Single-cell analysis reveals an antiviral network that controls Zika virus infection

In 2016, the world was gripped by the Zika virus (ZIKV) epidemic, which spread rapidly across the Americas, causing widespread concern due to its association with severe neonatal birth defects. Despite significant efforts to understand the virus, many questions remain about how the host immune system responds to ZIKV infection. A groundbreaking study by researchers at the Emory University School of Medicine has shed new light on this topic by leveraging advanced single-cell RNA sequencing (scRNA-seq) technology to investigate the intricate interplay between the virus and host cells.

ZIKV, like many other viruses, hijacks host cells to replicate and spread throughout the body. To gain insights into how the immune system responds to ZIKV infection at the single-cell level, the researchers adapted the 10× Genomics Chromium scRNA-seq assay. This innovative approach allowed them to simultaneously capture both viral RNA and host mRNA within individual cells. By profiling human monocyte-derived dendritic cells infected with ZIKV, the researchers were able to dissect the antiviral landscape with unprecedented detail.

Schematic for ZIKV-inclusive single cell RNA sequencing using the 10x Genomics assay

Overview of the cell preparation and 10x Genomics Chromium scRNA-seq assay. Mock and ZIKV treated cells are labeled with Feature barcoded antibodies, mixed 2:1, and then loaded in the 10x microfluidic chip with the ZIKV-specific primer. The reverse transcription reaction of host mRNA, ZIKV viral RNA, and Feature barcode takes place in individual water-in-oil emulsion droplets (GEMs). A unique barcode is added onto the nascent cDNA, allowing each transcript to be computationally traced back to its original cell. 

Surprisingly, the study revealed that even cells without detectable viral RNA showed signs of an antiviral response. These bystander cells expressed genes associated with a type I interferon (IFN) response, a key component of the innate immune system’s defense against viral infections. Meanwhile, within infected cells, the presence of viral RNA correlated with the downregulation of genes involved in both type I IFN-dependent and -independent antiviral pathways.

To further explore the intricate interactions between viral and host proteins, the researchers leveraged experimentally derived protein interaction data. Through this analysis, they uncovered a highly interconnected network linking the antiviral response to various host proteins, providing valuable insights into the molecular mechanisms underlying the host’s defense against ZIKV.

Overall, this study represents a significant step forward in our understanding of how the immune system responds to ZIKV infection at the single-cell level. By combining cutting-edge scRNA-seq technology with experimental protein interaction data, these researchers have unveiled a new paradigm for studying antiviral responses, offering potential targets for future therapeutic interventions. As we continue to unravel the complexities of host-virus interactions, studies like these pave the way for more effective strategies to combat emerging viral threats.

Moore KM, Pelletier A-N, Lapp S, Metz A, Tharp GK, Lee M, Bhasin SS, Bhasin M, Sékaly R-P, Bosinger SE, Suthar MS. (2024) Single-cell analysis reveals an antiviral network that controls Zika virus infection in human dendritic cells. J Virol [Epub ahead of print]. [abstract]

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