Journal Article

STAT1-mediated interferon signaling in the hematopoietic system is essential for restricting Usutu virus infection in vivo

Cafiero, Thomas R., Mullin, Sydney J., Nelson, Amy N., Schwartz, Robert E., Ploss, Alexander, Sinha, Saloni, Carver, Sebastian S., Lin, Aaron E.

2025

Overview

Usutu virus (USUV) is an emerging mosquito-borne flavivirus known to induce neuroinvasive disease in birds, mice, and humans in European and African countries. The mechanisms of infection and dissemination remain poorly understood. Thus, elucidating how USUV spreads in a susceptible host is crucial for identifying therapeutic targets. To investigate host defenses against USUV, we generated an infectious clone of the TC508 isolate. After characterizing its replication dynamics in cultured cells from multiple species, we investigated its pathogenesis in an array of mice with genetic perturbations. Previous studies demonstrated that whole-body deletion of type I interferon (IFN) signaling led to widespread USUV infection and fatality in mice. Here, we observed the same lethal phenotype in STAT1-deficient mice and identified hematopoietic cells specifically as central to USUV pathogenesis in a mammalian host. Deletion of STAT1 in all hematopoietic subsets, but not hepatocytes, neurons, macrophages or conventional dendritic cells, was sufficient for systemic viral dissemination and ultimate fatality. Conversely, mice lacking functional B, T, and natural killer (NK) cells but with intact myeloid cells were resistant to USUV. Our findings provide new insights into the tissue-specific barriers that regulate USUV infection and underscore the importance of innate immunity in host defense for this important emerging flavivirus.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Analysis / Animals / Antibodies / Biological response modifiers / Biology and Life Sciences / Birds / Brain research / Cellular signal transduction / Deletion / Dendritic cells / Encephalitis / Flavivirus - immunology / Flavivirus - pathogenicity / Flavivirus - physiology / Flavivirus Infections - immunology / Flavivirus Infections - virology / Flow cytometry / Genomes / Health aspects / Hematopoietic stem cells / Hematopoietic system / Hepatocytes / Humans / Immune response / Immunocompetence / Infection / Infections / Innate immunity / Interferon / Interferon Type I - metabolism / Interferons - metabolism / Invasiveness / Laboratory animals / Macrophages / Medical research / Medicine and Health Sciences / Medicine, Experimental / Mice / Mice, Inbred C57BL / Mice, Knockout / Myeloid cells / Natural immunity / Natural killer cells / Pathogenesis / Phenotypes / Research and Analysis Methods / Signal Transduction / STAT1 / Stat1 protein / STAT1 Transcription Factor - genetics / STAT1 Transcription Factor - metabolism / Therapeutic targets / Virulence / Virus Replication / Viruses / West Nile virus