# Spatial-Temporal Dissection of Stratified Host Tissue Responses to Severe acute respiratory syndrome-related coronaviruses in situ to Understand Intra-host Pathogenesis

> **NIH NIH DP2** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2022 · $372,900

## Abstract

PROJECT SUMMARY/ABSTRACT
Distinctive host-pathogen interactions and adaptations are the cornerstones of co-evolution between eukaryotes
and their viral pathogens. Given the rapid replication and mutation rates of RNA viruses within their host,
understanding these intra-host interactions in their native tissue context is central to developing next-generation
anti-viral and vaccines. The ongoing COVID-19 pandemic continues to thwart eradication due to SARS-CoV-2
Variants of Concern (VoC), where even minor changes to the spike protein can affect cellular entry, antibody
neutralization, vaccine efficacy and immune responses, thus leading to immune escape. Why do these variants,
along with other Severe acute respiratory syndrome–related coronaviruses (SARSr-CoVs), differ in their
host pathogenesis, and how do they achieve that? Are there differential host factors or responses that
influence tissue-specific tropism? These questions need to be answered with controlled experimental
approaches to dissect and deconvolute the coevolutionary viral-host interactions in situ. This proposal seeks to
combine powerful reverse genetics systems, next-generation tissue imaging platforms and robust animal models
towards the systematic determination of host immune responses, virus evasion strategies and both inter- and
intra-host viral dynamics. We propose to use these powerful methodologies to first determine host tissue
responses to individual VoCs within human COVID-19 autopsies and non-human primate necropsies. Next, we
seek to combine spatial-lineage tracing with tagged SARS-CoV-2 VoCs and other SARSr-CoVs that use ACE2
for entry in the humanized ACE2-K18 mouse model. To recapitulate intra-host viral variation in vivo, we will
engineer these viruses to include a short sequence of peptides encoding unique barcodes. Each set of barcodes
corresponds to a specific virus strain or variant. Infection of humanized ACE2 mice with a pool of these barcoded
viruses, coupled with antibody or hybridization-based spatial readouts and single-cell characterization of host
immune responses, will enable a methodical approach towards the systems-level investigation of intra-host viral
variation and competition dynamics. The spatial framework and conceptual advances resulting from this work
are applicable to a broad myriad of other biological systems and diseases, thus paving the way to better-
designed therapeutics and rapid responses to understand, control and eventually eradicate new biological
threats.

## Key facts

- **NIH application ID:** 10508593
- **Project number:** 1DP2AI171139-01
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Sizun Jiang
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $372,900
- **Award type:** 1
- **Project period:** 2022-09-06 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10508593

## Citation

> US National Institutes of Health, RePORTER application 10508593, Spatial-Temporal Dissection of Stratified Host Tissue Responses to Severe acute respiratory syndrome-related coronaviruses in situ to Understand Intra-host Pathogenesis (1DP2AI171139-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10508593. Licensed CC0.

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