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Principal Investigator: Sizun Jiang
Organization: BETH ISRAEL DEACONESS MEDICAL CENTER
Fiscal Year: 2024
Award: $478,605
Funding agency: National Institute of Allergy and Infectious Diseases
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.
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strains><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome coronavirus disease><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><System><Technology><Therapeutic><Tissue imaging><Tissues><Tropism><Vaccines><Variant><Variation><Viral><Viral Diseases><Viral Pathogenesis><Virus><Virus Diseases><Work><Wuhan coronavirus><angiotensin converting enzyme 2><angiotensin converting enzyme II><barcode><biologic><biological systems><combinatorial><computational methodology><computational methods><computer based method><computer methods><computing method><corona virus><coronavirus disease 2019><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 variant><coronavirus disease 2019 variant forms><coronavirus disease 2019 variant strains><coronavirus disease 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coronavirus 2 global pandemic><severe acute respiratory syndrome coronavirus 2 variant><severe acute respiratory syndrome coronavirus 2 variant forms><severe acute respiratory syndrome coronavirus 2 variant strains><technology platform><technology system><theories><tissue tropism><vaccine efficacy><variants of concern><viral infection><viral pathogen><virus infection><virus pathogen><virus pathogenesis><virus-induced disease>