Poster Presentation 16th Lorne Infection and Immunity 2026

Cell-specific immune responses to Zika brain infection revealed by single cell analysis of human brain organoids  (132219)

Michael Leitner 1 , Lachlan De Hayr 2 , Washington Romero 2 , Alexander Khromykh 2 , Andrii Slonchak 1
  1. QIMR Berghofer, Herston, QLD, Australia
  2. The University of Queensland, St Lucia, QLD, Australia

Zika virus (ZIKV) uniquely among flaviviruses crosses the placental barrier and infects the foetal brain, leading to congenital Zika syndrome. To study its effects on brain development, we previously established a human brain organoid (hBO) model of ZIKV neuropathogenesis1. Herein, we employed this model in combination with virus-inclusive single-cell RNA sequencing (scRNA-seq) to investigate cell-type-specific tropism and transcriptional responses to ZIKV in the developing human brain tissue.

Our analysis showed that ZIKV infects neural progenitor cells (NPCs), immature astrocytes, and both mature and immature neurons. Notably, mature astrocytes were uniquely resistant to ZIKV infection. We found that infected NPCs produce type I and III interferons (IFNs), although only a small proportion of infected cells expressed IFN genes. Mature astrocytes exhibited the strongest IFN response, possibly explaining their resistance. Notably, different cell types expressed distinct interferon-stimulated genes (ISGs). Astrocytes upregulated OAS3, MX1, IFITM1, IFITM3, and TRIM25, while expression of ISG20, OASL, and IFI6 was specific exclusively to infected NPCs. Common flavivirus-related ISGs such as Viperin and MX2 were minimally expressed. Beyond immune responses, gene ontology and pathway enrichment analyses revealed broader, cell-type-specific effects of ZIKV infection in the developing brain tissue. Specifically, ZIKV induced apoptosis and autophagy in NPCs, while both infected and uninfected neurons showed upregulation of genes involved in neuronal development.

In summary, we demonstrated that ZIKV exhibits broader cell-type tropism in the developing brain than previously recognised. We also revealed that the innate immune responses to ZIKV are not uniformly distributed across cell types but are finely cell-type specific, with differential sensing, signalling, and effector mechanisms depending on the cell type and infection status. We also revealed the pathways affected by the virus that may explain it’s ability to disrupt brain development.

  1. 1. Slonchak et al. Zika virus noncoding RNA cooperates with the viral protein NS5 to inhibit STAT1 phosphorylation and facilitate viral pathogenesis. Science Advances (2022) Vol 8, Issue 48, DOI: 10.1126/sciadv.add8095