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Defining the molecular inventory of staphylococcal tissue abscesses and its effects on the host-pathogen interface

Award Number: F32AI157215
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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Summary: Multidrug-resistant bacterial infections, particularly those caused by Staphylococcus aureus, are recognized as one of the greatest threats of the 21st century. Bloodstream infections are the most severe staphylococcal disease manifestation and are often fatal despite our best and most current therapies. Organ abscesses are primary contributors to S. aureus systemic infections and serve as initial reservoirs for the invading pathogen. Abscess formation itself follows distinct developmental stages, is actively facilitated by host and bacterium, and ultimately creates an advantageous niche for S. aureus. While past studies have generated an overview of abscess architecture, we lack information on the molecular composition of abscesses, particularly in the context of different abscess stages. This limited knowledge of the molecular events during abscess formation is especially alarming, for it hinders meaningful attempts at targeted design of anti-staphylococcal strategies. Our preliminary data show that abscess formation is characterized by the host’s extensive relocation of transition metals in proximity to the abscess in a process known as nutritional immunity. Consequently, in vivo imaging reveals that bacteria within the abscess are starved for zinc and iron. Since available metal levels can serve as biomarkers for invading pathogens, we hypothesize that fluctuating elemental distributions orchestrate bacterial activities associated with abscess formation. Along these lines, we showed that zinc starvation primes S. aureus for subsequent contact with different immune cell populations. Beyond these findings, however, the chronology and factors involved in metal relocation, detection of these stimuli by S. aureus, and corresponding bacterial responses are entirely unexplored. We thus plan to address these questions in this proposal. One current barrier to the design of meaningful investigations into the development of staphylococcal tissue abscesses is a significant degree of abscess heterogeneity, likely a result of different developmental stages of individual lesions in the same organ. To account for the non-synchronous nature of tissue abscesses, we have identified a group of potential proteinaceous markers for different abscess stages. These proteins will serve as molecular clocks so we can follow the progression of individual abscesses through the developmental process. Based on these markers, we will create in vivo reporters and characterize the molecular inventory of developing abscesses, focusing on changes in elemental and proteinaceous compositions. Here, we will correlate various in vivo imaging modalities, including 3D-bioluminiscent imaging, MRI, and imaging mass spectrometry, with advanced proteomics via micro Liquid Extraction Surface Analysis. Once we have established how the abscess microenvironment changes during different phases of abscess formation, we will perform transcriptome analysis of bacterial subpopulations to assess how environmental stimuli affect staphylococcal pathophysiology and, in turn, abscess development. Combined, the proposed experiments will examine the events at the host-pathogen interface and pave the way for novel and targeted treatment strategies to combat staphylococcal infections.


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 = -$62,692 )
2024	2023	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Allergy and Infectious Diseases Research	000	3	11/16/2023	NON-COMPETING CONTINUATION	-$46,863
2024	2023	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Allergy and Infectious Diseases Research	003	3	1/29/2024	NON-COMPETING CONTINUATION	-$1
2024	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Allergy and Infectious Diseases Research	002	2	1/29/2024	NON-COMPETING CONTINUATION	-$15,828
2024	2021	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Allergy and Infectious Diseases Research	001	1	12/14/2023	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = -$62,692

Issue Date FY: 2023 ( Subtotal = $46,864 )
2023	2023	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Allergy and Infectious Diseases Research	001	3	2/22/2023	NON-COMPETING CONTINUATION	$1,231
2023	2023	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Allergy and Infectious Diseases Research	000	3	11/9/2022	NON-COMPETING CONTINUATION	$45,633
														Subtotal = $46,864

Issue Date FY: 2022 ( Subtotal = $74,234 )
2022	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Allergy and Infectious Diseases Research	002	2	6/10/2022	NON-COMPETING CONTINUATION	$4
2022	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Allergy and Infectious Diseases Research	001	2	5/5/2022	NON-COMPETING CONTINUATION	$1,272
2022	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Allergy and Infectious Diseases Research	000	2	12/1/2021	NON-COMPETING CONTINUATION	$72,958
														Subtotal = $74,234

Issue Date FY: 2021 ( Subtotal = $71,062 )
2021	2021	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Allergy and Infectious Diseases Research	002	1	2/8/2021	NEW	$1,116
2021	2021	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Allergy and Infectious Diseases Research	003	1	9/1/2021	SUPPLEMENT FOR EXPANSION	$2,500
2021	2021	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Allergy and Infectious Diseases Research	000	1	12/15/2020	NEW	$67,446
2021	2021	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Allergy and Infectious Diseases Research	001	1	12/15/2020	NEW	$0
														Subtotal = $71,062

Grand Total All Awards = $129,468

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Defining the molecular inventory of staphylococcal tissue abscesses and its effects on the host-pathogen interface

Award Number: F32AI157215

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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