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Defining the impact of host factors on the molecular architecture and bacterial physiology of Staphylococcus aureus abscesses

Award Number: R01AI145992
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY / ABSTRACT Staphylococcus aureus is capable of infecting nearly every vertebrate organ system, triggering the formation of characteristic tissue lesions known as abscesses. Understanding how S. aureus survives within abscesses is critical to the development of new therapeutics, as these lesions represent the pathogen niche during infection. In this application, we will leverage a powerful mass spectrometry-based imaging platform to identify host and bacterial factors that contribute to staphylococcal disease. By defining how tissue niche and host biology drive molecular heterogeneity in abscesses, we will uncover new targets for tailored anti-staphylococcal therapeutics. Historically, it has been technically challenging to study the bacterial and host factors that contribute to abscess physiology for two primary reasons. First, approaches that seek to preserve abscess architecture within a tissue sample are inherently limited to the study of known microbial and host targets. This applies to techniques such as immunohistochemistry and fluorescence in situ hybridization, which can define the spatial distribution of analytes in a tissue but rely on pre-existing knowledge of targets. These approaches, by definition, cannot be used to discover unknown bacterial or host factors that contribute to disease. Conversely, discovery-based methods such as RNA sequencing or proteomics can identify novel, disease-associated analytes, but require destructive tissue processing that eliminates information regarding the spatial orientation of microbial and host molecules. To overcome these technical limitations, we created a mass spectrometry-based imaging platform to identify host and microbial analytes in abscessed tissue during invasive S. aureus infection. Because imaging mass spectrometry (IMS) does not require probes or detection reagents, this platform can define the localization and abundance of abscess-associated analytes in a spatially-defined manner, thereby enabling the discovery of microbial and host factors that contribute to disease pathogenesis. When applied to a model of disseminated S. aureus infection, this IMS-based platform enabled three-dimensional molecular imaging of the staphylococcal- host interface and powered the discovery of bacterial proteins that mark the pathogen niche within abscesses. Although individual abscesses typically have a similar histologic appearance, our IMS-based analysis revealed significant molecular heterogeneity between S. aureus lesions. We hypothesize that abscesses display molecular heterogeneity in response to tissue niche, antibacterial immune responses, and comorbid host conditions. To test this hypothesis, we will couple our IMS platform with laser capture microdissection to enable spatially-resolved proteomics of the staphylococcal-host interface. The proposed Aims will define the molecular architecture of abscesses across S. aureus infected tissues and determine how innate immune effector cells and host comorbidities drive heterogeneity in bacterial physiology and abscess molecular architecture in situ. In total, these experiments will decipher how host biology drives molecular heterogeneity during invasive infection.


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 = $646,808 )
2024	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Allergy and Infectious Diseases Research	000	5	2/29/2024	NON-COMPETING CONTINUATION	$646,808
														Subtotal = $646,808

Issue Date FY: 2023 ( Subtotal = $740,709 )
2023	2023	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Allergy and Infectious Diseases Research	000	4	2/21/2023	NON-COMPETING CONTINUATION	$740,709
														Subtotal = $740,709

Issue Date FY: 2022 ( Subtotal = $753,739 )
2022	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Allergy and Infectious Diseases Research	000	3	2/7/2022	NON-COMPETING CONTINUATION	$753,739
														Subtotal = $753,739

Issue Date FY: 2021 ( Subtotal = $755,506 )
2021	2021	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Allergy and Infectious Diseases Research	000	2	2/19/2021	NON-COMPETING CONTINUATION	$755,506
														Subtotal = $755,506

Issue Date FY: 2020 ( Subtotal = $800,040 )
2020	2020	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Allergy and Infectious Diseases Research	000	1	2/27/2020	NEW	$800,040
														Subtotal = $800,040

Grand Total All Awards = $3,696,802

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Defining the impact of host factors on the molecular architecture and bacterial physiology of Staphylococcus aureus abscesses

Award Number: R01AI145992

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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