Rotavirus susceptibility of antibiotic-treated mice ascribed to diminished expression of interleukin-22

• Published in: PloS one Vol. 16; no. 8; p. e0247738
• Main Authors: Schnepf, Daniel, Hernandez, Pedro, Mahlakõiv, Tanel, Crotta, Stefania, Sullender, Meagan E., Peterson, Stefan T., Ohnemus, Annette, Michiels, Camille, Gentle, Ian, Dumoutier, Laure, Reis, Celso A., Diefenbach, Andreas, Wack, Andreas, Baldridge, Megan T., Staeheli, Peter
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 12.08.2021; Public Library of Science (PLoS)
• Subjects: Animal models; Animals; Anti-Bacterial Agents - adverse effects; Anti-Bacterial Agents - pharmacology; Antibiotics; Antiviral drugs; Apoptosis; Bacteria; Biology; Biosynthesis; Cell death; Complications and side effects; Crick, Francis; Cytokines; Development and progression; Disease Susceptibility; Female; Gastrointestinal Microbiome - drug effects; Gene Expression Profiling; Genomes; Germfree; Health aspects; Immune response; Immunology; Infections; Infectious diseases; Innate immunity; Interferon; Interleukin; Interleukin 22; Interleukins; Interleukins - metabolism; Interleukins - physiology; Intestinal Mucosa - metabolism; Intestine; Laboratories; Life Sciences; Male; Medicine; Mice; Mice, Inbred C57BL; Mice, Knockout; Microbiomes; Microbiota; Microbiota (Symbiotic organisms); Mucosal immunity; Necroptosis; Pathogens; Physiological aspects; Polysaccharides; Probiotics; Pyroptosis; Real-Time Polymerase Chain Reaction; Replication; Risk factors; Rotavirus; Rotavirus - physiology; Rotavirus infections; Rotavirus Infections - etiology; Small intestine; Stat1 protein; Supervision; Susceptibility; Viral infections; Virology; Viruses; Germany; United Kingdom > UK; Belgium; St Louis Missouri; United States > US; Portugal
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0247738

The commensal microbiota regulates susceptibility to enteric pathogens by fine-tuning mucosal innate immune responses, but how susceptibility to enteric viruses is shaped by the microbiota remains incompletely understood. Past reports have indicated that commensal bacteria may either promote or repress rotavirus replication in the small intestine of mice. We now report that rotavirus replicated more efficiently in the intestines of germ-free and antibiotic-treated mice compared to animals with an unmodified microbiota. Antibiotic treatment also facilitated rotavirus replication in type I and type III interferon (IFN) receptor-deficient mice, revealing IFN-independent proviral effects. Expression of interleukin-22 (IL-22) was strongly diminished in the intestine of antibiotic-treated mice. Treatment with exogenous IL-22 blocked rotavirus replication in microbiota-depleted wild-type and Stat1 -/- mice, demonstrating that the antiviral effect of IL-22 in animals with altered microbiome is not dependent on IFN signaling. In antibiotic-treated animals, IL-22-induced a specific set of genes including Fut2 , encoding fucosyl-transferase 2 that participates in the biosynthesis of fucosylated glycans which can mediate rotavirus binding. Interestingly, IL-22 also blocked rotavirus replication in antibiotic-treated Fut2 -/- mice. Furthermore, IL-22 inhibited rotavirus replication in antibiotic-treated mice lacking key molecules of the necroptosis or pyroptosis pathways of programmed cell death. Taken together, our results demonstrate that IL-22 determines rotavirus susceptibility of antibiotic-treated mice, yet the IL-22-induced effector molecules conferring rotavirus resistance remain elusive.