Offspring born to influenza A virus infected pregnant mice have increased susceptibility to viral and bacterial infections in early life

Henning Jacobsen,Kerstin Walendy-Gnirß,Nilgün Tekin-Bubenheim,Ali Önder Yildirim,Arne Düsedau,Peter Openshaw,Tatjana Manuylova,Martin Wolff,Bianca E Schneider ,Helmut Fuchs,Fiona J Culley,Nancy Mounogou Kouassi,Andreas Kloetgen,Claudia Stoeger,Martin Zickler,Sonja Loges,Gundula Pilnitz-Stolze,Valérie Gailus‐Durner ,Aicha Jeridi,Susanne Krauss‐Etschmann ,Jochen Behrends,Nikolaus Berenbrok,Martin Hrabě De Angelis ,Karin Klingel,Vinícius Pinho Dos Reis ,Hanna Jania,Lucas Scholl,Isabel Ben-Batalla,Annette Gries,Gülşah Gabriel

doi:10.1038/s41467-021-25220-3

Abstract

Influenza during pregnancy can affect the health of offspring in later life, among which neurocognitive disorders are among the best described. Here, we investigate whether maternal influenza infection has adverse effects on immune responses in offspring. We establish a two-hit mouse model to study the effect of maternal influenza A virus infection (first hit) on vulnerability of offspring to heterologous infections (second hit) in later life. Offspring born to influenza A virus infected mothers are stunted in growth and more vulnerable to heterologous infections (influenza B virus and MRSA) than those born to PBS- or poly(I:C)-treated mothers. Enhanced vulnerability to infection in neonates is associated with reduced haematopoetic development and immune responses. In particular, alveolar macrophages of offspring exposed to maternal influenza have reduced capacity to clear second hit pathogens. This impaired pathogen clearance is partially reversed by adoptive transfer of alveolar macrophages from healthy offspring born to uninfected dams. These findings suggest that maternal influenza infection may impair immune ontogeny and increase susceptibility to early life infections of offspring.

Highlights

Influenza during pregnancy can affect the health of offspring in later life, among which neurocognitive disorders are among the best described
Maternal influenza A virus infection at E5.5 resulted in moderate disease displayed by delayed weight gain and increased morbidity scores during pregnancy compared to phosphate-buffered saline (PBS)-treated dams (Fig. 1b; Supplementary Fig. 1a, and Supplementary Table 1)
IL-6, TNF, MCP-1, and IL-1ß levels were significantly increased in the lungs of influenza A virus (IAV)-infected dams as compared to PBS or poly(I:C)-treated controls (Fig. 1f–h and Supplementary Fig. 1c–i)

Summary

Introduction

Influenza during pregnancy can affect the health of offspring in later life, among which neurocognitive disorders are among the best described. To tolerate the foreign tissue, the maternal immune system needs to mount many processes of immune adaptation and tolerance[4,5] These changes collectively orchestrate an anti-inflammatory and tolerogenic environment that allows placental development and suppresses fetal rejection[6]. This state of adapted immunity leads to increased vulnerability towards infection that can create a contradictory demand of maintaining fetal tolerance versus mounting an inflammatory immune response[7]. Polyriboinosinic-polyribocytidilic acid (poly(I: C)) or lipopolysaccharide (LPS) is used as a MIA inducing agent in order to mimic viral or bacterial infection, respectively These models using artificial immunogens possess specific advantages and disadvantages but their representative character regarding actual infections remains unclear

Methods

Results

Conclusion