# Novel Determinants of Streptococcus Pyogenes Virulence and Protective Immunity in the Primate Oropharynx: A Genome-wide Strategy

> **NIH NIH R56** · METHODIST HOSPITAL RESEARCH INSTITUTE · 2021 · $439,989

## Abstract

PROJECT SUMMARY
The human bacterial pathogen Streptococcus pyogenes (group A streptococcus, GAS) causes more than 600
million cases of pharyngitis annually worldwide. Despite 100 years of effort, this organism has successfully defied
attempts to create a vaccine that protects humans from pharyngitis and invasive infections. We believe a new
strategy is warranted and necessary. The proposed research seeks to discover, on a genome-wide scale using
a strategy not previously applied to GAS vaccinology, novel GAS genes contributing to pharyngitis, and exploit
this information for vaccine research efforts. It is our thesis that this knowledge gap has severely limited the
ability to fully understand the virulence determinants at work in the upper respiratory tract (URT) and create a
protective GAS vaccine. We will address these issues by combining our recent successes applying transposon-
directed insertion site sequencing (TraDIS) technology to GAS in several settings, together with our 19 years of
productively using a cynomolgus macaque (nonhuman primate, NHP) model of pharyngitis, in vaccinology
research. We will first use TraDIS to conduct in vivo genome-wide screens to systematically identify serotype
M89 GAS genes required for colonization, clinical disease, and persistence in the URT of NHPs. These data will
complement and enrich analogous information we have already generated for serotype M1 and M28 GAS. Our
central hypothesis is that defining the GAS genes that contribute to fitness in the NHP URT will
significantly improve our understanding of the molecular processes occurring in this niche, thereby
filling a massive knowledge gap and leading to new strategies for creating a vaccine that protects against
GAS pharyngitis. We propose the following three specific aims: Specific Aim 1: Exploit TraDIS for genome-
wide identification of serotype M89 GAS genes required for colonization, acute clinical disease, and persistence
(i.e., fitness) in the URT of NHPs. Specific Aim 2: Use our combined M1, M28, and M89 TraDIS URT screen
data to generate isogenic gene-deletion mutant strains and validate the importance of additional selected
candidate genes in causing GAS pharyngitis in NHPs. Specific Aim 3: Determine if vaccination of NHPs with
proteins encoded by genes identified in Specific Aims 1 and 2 confers protective immunity against experimental
pharyngitis caused by homologous (serotype M1) and heterologous (serotype M28) M protein serotypes of GAS.
The proposed line of research will exploit and significantly expand studies funded by an R21 grant, and our
innovative and successful application of TraDIS to GAS, our long history of GAS pharyngitis and vaccinology
studies using NHPs, our analyses of human specimens, and our contributions to understanding the basic biology
of GAS molecular pathogenesis and genomics. In essence, this research represents a new way forward for GAS
vaccine efforts. Important to note, an analogous strategy has been used to id...

## Key facts

- **NIH application ID:** 10387431
- **Project number:** 1R56AI148559-01A1
- **Recipient organization:** METHODIST HOSPITAL RESEARCH INSTITUTE
- **Principal Investigator:** James MALLORY Musser
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $439,989
- **Award type:** 1
- **Project period:** 2021-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10387431

## Citation

> US National Institutes of Health, RePORTER application 10387431, Novel Determinants of Streptococcus Pyogenes Virulence and Protective Immunity in the Primate Oropharynx: A Genome-wide Strategy (1R56AI148559-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10387431. Licensed CC0.

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