# Oxidative killing of Pneumococcus

> **NIH NIH R21** · UNIVERSITY OF GEORGIA · 2020 · $188,750

## Abstract

Streptococcus pneumoniae (Spn) is the main cause of community acquired pneumonia and
meningitis in children and the elderly, and of septicemia in HIV patients. Boosting the function of host
immune responses could offer novel intervention strategies against Spn. There is a critical gap in our
knowledge to identify new, broad range, anti-Spn mechanisms of the respiratory innate immune system.
Bronchial epithelial cells (BEC) are the primary responders to Spn infection. BECs orchestrate an
oxidative extracellular antimicrobial system present in the airway surface liquid consisting of the protein
lactoperoxidase (LPO), the thiocyanate anion (SCN-) and hydrogen peroxide (H2O2). LPO oxidizes SCN-
using H2O2 into microbicidal hypothiocyanite (OSCN-). Dual oxidase 1 (Duox1), an NADPH oxidase
protein highly expressed in the apical membrane of BECs, is the H2O2 source for the antimicrobial action
of LPO. Our preliminary result show that the Duox1/LPO-based system efficiently kills several strains of
Spn in different experimental systems. Our long-term goal is to determine whether the Duox1/LPO/SCN-
antibacterial system could be manipulated in Spn infection for therapeutic purposes in humans. The
objective of this proposal is to establish the anti-Spn role of the Duox1/LPO-based oxidative mechanism.
Based on preliminary data our central hypothesis is that the Duox1/H2O2/LPO/SCN- system kills Spn
bacteria in a strain-independent manner, attenuates infection and associated tissue damage in a mouse
model of Spn lung infection. To test this hypothesis, our specific aims are to determine the mechanism
of Spn killing by Duox1/LPO in vitro, to establish the in vivo role of Duox1 in Spn killing, and to explore
whether therapeutic manipulation of the Duox1/LPO-based system attenuates Spn pneumonia in an
animal model. The rationale for the proposed research is that we need to characterize how powerful the
Duox1/LPO-based system is in fighting Spn to explore its therapeutical potential in humans in the future.
It is anticipated that our aims will yield the following expected outcomes: 1) identification of the
antibacterial mechanism of the Duox1/LPO-based system against Spn, 2) establishing the in vivo
relevance of Duox1 in Spn infection; and 3) providing essential results on the therapeutic potential of the
Duox1/LPO-based mechanism to attenuate Spn lung infection. Our innovative work shows that a unique
antimicrobial system is powerful in killing Spn and explores a novel, nontraditional immune mechanism
for its potential to be used against a major lung pathogen. In summary, our proposal will have a positive
impact in the fields of airway epithelial and Spn biology, and general antibacterial innate immune
responses by identifying Duox1 and LPO, as a novel, crucial, innate immune weapons of the respiratory
innate immune system against Spn.

## Key facts

- **NIH application ID:** 9986347
- **Project number:** 1R21AI147097-01A1
- **Recipient organization:** UNIVERSITY OF GEORGIA
- **Principal Investigator:** Balazs Rada
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $188,750
- **Award type:** 1
- **Project period:** 2020-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986347

## Citation

> US National Institutes of Health, RePORTER application 9986347, Oxidative killing of Pneumococcus (1R21AI147097-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9986347. Licensed CC0.

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