Mild #SARS-CoV-2 #maternal #infection in mice induces transient offspring #neurodevelopmental aberrance

 

Significance

The rising global numbers of SARS-CoV-2 infections highlight the need to assess potential neurodevelopmental and psychiatric impact in children born to infected mothers. Human cohorts have provided conflicting conclusions, while mouse studies have focused on moderate-to-severe infection despite most infections in pregnant women being mild or asymptomatic. Our study shows that mild, respiratory tract–restricted SARS-CoV-2 infection in pregnant mice was sufficient to cause placental inflammation and transient changes in offspring brain gene expression, without altering gross brain structure or behavior under our experimental conditions. These findings suggest that soluble factors induced by maternal respiratory infection mediate placental inflammation and changes in offspring brain gene expression during the fetal and neonatal periods, which resolve in later childhood.

Abstract

Maternal viral infection during pregnancy has been identified as a risk factor for psychiatric disorders and neurodevelopmental abnormalities in offspring. With cumulative SARS-CoV-2 infections now numbering in the hundreds of millions globally, there is a need to evaluate the effects of maternal SARS-CoV-2 infection on offspring brain development and behavior. We developed a mouse model of mild COVID-19 during pregnancy in which SARS-CoV-2 infection is restricted to the respiratory tract. Infected mothers did not show weight loss or changes in litter size, but did exhibit detectable local and systemic immune responses, including placental inflammation. Characterization of the offspring’s cerebral cortex revealed transcriptomic changes in the fetus at E15 and on postnatal day 5 (P5), but no gross alterations in cytoarchitecture, synaptic density, or microglial abundance. We did not detect any significant changes in open-field or novel object recognition tests in P50 offspring born to SARS-CoV-2-infected dams. These findings suggest that mild maternal respiratory SARS-CoV-2 infection induces soluble factors that mediate placental inflammation and transient cerebral cortex alterations in offspring that resolve by later childhood.

Source: 

Link: https://www.pnas.org/doi/abs/10.1073/pnas.2518294123?af=R

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#Influenza A Virus #Infection Impairs #Neuronal Activity in Human iPSC-Derived NGN2 Neural Co-Cultures

 

Abstract

Influenza A virus (IAV) infection is associated with a wide variety of neurological complications, of which mild complications like impaired cognitive functioning are most prominent. Even though several studies have shown that many influenza viruses can enter the CNS, the neuropathogenesis of seasonal (H3N2 and H1N1) and pandemic (pH1N1 2009) IAV infections is poorly understood. Therefore, we aimed to investigate the cellular tropism, replication efficiency and associated functional consequences using a human stem cell-derived neural co-culture model of neurons and astrocytes. All viruses were able to infect neurons in the co-culture model, although this infection did not result in efficient replication and release of progeny virus. In addition, infection did not result in visible cell death or apoptosis. However, functional analyses revealed that IAV inoculation resulted in a reduction of spontaneous neural activity and a partial reduction of neural excitability. This study shows that seasonal and pandemic IAVs can disrupt neural homeostasis, without efficient virus replication or the induction of cell death. However, these functional changes in neural activity can contribute to cognitive problems during IAV infections in the acute and potentially post-acute phase of the infection.

Competing Interest Statement

The authors have declared no competing interest.

Funder Information Declared

ZonMw, The Dutch Organisation for knowledge and innovation in health, healthcare and well-being, https://ror.org/01yaj9a77, 91718308

The netherlands organisation for scientific research, OCENW.XS22.2.045, 024.003.001

Escmid, xx

European Union, 101084171

Source: BioRxIV, https://www.biorxiv.org/content/10.1101/2025.08.26.672266v1

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#COVID19-associated #neuroinflammation and #astrocyte death in the #brain linked to ORF3a-induced activation of Sur1-mediated ion channels

 

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic has disproportionately affected individuals with pre-existing medical conditions, such as neurocognitive disorders. Premorbid neurocognitive conditions compounded by COVID-19 can escalate into COVID-associated neurological complications, leading to severe illness or even death. As COVID-19 continues to persist and vaccines lose efficacy against emerging variants, individuals with neurocognitive disorders often experience prolonged symptoms that are further exacerbated by repeated breakthrough infections of highly diversified viral variants due to emergence of new viral mutations. Despite the significance of neurocognitive disorders as risk factors for COVID-19-related mortality and long COVID, the underlying causes remain largely unknown. In this study, we report a link between ORF3a expression and COVID-associated neuroinflammation and neurocytotoxicity in postmortem brain tissues from COVID-19 patients. These findings were further verified through neural cell-based in vitro and in vivo animal studies introducing ORF3a either alone or in the context of viral infection. As a membrane-associated protein, ORF3a induces upregulation of Sur1-regulated ion channels, resulting in intracellular Ca2+ influx, apoptosis, and necrosis through both NF-kB-dependent and independent proinflammatory responses in astrocytes. These findings reveal a novel clinical and mechanistic link between ORF3a and Sur1-regulated ion channels, which are highly responsive to neuroinflammatory conditions causing neurodegeneration. Additionally, we have identified a Food and Drug Administration-approved drug, glibenclamide, and a natural antiviral compound glycyrrhizin that effectively mitigates the neuropathological effects of ORF3a, underscoring the therapeutic potential and clinical significance of these findings.

Source: mBio, https://journals.asm.org/doi/full/10.1128/mbio.02012-25?af=R

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