Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Functional and antigenic evolution of SARS-related coronaviruses

Award Number: K99AI166250
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 06/10/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2023

Group Awards By:

View Award Description

Functional and antigenic evolution of SARS-related coronaviruses - PROJECT SUMMARY SARS-related coronaviruses (also known as sarbecoviruses) circulate in bat reservoirs, but two human spillovers in the past 20 years—SARS-CoV-1 in 2002 and SARS-CoV-2 in 2019—have caused globally devastating outbreaks. The emergence of SARS-CoV-2 from a previously unknown bat lineage highlights the pressing need to trace the evolutionary origins of viral properties that enable human spillover and develop therapeutic reagents that can broadly inhibit infection by diverse, potentially unsampled sarbecovirus lineages. Sarbecovirus zoonosis depends in part on the evolution of viruses to interact with ACE2 receptors on the surface of human and potential intermediate hosts’ cells, mediated by the viral spike receptor-binding domain (RBD). The RBD is also a key component to therapeutic control of SARS-CoV-2 and presumably other sarbecoviruses, as it is the target of the most potently neutralizing antibodies, including those in clinical development and in polyclonal human sera. Although I and others have begun surveying the impacts of mutations within SARS-CoV-2 itself on important biochemical phenotypes including binding to ACE2 receptor and antiviral antibodies, these studies have only limited utility in understanding the broader evolution of sarbecovirus RBDs, which exhibit considerable divergence in sequence and function. To characterize sarbecovirus functional and antigenic evolution, I propose to combine high-throughput protein binding experiments with computational evolutionary analyses, functional virology, and biochemistry: 1. I will profile the ACE2-binding specificities of all known sarbecovirus RBDs and their evolutionary precursors. I hypothesize that the ability to bind ACE2, including the human ACE2 ortholog, is more evolutionarily and geographically widespread than previously appreciated. 2. I will systematically characterize how diverse RBD mutations affect ACE2-binding phenotypes. I hypothesize that human ACE2 binding is an easily evolvable trait in sarbecovirus lineages where it has not been previously considered. I also hypothesize that divergence among sarbecovirus lineages shifts the genetic and biochemical determinants of ACE2 binding over evolutionary time. 3. I will identify RBD epitopes that are susceptible to broad pan-sarbecovirus antibody binding. By determining the relationship between breadth and other antibody properties across RBD epitopes, I highlight key features to target in the design of next-generation pan-sarbecovirus vaccines and antibody therapeutics. Identification of the evolutionary and biochemical basis for key sarbecovirus features enhances viral surveillance and therapeutic development, preparing for or even preventing future sarbecovirus spillovers. The new experimental expertise, broader training and mentorship, and research systems developed in this work will enable me to achieve my goal of leading an academic lab studying protein evolution at the host-virus interface.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = -$2,960 )
2024	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	1	2/27/2024	NEW	-$2,960
														Subtotal = -$2,960

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	1	8/15/2023	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $128,574 )
2022	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	1	6/9/2022	NEW	$128,574
2022	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	001	1	7/13/2022	NEW	$0
														Subtotal = $128,574

Grand Total All Awards = $125,614

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Functional and antigenic evolution of SARS-related coronaviruses

Award Number: K99AI166250

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 06/10/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2023

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer