Approximately 1/5 of adults hospitalized for community-acquired pneumonia (CAP) experience cardiac arrhythmia, congestive heart failure, and/or myocardial infarction and this contributes substantially to mortality. We have made the novel and seminal observation that Streptococcus pneumoniae, the leading cause of CAP, can enter the myocardium during invasive pneumococcal disease (IPD) and forms microscopic vacuolar lesions (i.e. microlesions) filled with extracellular pneumococci. In mice with IPD, cardiac microlesion formation was concomitant with aberrant cardiac electrophysiology indicative of ongoing heart failure. In stark contrast to cardiac infections caused by other bacteria, S. pneumoniae cardiac microlesion formation is remarkable due to the complete absence of infiltrated immune cells. Why this occurs is unknown, yet the lack of a host response is undoubtedly permissive for heart damage. We hypothesize that S. pneumoniae forms an immunoquiescent biofilm within the cardiac microlesion. Our preliminary results support this notion and demonstrate that biofilm S. pneumoniae (BF-Spn) does not incite NF?B activation from host cells nor results in the production of pro-inflammatory cytokines. Our goal is to discern the host-pathogen interactions that occur during cardiac microlesion formation and identify targets for intervention.
Aim 1 : Determine the requirement for biofilm formation during pneumococcal cardiac microlesion formation. We will examine cardiac microlesions for the presence of biofilm extracellular matrix components and test isolated S. pneumoniae for the biofilm phenotype. We will test the ability of S. pneumoniae mutants deficient in the ability to form biofilms in vitro for their ability to form cardiac microlesions in vivo. We will compare the cytokine and chemokine response of cardiomyocytes exposed to planktonic (P-Spn) and BF-Spn.
This aim will directly test if S. pneumoniae within cardiac microlesions are in an immunoquiescent biofilm.
Aim 2 : Characterize S. pneumoniae within cardiac microlesions and identify novel virulence determinants required for their formation. Using RNA-sequencing we will characterize and then compare the gene expression profile of S. pneumoniae in cardiac microlesions to those in the blood of infected mice. Genes with high in vivo gene expression will be deleted and isogenic mutants tested for the ability to cause cardiac microlesions.
This aim will characterize how S. pneumoniae adapts to growth within the heart and identify in an unbiased manner targets for intervention.
Aim 3 : Characterize the cardiomyocyte response to pneumolysin exposure. We will measure the cytokine/chemokine response and susceptibility of cardiomyocytes to pneumolysin, the S. pneumoniae pore forming toxin, and bacterial cell wall. We will test if S. pneumoniae activates the NLRP3 inflammasome within cardiomyocytes. We will determine if sub-lytic levels of pneumolysin trigger the intrinsic pathway of apoptosis in cardiomyocytes.
This aim will discern if cardiomyocytes exposed to S. pneumoniae undergo a cell death program that is not inflammatory.

Public Health Relevance

Streptococcus pneumoniae is responsible for >1.5 million deaths annually; many of which are the result of an adverse cardiac event during infection. We have made the seminal observation that cardiac lesions filled with bacteria form in the heart during S. pneumoniae infection and this is associated with heart failure. This proposal seeks to examine the host-pathogen interactions that occur during cardiac lesion formation and to identify potential targets for intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI114800-04
Application #
9377528
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Lu, Kristina
Project Start
2015-11-01
Project End
2019-10-31
Budget Start
2017-11-01
Budget End
2018-10-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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Shenoy, Anukul T; Brissac, Terry; Gilley, Ryan P et al. (2017) Streptococcus pneumoniae in the heart subvert the host response through biofilm-mediated resident macrophage killing. PLoS Pathog 13:e1006582
Spencer, Brady L; Saad, Jamil S; Shenoy, Anukul T et al. (2017) Position of O-Acetylation within the Capsular Repeat Unit Impacts the Biological Properties of Pneumococcal Serotypes 33A and 33F. Infect Immun 85:
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Lizcano, Anel; Akula Suresh Babu, Ramya; Shenoy, Anukul T et al. (2017) Transcriptional organization of pneumococcal psrP-secY2A2 and impact of GtfA and GtfB deletion on PsrP-associated virulence properties. Microbes Infect 19:323-333
Brissac, Terry; Shenoy, Anukul T; Patterson, LaDonna A et al. (2017) Cell invasion and pyruvate oxidase derived H2O2 are critical for Streptococcus pneumoniae mediated cardiomyocyte killing. Infect Immun :
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González-Juarbe, Norberto; Shen, Haiqian; Bergman, Molly A et al. (2017) YopE specific CD8+ T cells provide protection against systemic and mucosal Yersinia pseudotuberculosis infection. PLoS One 12:e0172314
Calhoun, Cheresa; Shivshankar, Pooja; Saker, Mirna et al. (2016) Senescent Cells Contribute to the Physiological Remodeling of Aged Lungs. J Gerontol A Biol Sci Med Sci 71:153-60
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