University of Illinois Urbana-Champaign

Gestational influenza A virus disrupts downstream maternal and fetal immune profiles in a dose- and time-dependent manner

Otero, Ashley; Gonzalez-Ricon, Rafael Jaime; Chalen, Izan; Antonson, Adrienne

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https://hdl.handle.net/2142/132826

Description

Title
Gestational influenza A virus disrupts downstream maternal and fetal immune profiles in a dose- and time-dependent manner
Author(s)
  • Otero, Ashley
  • Gonzalez-Ricon, Rafael Jaime
  • Chalen, Izan
  • Antonson, Adrienne
Issue Date
2023-11-13
Keyword(s)
neurodevelopmental disorders
Date of Ingest
2026-02-22T17:13:53-06:00
Abstract
Epidemiological studies link neurodevelopmental disorders (NDDs) with exposure to maternal viral infection in utero. The hypothesized mechanism governing this link comes from animal models that initiate maternal inflammation with a non-pathogenic viral mimic to induce an acute immune response. These studies indicate that maternal intestinal T helper 17 (TH17) cells are activated to produce interleukin (IL)-17, and this pro-inflammatory cytokine is implicated as a major driver of fetal brain abnormalities. Priming of TH17 cells is also observed following respiratory influenza A virus (IAV) infection; however, whether these TH17 cells might be driving fetal brain abnormalities during gestational IAV infection has never been examined. We aim to determine how IAV infection during pregnancy impacts maternal intestinal immune cells and if IAV-mediated activation of these cells is sufficient to result in aberrant brain 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 intestine, placentas and fetal brains were collected on GD11.5 and 16.5, two- and seven-days post inoculation (dpi) to evaluate peak innate and adaptive immunity, respectively. Pregnant dams received 104 TCID50 X31 (X31hi; n=12, n=10), 103 TCID50 X31 (X31mod; n=14, n=9), or a mock-inoculation with saline (control; n=13, n=10) across three identical replicates per end point. Lung histopathology scores, viral expression, and inflammatory genes were upregulated in a dose- and time-dependent manner. Respiratory IAV infection led to colonic shortening at both time points despite no detection of virus in the intestine. Morphological changes were accompanied by upregulation of TH17 cell gene markers in the intestine at the high viral titer only. This includes genes encoding RORγt and IL-6, indicating priming of naïve T cells into TH17 cells. Flow cytometric analyses of intestinal TH17 cells at 2 and 7 dpi revealed a complex dose-dependent phenotypic shift. Placental immune transcripts were altered in a dose-dependent manner, demonstrating possible sequestering of adaptive immune cells and recruitment of neutrophils at the maternal-fetal interface. Immunohistochemistry revealed no changes in fetal microglial colonization patterns or proliferative capacities at GD11.5. Ongoing studies will analyze the fetal brain at GD16.5. So far, our data show that a higher infectious dose of gestational IAV is necessary to induce downstream immune changes, confirming the use of live pathogens in NDD modeling to evaluate the complete immune response and improve translation to the clinic.
Publisher
Society for Neuroscience
Series/Report Name or Number
Neuroscience 2023
Type of Resource
text
Genre of Resource
conference paper

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