Prenatal maternal infection promotes tissue-specific immunity and inflammation in offspring

• Published in: Science (American Association for the Advancement of Science) Vol. 373; no. 6558
• Main Authors: Lim, Ai Ing, McFadden, Taryn, Link, Verena M., Han, Seong-Ji, Karlsson, Rose-Marie, Stacy, Apollo, Farley, Taylor K., Lima-Junior, Djalma S., Harrison, Oliver J., Desai, Jigar V., Lionakis, Michail S., Shih, Han-Yu, Cameron, Heather A., Belkaid, Yasmine
• Format: Journal Article
• Language: English
• Published: Washington The American Association for the Advancement of Science 27.08.2021
• Subjects: Accessibility; Adaptive systems; Adults; Antigen presentation; Antigens; Antiinfectives and antibacterials; Antimicrobial peptides; Chromatin; Clonal deletion; Colitis; Context; Cytokines; Developmental stages; Dextran; Dextran sulfate; Dextrans; Digestive system; Disorders; Epigenetics; Epithelium; Exposure; Fetuses; Fitness; Food; Gastrointestinal tract; Gene expression; Gene sequencing; Homeostasis; Immune system; Immunity; Immunological memory; Imprinting; Infections; Inflammation; Inflammatory bowel disease; Inflammatory diseases; Injection; Interleukin 6; Intestine; Long-term effects; Lymphocytes; Lymphocytes T; Microbiota; Microorganisms; Offspring; Pathogens; Peptides; Pregnancy; Prenatal development; Prenatal Influences; Salmonella; Salmonella Typhimurium; Stem cells; Tissues; Weaning; Yersinia pseudotuberculosis
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.abf3002

Most infections that occur during pregnancy are mild and transient. However, whether such pathogen encounters can shape the long-term trajectory of the offspring’s immune system remains unclear. Lim et al . infected pregnant mice with the common food-borne pathogen Yersinia pseudotuberculosis (YopM) (see the Perspective by Amir and Zeng). Although the infection was maternally restricted and short-lived, the offspring harbored greater numbers of intestinal T helper 17 cells into adulthood. Interleukin-6 (IL-6) mediated this tissue-restricted effect by acting on fetal intestinal epithelium during development. Although offspring from mothers infected with YopM or injected with IL-6 showed enhanced resistance to oral infection with Salmonella Typhimurium, they also exhibited higher susceptibility toward enteric inflammatory disease. —STS Prebirth exposure to interleukin-6 affects fetal intestinal epithelium, resulting in heightened immunity to the microbiota and pathogens. The immune system has evolved in the face of microbial exposure. How maternal infection experienced at distinct developmental stages shapes the offspring immune system remains poorly understood. Here, we show that during pregnancy, maternally restricted infection can have permanent and tissue-specific impacts on offspring immunity. Mechanistically, maternal interleukin-6 produced in response to infection can directly impose epigenetic changes on fetal intestinal epithelial stem cells, leading to long-lasting impacts on intestinal immune homeostasis. As a result, offspring of previously infected dams develop enhanced protective immunity to gut infection and increased inflammation in the context of colitis. Thus, maternal infection can be coopted by the fetus to promote long-term, tissue-specific fitness, a phenomenon that may come at the cost of predisposition to inflammatory disorders.