# Novel models for analysis of toxin synergy in Streptococcus pyogenes pathogenesis

> **NIH NIH R21** · WASHINGTON UNIVERSITY · 2020 · $196,459

## Abstract

Abstract
 Many pathogenic bacteria inject effector proteins into host cells in order to reprogram cellular
behavior. Insight into function is typically gained from studying each effector in isolation. However,
bacteria often employ multiple effectors and it is rarely considered how effector ensembles synergize to
promote unique cellular behaviors that cannot be predicted from analyses of each effector in isolation.
Thus, understanding the molecular basis of effector synergy is crucial for unraveling how cellular
reprogramming contributes to pathogenesis and the selective pressures driving effector evolution.
 Effector synergy has emerged as an important concept for understanding the pathogenesis of the
myriad diseases caused by Streptococcus pyogenes, whose virulence derives from its production of
multiple effectors that reprogram host cell behavior. An important example is Cytolysin-Mediated
Translocation (CMT), a process by which the cytolysin Streptolysin O (SLO) translocates an effector,
the S. pyogenes NAD+ glycohydrolase (SPN), across the host cell membrane into its cytosol. Synergy
continues post-translocation, as intracellular SPN modifies cellular reprogramming initiated by SLO. A
complication, is that SPN has diverged into two widely distributed haplotypes, one of which lacks its
signature NAD+ glycohydrolase activity (NADase-). Why both variants are under selection and how
each reprograms cellular behaviors to promote pathogenesis is not understood.
 There are multiple significant gaps in our understanding of synergy in CMT, including how the two
toxins interact with host cells to promote the translocation of SPN and how the biological activities of
SLO and SPN act synergistically to promote cell signaling and cell death. To address these questions,
this proposal has two overall goals: 1. To develop novel infection-free models of CMT for analysis of
specific steps leading to membrane translocation and cellular toxicity using new insights gained from
understanding that SLO has two distinct modes on binding to host cells, only one of which can support
CMT; and 2. To gain mechanistic insight into translocation, toxicity and signaling by conducting an
unbiased forward screen to identify host cell genes that support these activities. Identification of these
genes and development of new CMT models has the potential to be transformative in our
understanding of CMT and toxin synergy.

## Key facts

- **NIH application ID:** 9820718
- **Project number:** 5R21AI142554-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Michael G. Caparon
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $196,459
- **Award type:** 5
- **Project period:** 2018-11-08 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9820718

## Citation

> US National Institutes of Health, RePORTER application 9820718, Novel models for analysis of toxin synergy in Streptococcus pyogenes pathogenesis (5R21AI142554-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9820718. Licensed CC0.

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