# Mechanisms of pneumococcal persistence during carriage

> **NIH NIH R37** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2021 · $508,502

## Abstract

Microbial infection often begins with colonization. Success for an organism requires persistence
during colonization for a sufficient period to allow for host-to-host transmission. For the leading
bacterial pathogen Streptococcus pneumoniae (Spn), colonization occurs along the mucosal
surfaces of the upper respiratory tract. Extensive experience with vaccination has shown that
interruption of colonization is the key to reducing the burden of all Spn disease. Our ongoing
project examines the biology of Spn colonization, which occurs in recurrent episodes that are
prolonged (lasting weeks to months), variable in duration by serotype, and more common during
early life. We have established models of infection in adult and infant mice that recapitulate each
of these characteristics of Spn colonization in the natural host. Our preliminary data using these
models establish the importance of two bacterial factors, the pore-forming toxin pneumolysin (Ply)
and capsule, the determinant of serotype. Additionally, we have shown critical roles for three host
factors, the alarmin IL-1α, the cytokine IL-17, and the macrophage scavenger receptor MARCO.
This proposal examines the relationship between these factors. In Aim#1, we test the hypothesis
that IL-1α is released in a Ply-dependent manner following Spn uptake by neutrophils and triggers
the differentiation/proliferation of CD4+ T cells to express IL-17. A further aspect of this aim is that
attenuated neutrophil responses during infancy delay the IL-17 response resulting in more
persistent colonization. Elevated IL-17 levels are required to drive an increase in numbers of
macrophages derived from the pool of inflammatory monocytes. In Aim#2, we test the contribution
of the subset of macrophages expressing MARCO as the effectors of clearance and whether
MARCO interactions with the Spn capsule dictate clearance dynamics. In this aim, we generate
a MARCO humanized mouse to determine if this interaction is responsible for differences in host-
specific patterns of colonization among serotypes. In Aim#3, we explore how inflammation
induced by Spn colonization promotes exit of the organism from its host (shedding) at levels
permissive for transmission in our animal model. Specifically, we test the hypothesis that Ply-
dependent stimulation of Type I interferons increase the flow of nasal secretions and Spn
shedding. We also test the hypothesis that Spn takes advantage of the recruitment of neutrophils
and their ability to bind to the organism to `hitch a ride' out of the host with purulent secretions.
The overall goal of this project is an understanding of these determinants of colonization with a
long-term view towards a more comprehensive approach to address the continuing public health
problem of the pneumococcus.

## Key facts

- **NIH application ID:** 10205997
- **Project number:** 5R37AI038446-27
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Jeffrey Neal Weiser
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $508,502
- **Award type:** 5
- **Project period:** 1996-04-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10205997

## Citation

> US National Institutes of Health, RePORTER application 10205997, Mechanisms of pneumococcal persistence during carriage (5R37AI038446-27). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10205997. Licensed CC0.

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