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https://hdl.handle.net/2142/132825
Description
Title
Influenza A virus infection during pregnancy disrupts fetal brain macrophages and neocortical development in a dose-dependent manner
Author(s)
Otero, Ashley
Connolly, Meghan
Gonzalez-Ricon, Rafael Jaime
Chalen, Izan
Antonson, Adrienne
Issue Date
2024-10-07
Keyword(s)
maternal immune activation
Date of Ingest
2026-02-22T17:06:42-06:00
Abstract
Yolk-sac-derived brain-resident macrophages–microglia and border-associated macrophages (BAMs)–are among the first cells to migrate to the brain and are present at the onset of neurogenesis, placing them at the center of early neuronal support. During fetal brain development, microglia stimulate cortical neural precursor cell (NPC) proliferation and migration and subsequent phagocytosis of excess NPCs in the cortex. Disruption of these microglial-dependent processes has been observed in rodent models that initiate maternal immune activation (MIA) with sterile immunostimulants, and several of these studies directly implicate microglia in MIA-mediated cortical pathologies. Less is known about BAMs, which do not infiltrate the brain parenchyma but rather reside in peripheral regions where they carry out constant immune surveillance. To date, no study has examined how gestational influenza A virus (IAV) infection, which is linked with increased incidence of neurodevelopmental disorders in human offspring, impacts embryonic brain-resident macrophages. We hypothesize that systemic inflammation from live IAV infection during pregnancy redirects fetal brain-resident macrophages from their normal neurotrophic support roles, resulting in altered cortical development. To test our hypothesis, we inoculated pregnant C57BL/6NTac mice on gestational day (GD)9.5 with H3N2 IAV strain X31. Maternal serum, lungs, and fetal brains were collected on GD16.5, seven days-post-inoculation. Pregnant dams received 104 TCID50 X31 (X31hi; n=10), 103 TCID50 X31 (X31mod; n=9), or a mock inoculation with saline (control; n=10) across three identical replicates per end point. Maternal immune responses, as well as fetal microglia, border-associated macrophages (BAMs), and cortical neurons, were characterized at both time points and complemented with fetal brain transcriptomics. We observed a dose-dependent reduction in upper excitatory neuronal markers and cortical thickness, concomitant with a downregulation in fetal brain transcripts related to neuronal migration. We also found an increase in the number of meningeal BAMs and an overall increase in brain-resident macrophage phagocytic capacity in our high-dose fetal brains only. Ongoing experiments aim to analyze cellular functional capacity in vitro. Overall, our data support the existence of an infection severity threshold for IAV-induced fetal cortical abnormalities and altered brain-resident macrophages, confirming the use of live pathogens in MIA modeling to improve translatability to the clinic.
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