# Cardiac microlesion formation during invasive pneumococcal disease

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $442,403

## Abstract

ABSTRACT:
One-in-four adults hospitalized for community-acquired pneumonia (CAP) experience an adverse cardiac
event. Clinical epidemiological studies, as well as those performed in mice, non-human primates, and with
human autopsy samples indicate that Streptococcus pneumoniae (Spn), the leading cause of CAP, can invade
the heart from the bloodstream and cause direct cardiotoxicity. Within the myocardium Spn cause focal areas
of damage we have called microlesions and these disrupt contractility. One recent break-through in our
understanding of Spn pathogenesis was the observation that pneumococci are taken up by cardiomyocytes
and Spn kill these cells from within. What is more, the pore-forming toxin pneumolysin and Streptococcal
pyruvate oxidase (SpxB) derived H2O2 were both requisite for cardiotoxicity. Herein, our goal is to gain an
understanding of the events that take place within a cardiomyocyte immediately after Spn uptake.
Along such lines, results from in vitro and in vivo experiments, including dual-species RNA sequencing of Spn-
infected hearts, have revealed highly compelling connections between changes in carbon availability, H2O2
production, biofilm / cardiac microlesion formation, and pneumolysin production. Thus, we hypothesize that
glucose restriction encountered by Spn within a cardiomyocyte, and again in cardiac microlesions, results in
metabolic and gene expression changes that enhance bacterial cardiotoxicity. To test this hypothesis and learn
how pneumolysin and H2O2 work together to kill cardiomyocytes we will:
AIM 1: Determine how environmental glucose, metabolism, and virulence are interlinked. To elucidate
the basis, extent, and consequences of these connections we will: 1) determine how purposeful shunting of
pyruvate metabolism (by means of mutation) towards the production of acetate, lactate, and/or formate impacts
gene expression under high and low glucose conditions; 2) identify how Spn gene expression changes in
longitudinal fashion after bacterial uptake by a cardiomyocyte and how this is linked to changes in Spn
metabolism; 3) determine the importance of metabolism-linked genes to Spn survival within a cardiomyocyte,
killing of the cardiomyocyte, and the overall disease process.
AIM 2: Determine how bacterial derived H2O2, together with pneumolysin, kills cardiomyocytes. SpxB
derived H2O2 and pneumolysin are both required for Spn killing of cardiomyocytes; each alone is insufficient.
To determine why we will: 1) determine how varying production of H2O2 and pneumolysin together modulate
the form of cardiomyocyte death; 2) determine if H2O2 potentiates pneumolysin production, its release from
Spn, or host cell membrane targeting; and, 3) determine if SpxB-derived H2O2 contributes to the ion
dysregulation that has previously been implicated in pneumolysin-induced necroptosis. This aim, at its
completion, will advance our understanding of how Spn kills host cells.

## Key facts

- **NIH application ID:** 10069299
- **Project number:** 5R01AI114800-07
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Carlos J Orihuela
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $442,403
- **Award type:** 5
- **Project period:** 2014-11-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10069299

## Citation

> US National Institutes of Health, RePORTER application 10069299, Cardiac microlesion formation during invasive pneumococcal disease (5R01AI114800-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10069299. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*