Tuesday, July 1, 2025 7/1/2025

Host range determinants of bacterial exfoliative toxins

Award Number: R21AI173839
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/16/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2026

Group Awards By:

View Award Description

Host range determinants of bacterial exfoliative toxins - PROJECT SUMMARY The host range, or tropism, of pathogen virulence factors is a key determinant of infection. A detailed understanding of host and pathogen mutations that control species tropism is required in order to assess the risk of future zoonotic disease outbreaks, improve animal infection models, and design new therapeutics that take advantage of host specificity. The objective of this proposal is to define barriers to cross-species activity in bacterial virulence factors at high resolution, leveraging staphylococcal exfoliative toxins as a study system. Exfoliative toxins encoded by pathogenic bacteria in the genus Staphylococcus cause life- threatening skin diseases including staphylococcal scalded skin syndrome and bullous impetigo characterized by widespread blistering and damage to the epidermis. Exfoliative toxins are proteases that act by selectively cleaving the skin desmosomal cadherin desmoglein-1, leading to loss of epidermal barrier function and blister formation. Our central hypothesis is that virulence factor activity is dependent on genetic compatibilities between hosts and pathogens, and that interrogating these compatibilities will uncover specific barriers to host tropism. In preliminary work, we found that genes encoding desmoglein-1 have undergone rapid evolution and repeated natural selection across non-human primates within a small protein surface sufficient to restrict toxin activity. We have also developed tractable in vitro assays to measure toxin cleavage of recombinant desmglein-1 from various host species. The Specific Aims of this proposal are to 1) generate a high-resolution map of mutations in desmoglein-1 that restrict toxin tropism, and 2) test how toxin mutations at the desmoglein-1 binding interface contribute to host tropism. In Aim 1 we will perform combinatorial mutagenesis of the toxin recognition surface in desmoglein-1 to produce a genetic map defining the barriers of host recognition. In Aim 2 we will apply structural and biochemical approaches to resolve the desmoglein- exfoliative toxin binding interface combined with genetics to assess how toxin mutations at this surface control host tropism. Collectively this proposal will establish a framework to define genetic barriers to bacterial infections at high-resolution, applied towards the goal of anticipating and preventing future disease outbreaks.


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: 2025 ( Subtotal = $0 )
2025	2024	UNIVERSITY OF OREGON	1776 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Allergy and Infectious Diseases Research	000	2	6/24/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $184,375 )
2024	2024	UNIVERSITY OF OREGON	1776 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Allergy and Infectious Diseases Research	000	2	7/31/2024	NON-COMPETING CONTINUATION	$184,375
														Subtotal = $184,375

Issue Date FY: 2023 ( Subtotal = $221,250 )
2023	2023	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Allergy and Infectious Diseases Research	000	1	8/16/2023	NEW	$221,250
														Subtotal = $221,250

Grand Total All Awards = $405,625

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Host range determinants of bacterial exfoliative toxins

Award Number: R21AI173839

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/16/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2026

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer