Quantitative and Spatial Differences in Host Response Dynamics to SARS-CoV-2 Variants of Concern

Recurrently emerging SARS-CoV-2 variants of concern (VOC) present increasingly sophisticated immune escape strategies that fuel global infection rates, as exemplified by the raging B.1.1.529 variant known as omicron, rendering ending this pandemic notoriously challenging. It is therefore paramount to rapidly adapt research strategies to understand the rich repertoire of both viral behavior and anti-viral responses to VOCs in order to develop timely and universal interventions. Readily adaptable spatial transcriptomics approaches facilitate such dynamic investigations and allow to map the severe heterogeneity presented by SARS-CoV-2 VOCs. To draw on maximum sensitivity and specificity at subcellular resolution, we resorted to the novel spatial multiplexed single-cell mRNA in-situ hybridization technology called Molecular Cartography™ (MC) developed by Resolve Biosciences. Using MC, we dissect transcriptional responses to SARS-CoV-2 in various cell lines of pulmonary, colorectal, and hepatocellular origin and compare immune escape strategies of relevant VOCs including B.1.617.2 (delta) and B.1.1529. Furthermore, spatially discriminating higly infected from bystander cells allowed discerning primary from secondary anti-viral responses and pinpoint molecular signatures unique to individual VOCs. Interestingly, virus-induced dysregulation of the JAK/STAT and NFB signaling pathways by all tested VOCs highlighted their importance as therapeutic targets. We further show that SARS-CoV-2 nucleocapsid protein transcripts majorly locate  vicinal to the cell nucleus. Finally, by spatially tracking antiviral response dynamics emanating from the primary infected cell, we  elucidate differences in temporally diverging infection sites and evaluate responses to virus propagation. Overall, MC allowed gaining a thorough comparative understanding of host response dynamics to diverse SARS-CoV-2 VOCs that is imperative to prepare for future VOCs and aid in ending this pandemic.

Learning Objectives:

1. Discuss the importance of spatial analysis in SARS-CoV-2 research.

2. Explain the complex heterogeneity in host-pathogen responses to SARS-CoV-2 variants of concern (VOC).

3. Identify major anti-viral signaling pathways hijacked by SARS-CoV-2 VOCs.