At the crux of maternal immune activation: Viruses, microglia, microbes, and IL‐17A

• Published in: Immunological reviews Vol. 311; no. 1; pp. 205 - 223
• Main Authors: Otero, Ashley M., Antonson, Adrienne M.
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.10.2022; John Wiley and Sons Inc
• Subjects: Adjuvants, Immunologic; Animal models; Animals; Behavior, Animal - physiology; Complications; Disease Models, Animal; Disorders; Environmental risk; Female; Fetuses; Humans; Immune response; Immunostimulants; Infections; Inflammation; Influenza; influenza virus; Interleukin-17; Invited Review; Invited Reviews; maternal immune activation; Mental disorders; microbial signaling; Microglia; Microglial cells; Microorganisms; Neurodevelopment; Neurodevelopmental disorders; Offspring; Pathogens; Phenotypes; Pregnancy; Prenatal development; Prenatal experience; Prenatal Exposure Delayed Effects; Risk analysis; Risk factors; Signs and symptoms; Stimulants; TH17 cells; Viral infections; Viruses; influenza virus; microbial signaling; maternal immune activation; neurodevelopment; TH17 cells; microglia
• ISSN: 0105-2896; 1600-065X
• DOI: 10.1111/imr.13125

Summary Inflammation during prenatal development can be detrimental to neurodevelopmental processes, increasing the risk of neuropsychiatric disorders. Prenatal exposure to maternal viral infection during pregnancy is a leading environmental risk factor for manifestation of these disorders. Preclinical animal models of maternal immune activation (MIA), established to investigate this link, have revealed common immune and microbial signaling pathways that link mother and fetus and set the tone for prenatal neurodevelopment. In particular, maternal intestinal T helper 17 cells, educated by endogenous microbes, appear to be key drivers of effector IL‐17A signals capable of reaching the fetal brain and causing neuropathologies. Fetal microglial cells are particularly sensitive to maternally derived inflammatory and microbial signals, and they shift their functional phenotype in response to MIA. Resulting cortical malformations and miswired interneuron circuits cause aberrant offspring behaviors that recapitulate core symptoms of human neurodevelopmental disorders. Still, the popular use of “sterile” immunostimulants to initiate MIA has limited translation to the clinic, as these stimulants fail to capture biologically relevant innate and adaptive inflammatory sequelae induced by live pathogen infection. Thus, there is a need for more translatable MIA models, with a focus on relevant pathogens like seasonal influenza viruses.