# Complementary Mechanisms of Protection Against Pneumococcal Infection

> **NIH VA I01** · VA EASTERN COLORADO HEALTH CARE SYSTEM · 2020 · —

## Abstract

A leading cause of pneumonia and related morbidity and mortality is the mucosal pathogen, Streptococcus
pneumoniae. Beginning at the upper respiratory mucosa, infection begins with colonization which can then be
complicated by pneumonia and invasive bloodstream infections. The most prominent antibody in these
mucosal sites is the IgA1 subclass. IgA1 antibodies to the pneumococcal capsule, its primary virulence factor,
are generated in response to colonization, symptomatic infection and vaccination. The variable region of IgA1
binds to the organism and the constant region binds to phagocytes (e.g., alveolar macrophages and
neutrophils). A pneumococcal enzyme, IgA1 protease, is expressed on the surface of the bacteria. IgA1 bound
to the capsule is cleaved by the protease at the bridging hinge between the variable and constant region,
thereby inhibiting the ability of IgA1 to support phagocytosis, killing and clearance of the organism. Residual
variable regions that remain on the surface modify the bacteria's surface and enhance binding to epithelial cell
receptors, likely promoting colonization with the organism. This subversion of the protective host response to
S. pneumoniae predisposes older veterans to increased risk for serious infection.
 Preventing the bacteria's inactivation of the host's response can be achieved by a subset of patients with
invasive pneumococcal disease who generate IgG in serum that neutralizes the protease's ability to cleave
IgA. Moreover, we have generated murine monoclonal antibodies (mMabs) that bind and some neutralize the
protease. We propose to advance our understanding of the structure-function relationships of the protease
and consider the feasibility of advancing this protein as a primary or adjunctive vaccine candidate. In this
context, we Hypothesize that:
1) Neutralizing antibodies to IgA1 protease recognize conserved epitopes on the enzyme.
2) Protease-neutralizing antibodies with human IgA1 and prevent epithelial cell binding in
 vitro and colonization with intranasal challenge in vivo by inhibition of IgA1 cleavage.
3) Antibodies to IgA1 protease protect mice against fatal mucosal infection with S. pneumoniae indirectly by
inhibiting cleavage of human IgA1 bound to the bacterial surface and directly by surface binding and
mediating phagocytosis of the organism.
To address these Hypotheses, we propose to pursue the following Specific Aims:
Aim 1. Characterize the epitopes targeted by protease-neutralizing monoclonal antibodies (Mabs) and their
 genetic conservation.
Aim 2. Characterize the epitopes targeted by protease-neutralizing monoclonal antibodies (Mabs) and their
 genetic conservation.
Aim 3. Determine the ability of protease-specific Mab's to protect against fatal infection after mucosal
 challenge in vivo and the mechanisms underlying protection.
 This work is directed to determine the targets of the protease-neutralizing antibodies, the geographic and
molecular diversity of pneumococcal proteases...

## Key facts

- **NIH application ID:** 9913982
- **Project number:** 5I01BX004320-02
- **Recipient organization:** VA EASTERN COLORADO HEALTH CARE SYSTEM
- **Principal Investigator:** Edward N Janoff
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9913982

## Citation

> US National Institutes of Health, RePORTER application 9913982, Complementary Mechanisms of Protection Against Pneumococcal Infection (5I01BX004320-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9913982. Licensed CC0.

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