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

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. 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.