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Microbial and Host Factors that Promote Epithelial Disruption and S. pneumoniae Transit out of the Lung

Award Number: SC2GM141988
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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Microbial and Host Factors that Promote Epithelial Disruption and S. pneumoniae Transit out of the Lung - Project Summary Streptococcus pneumoniae causes ~900,000 cases of pneumococcal pneumonia annually in the US, with a mortality rate of 5-7%, making this disease a major health and financial burden. S. pneumoniae lung infections can spread to the bloodstream (bacteremia) and lead to severe patient outcomes. The goal of the proposed research is to elucidate the microbial (Aim 1) and host (Aim 2) factors that enable this bacterium to transit from the lung to the blood, an ability that is critical for many respiratory pathogens to cause disseminated infection. An important virulence factor during S. pneumoniae infection is pneumolysin (PLY), a pore forming toxin, which has been implicated in the development of bacteremia. S. pneumoniae infections are also characterized by an excessive immune response mediated primarily by white blood cells called polymorphonuclear cells (PMNs) that can cause host damage and result in lethal infection. Our overall hypothesis is that PLY and PMN migration disrupt the lung epithelium, promoting bacterial transit from the lung into the bloodstream. We will investigate this hypothesis by using an in vitro transepithelial migration assay, which allows us to assess how bacteria transit across the lung epithelium, analogous to bacterial dissemination from the lungs into the bloodstream in vivo. This versatile system models diverse microenvironments, is easy to maintain, and integrates seamlessly with other molecular biology and microbiology techniques. In Aim 1 we will determine how PLY disrupts intercellular junctions of the lung epithelium and how that promotes S. pneumoniae transit out of the lungs independent of PMNs. To assess PLY-mediated removal of intercellular junction proteins, we will infect polarized lung epithelial monolayers with PLY-proficient (WT) or PLY-deficient isogenic bacterial strains, stain intercellular junction proteins with fluorescent antibodies, image the monolayers by confocal microscopy, and use Image J and Prism software to perform quantitative image and statistical analysis, respectively. In parallel, we will quantify S. pneumoniae transit across lung epithelial monolayers to connect PLY-mediated disruptions of intercellular junctions to changes in bacterial migration in the absence of PMNs. In Aim 2 we will identify how PMNs disrupt intercellular junctions of the lung epithelium and how this perturbation promotes S. pneumoniae transit out of the lungs. To evaluate PMN-mediated removal of intercellular junction proteins, we will infect polarized lung epithelial monolayers with WT S. pneumoniae in the presence or absence of PMNs, stain intercellular junction proteins with fluorescent antibodies, image the monolayers by confocal microscopy, and use Image J and Prism software to perform quantitative image and statistical analysis, respectively. In parallel with these experiments, we will measure S. pneumoniae transit across the lung epithelial monolayers to connect PMN-mediated monolayer disruptions with changes in bacterial migration. Collectively, these experiments will explain how microbial and host factors disrupt the lung epithelium, leading to bacterial dissemination, a fundamental process in S. pneumoniae pathogenesis and other lung 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: 2025 ( Subtotal = $0 )
2025	2023	SAN JOSE STATE UNIVERSITY RESEARCH FOUNDATION	1 WASHINGTON SQ	SAN JOSE	CA	95112	SANTA CLARA	USA	Biomedical Research and Research Training	000	3	6/16/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $146,500 )
2023	2023	SAN JOSE STATE UNIVERSITY RESEARCH FOUNDATION	210 4TH ST 3RD FL	SAN JOSE	CA	95112	SANTA CLARA	USA	Biomedical Research and Research Training	000	3	3/17/2023	NON-COMPETING CONTINUATION	$146,500
														Subtotal = $146,500

Issue Date FY: 2022 ( Subtotal = $146,500 )
2022	2022	SAN JOSE STATE UNIVERSITY RESEARCH FOUNDATION	210 4TH ST 3RD FL	SAN JOSE	CA	95112	SANTA CLARA	USA	Biomedical Research and Research Training	001	2	6/15/2022	NON-COMPETING CONTINUATION	$14,650
2022	2022	SAN JOSE STATE UNIVERSITY RESEARCH FOUNDATION	210 4TH ST 3RD FL	SAN JOSE	CA	95112	SANTA CLARA	USA	Biomedical Research and Research Training	000	2	3/24/2022	NON-COMPETING CONTINUATION	$131,850
														Subtotal = $146,500

Issue Date FY: 2021 ( Subtotal = $146,500 )
2021	2021	SAN JOSE STATE UNIVERSITY RESEARCH FOUNDATION	210 FOURTH ST 4TH FL	SAN JOSE	CA	95112	SANTA CLARA	USA	Biomedical Research and Research Training	000	1	3/11/2021	NEW	$146,500
														Subtotal = $146,500

Grand Total All Awards = $439,500

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Microbial and Host Factors that Promote Epithelial Disruption and S. pneumoniae Transit out of the Lung

Award Number: SC2GM141988

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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