) is a β-herpesvirus that establishes asymptomatic infections in immunocompetent individuals but can cause severe or even life-threatening symptoms immunocompromised patients. HCMV replicate wide variety of cells through the engagement diverse cell factors with viral envelope protein gH/gL/gO (trimer) gH/gL/UL128/UL130/UL131a (pentamer), allowing for systemic spread within human host. This study explores infection tropism and dynamics microglia, demonstrating susceptibility microglia to both clinical laboratory strains, albeit lower efficacy strain, implying gH/gL-trimer -pentamer mediate virus entry microglia. The importance gH/gL pentamer was demonstrated by inhibition upon pre-incubation soluble neuropilin-2 (NRP-2) factor. Further, we be effectively inhibited monoclonal antibodies specific complexes hyperimmunoglobulin. Lastly, report prevented newly characterized chemical inhibitors. Altogether, these findings underscore potential as valuable models studying neurotropism strategies block impact neurological disorders.

Language: Английский

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Interaction of the pre- and postnatal environment in the maternal immune activation model

Discover Mental Health, Journal Year: 2023, Volume and Issue: 3(1)

Published: Aug. 22, 2023

Adverse influences during pregnancy are associated with a range of unfavorable outcomes for the developing offspring. Maternal psychosocial stress, exposure to infections and nutritional imbalances known risk factors neurodevelopmental derangements according psychiatric neurological manifestations later in offspring life. In this context, maternal immune activation (MIA) model has been extensively used preclinical research study how stimulation system gestation derails tightly coordinated sequence fetal neurodevelopment. The ensuing consequence MIA brain structure function majorly manifested behavioral cognitive abnormalities, phenotypically presenting periods adolescence adulthood. These observations have interpreted within framework "double-hit-hypothesis" suggesting that an elevated disorders results from individual being subjected two adverse environmental at distinct life, jointly leading emergence pathology. early postnatal period, which caregiving parent is major determinant newborn´s environment, constitutes window vulnerability external stimuli. Considering not only affects fetus, but also impinges on mother´s brain, state heightened malleability pregnancy, impact behavior postpartum may importantly contribute detrimental consequences her progeny. Here we review current information interaction between prenatal environments modulation development their relevance pathophysiology model.

Language: Английский

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Congenital infectious encephalopathies from the intrapartum period to postnatal life

Seminars in Fetal and Neonatal Medicine, Journal Year: 2024, Volume and Issue: 29(1), P. 101526 - 101526

Published: Feb. 1, 2024

Language: Английский

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Influenza A virus during pregnancy disrupts maternal intestinal immunity and fetal cortical development in a dose- and time-dependent manner

Molecular Psychiatry, Journal Year: 2024, Volume and Issue: unknown

Published: July 3, 2024

Abstract Epidemiological studies link exposure to viral infection during pregnancy, including influenza A virus (IAV) infection, with increased incidence of neurodevelopmental disorders (NDDs) in offspring. Models maternal immune activation (MIA) using mimetics demonstrate that intestinal T helper 17 (T H 17) cells, which produce effector cytokine interleukin (IL)-17, leads aberrant fetal brain development, such as neocortical malformations. Fetal microglia and border-associated macrophages (BAMs) also serve potential cellular mediators MIA-induced cortical abnormalities. However, neither the inflammation-induced cell pathway nor brain-resident have been thoroughly examined models live pregnancy. Here, we inoculated pregnant mice two infectious doses IAV evaluated peak innate adaptive responses dam fetus. While respiratory led dose-dependent colonic shortening microbial dysregulation, there was no elevation cells IL-17. Systemically, resulted consistent dose- time-dependent increases IL-6 IFN-γ. abnormalities global changes transcripts were observable high-but not moderate-dose group. Profiling BAMs revealed differences numbers meningeal but choroid plexus BAMs, while microglial proliferative capacity Iba1 + remained constant. phagocytic CD68 expression, a fashion. Taken together, our findings indicate certain features MIA are conserved between mimetic models, others not. Overall, provide evidence an severity threshold for downstream inflammation abnormalities, recapitulates key feature epidemiological data further underscores importance pathogens NDD modeling better evaluate complete response improve translation clinic.

Language: Английский

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