Abstract
Exposure to infection in utero predisposes towards psychiatric diseases such as autism, depression and schizophrenia in later life. The mechanisms involved are typically studied by administering mimetics of double-stranded (ds) virus or bacterial infection to pregnant rats or mice. The effect of single-stranded (ss) virus mimetics has been largely ignored, despite evidence linking prenatal ss virus exposure with psychiatric disease. Understanding the effects of gestational ss virus exposure has become even more important with recent events. In this study, in pregnant mice, we compare directly the effects, on the maternal blood, placenta and the embryonic brain, of maternal administration of ds-virus mimetic poly I:C (to activate Toll-like receptor 3, TLR3) and ss-virus mimetic resiquimod (to activate TLR7/8). We find that, 4 h after the administration, both poly I:C and resiquimod elevated the levels of IL-6, TNFα, and chemokines including CCL2 and CCL5, in maternal plasma. Both agents also increased placental mRNA levels of IL-6 and IL-10, but only resiquimod increased placental TNFα mRNA. In foetal brain, poly I:C produced no detectable immune-response-related increases, whereas pronounced increases in cytokine (e.g. Il-6, Tnfα) and chemokine (e.g. Ccl2, Ccl5) expression were observed with maternal resiquimod administration. The data show substantial differences between the effect of maternal exposure to a TLR7/8 activator as compared to a TLR3 activator. There are significant implications for future modelling of diseases where maternal ss virus exposure contributes to environmental disease risk in offspring.
Highlights
Exposure to infection in utero predisposes towards psychiatric diseases such as autism, depression and schizophrenia in later life
LPS reproduces the effects of bacterial infection by stimulating the Toll-like receptor (TLR) TLR4, while polycytidylic acid (poly I):C reproduces the effects of ds-virus infection by stimulating TLR3
This study provides a direct comparison of the pattern of immune response to poly I:C and resiquimod in maternal, placental and foetal brain compartments
Summary
Exposure to infection in utero predisposes towards psychiatric diseases such as autism, depression and schizophrenia in later life. In pregnant mice, we compare directly the effects, on the maternal blood, placenta and the embryonic brain, of maternal administration of ds-virus mimetic poly I:C (to activate Toll-like receptor 3, TLR3) and ss-virus mimetic resiquimod (to activate TLR7/8). The infectious agent or immune response molecules impact upon differentiating or migrating neurons e.g. inter-neurons, and can affect microglia in the developing CNS with consequences for processes such as synaptic p runing[10] How these processes operate to raise risk of psychiatric disease remains uncertain. Despite the fact that some of the prenatal infectious agents most strongly linked to schizophrenia risk (rubella virus and influenza virus) are ss-viruses, models of maternal immune infection with ss-virus mimetics such as resiquimod or imiquimod, which stimulate TLR7/816,17 are rarer. We have directly compared the most commonly used strategy for studying the effects of MIA (poly I:C administration in mice) with a novel strategy using resiquimod to mimic ss- virus infection
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