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Cardiac microlesion formation during invasive pneumococcal disease

Award Number: R01AI114800
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: 11/01/2014
PERIOD OF PERFORMANCE END DATE: 05/31/2030

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Cardiac microlesion formation during invasive pneumococcal disease - One-in-five adults hospitalized for Streptococcus pneumoniae (Spn, the pneumococcus) pneumonia experience a major adverse cardiac event (MACE) with affected individuals four times more likely to die than those with pneumonia alone. Spn-associated MACE is the result of the physiological stress imposed on the heart as well as direct cardiac damage caused by harmful bacterial products. This competitive Multi-PI R01 renewal is focused on identifying the molecular mechanisms underlying the hyper-virulence of Global Pneumococcal Sequence Cluster 10 (GPSC10). GPSC10 is a globally distributed and expanding genetic lineage of Spn which causes MACE at 2.5-fold the rate of all other GPSC. Moreover, GPSC10 is multi-drug resistant and has member isolates carrying serotypes not covered by the newest 20-valent conjugate vaccine. Thus, current prophylactic and therapeutic approaches against GPSC10 are inadequate. Our goal is to identify the genetic determinants responsible for GPSC10 hyper-virulence and determine if the encoded proteins are viable targets for intervention. Our hypotheses are: 1) genes present in GPSC10 and absent in non-invasive / non-cardiotropic GPSC are responsible for its enhanced virulence, and 2) virulence determinants encoded by these genes can be blocked for protection against severe disease, cardiac damage, and MACE. Note, that in pilot studies we have already determined that a particular allele of zmpB, a gene encoding a zinc metalloprotease (Zmp), is disproportionately present among GPSC10 isolates; that an isogenic zmpB deficient mutant, i.e., ∆zmpB, had substantially reduced capacity to cause cardiac damage in mice versus wildtype Spn; and collected data that suggests immunization with recombinant (r)ZmpB is protective against cardiac damage following invasive disease. Thus, our chosen approach is strong. AIM 1: Identify the genetic determinants responsible for GPSC10 hyper-virulence and cardiac tropism. Using Spn whole genome sequences, deidentified metadata corresponding to in-house clinical isolates, and results obtained from mice experimentally challenged with clinical isolates, we will perform multiple bacterial genome wide association studies (bGWAS) to identify the genetic elements whose presence correlate with GPSC10 hyper-virulence. Genes identified as associated with cardiac damage will be deleted in diverse Spn, including GPSC10, and their contribution to disease verified in vivo. AIM 2: Determine how ZmpB contributes to cardiac damage and assess the protective efficacy of antibody. We will confirm the role of ZmpB not only in acute cardiac injury, but also with regard to the adverse cardiac remodeling and dysfunction that takes place post-infection. We will determine the molecular basis for its secretion, a novel feature of ZmpB versus other zinc metalloproteases found in Spn and determine the impact of blocking this process on virulence and disease. We will test if immunization with ZmpB confers cardiac protection and whether passive administration of antibody has therapeutic efficacy.


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 = $534,877 )
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	001	11	5/23/2025	COMPETING CONTINUATION	$547,115
2025	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	10	4/21/2025	NON-COMPETING CONTINUATION	-$12,238
														Subtotal = $534,877

Issue Date FY: 2024 ( Subtotal = $437,177 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	001	10	5/16/2024	NON-COMPETING CONTINUATION	$43,718
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	10	11/3/2023	NON-COMPETING CONTINUATION	$393,459
														Subtotal = $437,177

Issue Date FY: 2023 ( Subtotal = $444,846 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	9	11/28/2022	NON-COMPETING CONTINUATION	$444,846
														Subtotal = $444,846

Issue Date FY: 2022 ( Subtotal = $437,199 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	8	11/1/2021	NON-COMPETING CONTINUATION	$437,199
														Subtotal = $437,199

Issue Date FY: 2021 ( Subtotal = $442,403 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	7	11/24/2020	NON-COMPETING CONTINUATION	$442,403
														Subtotal = $442,403

Issue Date FY: 2020 ( Subtotal = $455,461 )
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	001	6	12/10/2019	COMPETING CONTINUATION	$455,461
2020	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	002	5	4/22/2020	NON-COMPETING CONTINUATION	$0
2020	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	5	12/9/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $455,461

Issue Date FY: 2019 ( Subtotal = $361,860 )
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	5	10/25/2018	NON-COMPETING CONTINUATION	$361,860
														Subtotal = $361,860

Issue Date FY: 2018 ( Subtotal = $361,860 )
2018	2018	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	4	10/26/2017	NON-COMPETING CONTINUATION	$361,860
														Subtotal = $361,860

Issue Date FY: 2017 ( Subtotal = $364,297 )
2017	2017	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	3	10/25/2016	NON-COMPETING CONTINUATION	$364,297
														Subtotal = $364,297

Issue Date FY: 2016 ( Subtotal = $379,130 )
2016	2016	UNIVERSITY OF ALABAMA AT BIRMINGHAM	1530 3rd Avenue South, AB 1170	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	001	2	11/11/2015	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$379,130
2016	2015	UNIVERSITY OF TEXAS HEALTH SCIENCE CTR AT SAN ANTONIO	7703 FLOYD CURL DRIVE	SAN ANTONIO	TX	78284	BEXAR	USA	Allergy and Infectious Diseases Research	000	1	11/10/2015	NEW	$0
														Subtotal = $379,130

Issue Date FY: 2015 ( Subtotal = $383,582 )
2015	2015	UNIVERSITY OF TEXAS HEALTH SCIENCE CTR AT SAN ANTONIO	7703 FLOYD CURL DRIVE	SAN ANTONIO	TX	78229	BEXAR	USA	Allergy and Infectious Diseases Research	000	1	10/29/2014	NEW	$383,582
														Subtotal = $383,582

Grand Total All Awards = $4,602,692

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Cardiac microlesion formation during invasive pneumococcal disease

Award Number: R01AI114800

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: 11/01/2014

PERIOD OF PERFORMANCE END DATE: 05/31/2030

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