# Determining the mechanisms by which YesMN drives pneumococcal host-to-host transmission

> **NIH NIH R21** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2021 · $193,750

## Abstract

Description.
Streptococcus pneumoniae (Spn, the pneumococcus), a gram-positive human pathogen, is a significant cause
of morbidity and mortality worldwide. Pneumococcus causes more deaths than any other infectious disease,
with children and the elderly at the highest risk. Epidemiological data suggest host-to-host transmission
of Spn is the critical first step required for both the carrier- and the disease-state, suggesting that it is
imperative to block host-to-host events. However, because of the inherent complexities in studying natural
transmission and the absence of tractable animal models, Spn transmission is one of the least understood
aspects of this pathogen's lifecycle. We developed a tractable infant mouse model that has allowed for the
identification of host and bacterial factors that contribute towards the transmission process. More recently, we
screened random pools of transposon mutants (Tn-seq) and identified novel Spn genes whose products are
involved in host-to-host transmission. This list of Spn transmission factors included YesMN, a poorly defined
two-component system (TCS). Generally, TCS mediate rapid transcriptional changes in response to external
stimuli. Hence, our focus in this proposal is the TCS YesMN. We premise that within the upper respiratory
(URT), pneumococcus undergoes transcriptional alterations facilitated by YesMN that sense the host
environment and respond accordingly, allowing for Spn persistence and enable it to transit from one host to
another. We identified the putative regulon of YesMN through an in vitro RNA-seq screen, which included
genes involved in zinc (Zn) homeostasis. Thus, in Aim #1, we will follow up on these putative regulon
members and determine their contribution to the transmission process. We will also test whether Zn, a highly
regulated metal by the host, acts as a signal for YesMN. As pneumococcal pneumonia is considered a clinical
complication of influenza A virus (IAV) infection, we further tested whether YesMN affects Spn fitness under
the Spn-IAV coinfection setting. We observed that with a concurrent IAV infection, Spn modifies its
transcriptome, with a significant contribution from YesMN, which provides a fitness advantage in the URT. By
taking a separate approach in Aim #2, we will carry out a novel in vivo RNA-seq screen on samples obtained
from the URT and determine YesMN regulated genes that are potentially involved in providing fitness
to Spn under these dynamic coinfection conditions. Results from our current studies would, for the first time,
provide an understanding of the Spn transcriptional dynamics occurring in the URT that promote host-to-host
transmission and whether the identified factors could be potential targets to reduce pneumococcal disease
burden.

## Key facts

- **NIH application ID:** 10186702
- **Project number:** 5R21AI154047-02
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Muhammad Ammar Zafar
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $193,750
- **Award type:** 5
- **Project period:** 2020-06-10 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10186702

## Citation

> US National Institutes of Health, RePORTER application 10186702, Determining the mechanisms by which YesMN drives pneumococcal host-to-host transmission (5R21AI154047-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10186702. Licensed CC0.

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