Oral Presentation Lorne Infection and Immunity 2020

Flaviviruses target HSP90 to broadly inhibit JAK/STAT signalling; a mechanism leading to ZIKV dysregulation of neural stem cell differentiation. (#6)

Justin A Roby 1 2 , Katharina Esser-Nobis 2 , Elyse C Dewey-Verstelle 2 , Marian R Fairgrieve 2 , Emily A Hemann 2 , Johannes Schwerk 2 , Amy Y Lu 2 3 , Caleb A Stokes 2 , Frank W Soveg 2 , Lauren D Hatfield 2 , Brian C Keller 4 , Alexander Shapiro 5 , Adriana Forero 2 , Jennifer E Stencel-Baerenwald 2 , Jessica E Young 6 , Ram Savan 2 , Jade K Forwood 1 , Michael Gale Jr 2 3
  1. School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW, Australia
  2. Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington, Seattle, Washington, United States
  3. Department of Global Health, University of Washington, Seattle, Washington, United States
  4. Division of Pulmonary, Critical Care & Sleep Medicine, The Ohio State University College of Medicine, Columbus, Ohio, United States
  5. Shorewood High School, Shoreline, Washington, United States
  6. Institute for Stem Cell and Regenerative Medicine, Department of Pathology, University of Washington, Seattle, Washington, United States

Pathogenic flaviviruses (such as West Nile virus and Zika virus (ZIKV)) inhibit host cell interferon-responsive Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling to antagonize antiviral activity and promote pathogenesis, with diverse mechanisms of this inhibition proposed. Surprisingly, we revealed that flaviviruses inhibit JAK/STAT signalling in response to many different cytokines not just interferons. Flaviviruses drive this broad inhibition via a mechanism that involves viral nonstructural protein 5 (NS5) interaction with host heat shock protein 90 (HSP90) within infected cells. HSP90-NS5 interaction was associated with reduced HSP90-JAK1 interaction and a loss of abundance of several host kinase clients of this chaperone, including JAK family proteins. Decreased JAK protein abundance led to refractory signal transmission, with a failure to phosphorylate STAT proteins in response to cytokines. The unforeseen importance of this general blockade for disease phenotypes was illustrated by ZIKV inhibition of JAK/STAT signalling in response to cytokines critical for foetal brain development. Neural stem cells infected with ZIKV displayed early deficits in cytokine-driven gliogenic and neurogenic differentiation. We thus identified ZIKV dysregulation of host HSP90 function as a potential mechanism for virus-induced microencephaly. Moreover, constitutive JAK/STAT signalling in glioblastoma cells was shown to be blocked by flaviviruses, providing insight into the mechanism responsible for the anti-cancer properties of these viruses. This novel HSP90 interaction axis constitutes a promising target both for antiviral development (aiming to disrupt viral NS5 interaction) and for anti-cancer therapeutic design (mimicking viral HSP90 perturbation).