# Revealing Stochastic Switches in Bacteria

> **NIH NIH R01** · NEW YORK UNIVERSITY · 2024 · $379,877

## Abstract

PROJECT SUMMARY
Stochastic switches are a broad class of genetic mechanisms that enable single cells to switch certain genes
on and off randomly, without responding to their environment. Such switches are prevalent in pathogenic
bacteria, where they are often involved in generating diverse surface protein repertoires across the bacterial
population, which enables a subset of cells to avoid detection by the immune system. In general, stochastic
switches provide a strategy for survival in fluctuating environments, by maintaining subpopulations of cells in
pre-adapted states that are prepared for future, possibly unpredictable, environmental stresses. In particular,
these strategies are known to be important in antibiotic persistence, a non-genetic, reversible, physiological
state with enhanced tolerance for antibiotics that occurs in a subpopulation of bacterial cells.
This grant applies novel microfluidic devices that enable single cell observations persister cell lineages, with
transcriptomics, and bioinformatics to study three major facets of stochastic switching. We use microscopy and
synthetic biology to understand why bacterial aggregation, a behavior that enhances survival under
antimicrobial treatment, is regulated by stochastic switching, and how to reverse aggregate states using small
molecule inhibitors of key genetic pathways. We use a novel custom microfluidics setup that enables single-
cell lineage tracking on hundreds of thousands of cells to observe antibiotic persister states that could not
previously be observed, and apply transcriptomics to reveal molecular mechanisms of persistence. We use a
new population genetic approach to modeling bacterial recombination, which can be flexibly applied to infer
recombination parameters from large-scale genomic and metagenomic sequencing datasets. We apply this
method to study how stochastic switching is influenced by recombination in the context of the human gut
microbiome.
The proposed research will substantially advance understanding of the role of stochastic switches,
aggregation, and recombination in bacterial adaptation. Through its emphasis on precise quantification using
powerful single cell microfluidics and microscopy, the research will yield new avenues to address antibiotic
persistence of bacteria, to perturb bacterial aggregated states, and to understand how the human gut
environment selects for and maintains antibiotic resistance and surface antigen genes.

## Key facts

- **NIH application ID:** 10906079
- **Project number:** 5R01GM097356-12
- **Recipient organization:** NEW YORK UNIVERSITY
- **Principal Investigator:** EDO L KUSSELL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $379,877
- **Award type:** 5
- **Project period:** 2011-09-15 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10906079

## Citation

> US National Institutes of Health, RePORTER application 10906079, Revealing Stochastic Switches in Bacteria (5R01GM097356-12). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10906079. Licensed CC0.

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