Conditional Stat1 Ablation Reveals the Importance of Interferon Signaling for Immunity to Listeria monocytogenes Infection

PLoS Pathogens

Boris Reizis¹  Ulrich Kalinke²  Christine Schneckenleithner³  Thomas Decker³  Veronika Sexl⁴  Ursula Reichart⁴  Birgit Strobl⁵  Dagmar Stoiber⁶  Verena Maier⁷  Elisabeth Kernbauer⁷  Mathias Müller⁷  Amanda Jamieson⁸ 

[1] Biomodels Austria, University of Veterinary Medicine Vienna, Vienna, Austria;Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York, United States of America;Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria;Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria;Institute of Pharmacology, Centre for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria;Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Vienna, Austria;Max F. Perutz Laboratories, University of Vienna, Vienna, Austria;Twincore, Center for Experimental and Clinical Infection Research, Hannover, Germany

关键词: T cells;    STAT signaling;    Spleen;    Cytokines;    Macrophages;    Cell signaling;    Immune response;    Listeria monocytogenes;   

DOI  :  10.1371/journal.ppat.1002763

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Signal transducer and activator of transcription 1 (Stat1) is a key player in responses to interferons (IFN). Mutations of Stat1 cause severe immune deficiencies in humans and mice. Here we investigate the importance of Stat1 signaling for the innate and secondary immune response to the intracellular bacterial pathogen Listeria monocytogenes (Lm). Cell type-restricted ablation of the Stat1 gene in naïve animals revealed unique roles in three cell types: macrophage Stat1 signaling protected against lethal Lm infection, whereas Stat1 ablation in dendritic cells (DC) did not affect survival. T lymphocyte Stat1 reduced survival. Type I IFN (IFN-I) signaling in T lymphocytes reportedly weakens innate resistance to Lm. Surprisingly, the effect of Stat1 signaling was much more pronounced, indicating a contribution of Stat1 to pathways other than the IFN-I pathway. In stark contrast, Stat1 activity in both DC and T cells contributed positively to secondary immune responses against Lm in immunized animals, while macrophage Stat1 was dispensable. Our findings provide the first genetic evidence that Stat1 signaling in different cell types produces antagonistic effects on innate protection against Lm that are obscured in mice with complete Stat1 deficiency. They further demonstrate a drastic change in the cell type-dependent Stat1 requirement for memory responses to Lm infection.

【 授权许可】

CC BY