# Discovery of bacterial defense and phage counter-defense strategies

> **NIH NIH DP2** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $491,750

## Abstract

PROJECT SUMMARY
 Bacteria encode a diverse array of molecular systems to defend against infecting phages. In response,
phages have devised many counter-defense strategies to overcome this immunity and re-establish infection.
Mounting evidence suggests that most bacterial defense systems and phage counter-defenses in nature have
not been identified. This is a major knowledge gap because the interplay between these systems often
determines whether a phage successfully infects its bacterial host. These phage infections, in turn, have major
impacts on the evolution and treatment of infectious disease. For instance, pathogenesis in bacteria often
evolves due to the integration of a prophage that expresses a toxin or other virulence factor. At the same time,
phages are increasingly viewed as potential therapeutics to treat bacterial infections, especially in cases where
multi-drug resistance renders conventional treatments unsuccessful. Thus, it is important to better understand
the natural diversity of bacterial defense and phage counter-defense systems. To meet this need, we will devise
new high-throughput functional selections to find defense and counter-defense systems in microbial ecosystems
and in libraries of synthesized phage open reading frames. This functional approach does not rely on sequence
similarity to predict defense and counter-defense systems, so overcomes the limitations of conventional,
homology-based discovery methods. This strategy, therefore, is expected to identify many new defense and
counter-defense genes beyond what is known currently. It is especially valuable for examining functions encoded
in phage genomes and bacterial genomic islands, as most genes from these sources are of unknown function.
Since nearly all bacteria should encode anti-phage defense systems, and almost all phages will encode counter-
defense strategies, we expect to make many new discoveries. Because these discoveries are predicted to be
novel, we will use a combination of genetic and functional assays to describe their mechanisms of action. We
will use Escherichia coli as a host for our functional selections, not only because this will allow us to construct
large functional libraries, but also because virulence in this pathogen is driven by prophage-expressed toxins
and because its phages are among those used most commonly to develop phage therapies. Thus, our findings
will not only be broadly relevant to pathogenesis and phage therapy across bacteria, but also will yield these
insights specifically in the context of this important human pathogen.

## Key facts

- **NIH application ID:** 10049809
- **Project number:** 1DP2AI154402-01
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Kevin J Forsberg
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $491,750
- **Award type:** 1
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10049809

## Citation

> US National Institutes of Health, RePORTER application 10049809, Discovery of bacterial defense and phage counter-defense strategies (1DP2AI154402-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10049809. Licensed CC0.

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