Enhanced Preprints

Rubella virus tropism and single cell responses in human primary tissue and microglia-containing organoids

  1. Galina Popova
  2. Hanna Retallack
  3. Chang N. Kim
  4. David Shin
  5. Albert Wang
  6. Joseph DeRisi author has email address
  7. Tomasz J. Nowakowski author has email address
  1. Department of Anatomy, University of California San Francisco, San Francisco, CA, USA
  2. Department of Psychiatry, University of California San Francisco, San Francisco, CA, USA
  3. Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, USA
  4. Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA
  5. Chan Zuckerberg Biohub, San Francisco, CA, USA
  6. Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA

Editors

  • Reviewing Editor
    Joseph Gleeson
    University of California, San Diego, La Jolla, United States of America
  • Senior Editor
    Sara Sawyer
    University of Colorado Boulder, Boulder, United States of America

Reviewer #1 (Public Review):

The authors sought to address the longstanding question of which cell types are infected during congenital or perinatal rubella virus infection. They used brain slice and organoid-microglia experimental models to demonstrate that the main cell types targeted by rubella virus are microglia. It does not appear that microglia support rubella virus production in this experimental system, though future studies would be needed to address this more thoroughly. The authors further show that infection results in augmented interferon responses in neighboring neuronal cells but not in the microglia themselves. The data support the conclusions, with major strengths being the sophisticated primary cell models and single-cell RNA-Seq used to pinpoint microglia as the main cellular targets of rubella virus, and neurons as the bystander targets of immune signaling. This study reveals a new cellular target that will have important implications for basic studies on rubella virus-host interactions and for the potential development of therapies or improved vaccines targeting this virus. As rubella virus is a pathogen of high concern during human pregnancy, this study also has important implications in the field of neonatal infectious diseases.

Reviewer #2 (Public Review):

In this manuscript by Popova et al., the authors report the pathological impact of Rubella virus (RV) infection on human brain development. In particular, they uncovered a selective tropism of Rubella virus for microglial cells in cultured slices of human developing brain and 2D mixed fetal brain cell culture. Their results suggest that RV infection of microglia relies on the presence of diffusible factors from other cell populations. Moreover, the authors showed that RV infection of human brain organoids supplemented or not with microglia leads to interferon response and dysregulation of gene involved in brain development. This set of data will help understanding the cellular specificity and pathological mechanisms occurring in the developing brain upon RV infection. The data provided are overall of high quality and shed new light on the cellular tropism and the pathomechanisms of RV infection.

  1. Howard Hughes Medical Institute
  2. Wellcome Trust
  3. Max-Planck-Gesellschaft
  4. Knut and Alice Wallenberg Foundation