# Developing a set of robust tools to interrogate Legionella effector function

> **NIH NIH R03** · JOHNS HOPKINS UNIVERSITY · 2021 · $81,875

## Abstract

PROJECT SUMMARY
 Infectious disease is a major threat to human health worldwide. The emergence of antibiotic
resistance pathogens necessitates the development of new drugs to treat infection. Virulence
factors that pathogens employ to promote their survival and growth in host cells represent
promising targets for therapeutic intervention.
 Most bacterial pathogens employ sophisticated secretion systems to translocate bacterial
proteins called effectors into the host cell to modulate host cell processes for their own benefit.
The bacterial pathogen Legionella, which causes life-threatening pneumonia in humans, has
one of the largest repertoires of effector proteins described to date. Defects in secretion have
pleiotropic effects on Legionella pathogenesis as they prevent both the formation of a replication
permissive vacuole and bacterial escape from a degradative lysosomal compartment. This limits
bacterial burden by preventing their proliferation while enabling pathogen killing by the host cell.
Despite the crucial role of the secretion system itself, the contributions of individual effectors
and the critical events responsible for Legionella pathogenesis remain poorly understood.
 A major obstacle in defining how Legionella causes disease is the lack virulence defects
associated with loss of individual effectors. This can result from redundancy between effectors
or the analysis of a limited set of host cell types and/or virulence traits. Moreover, effectors are
typically studied in isolation despite the coordinated activities of many effectors during infection,
with some modulating parallel or complementary host pathways, some functioning in pairs as
on/off switches and some regulating the activity of other effectors. Defining critical events
responsible for disease and the effectors governing these processes requires a high throughput
strategy to simultaneously analyze the entire collection of effectors under a variety of conditions.
 The goal of the proposed work is to generate a library L. pneumophila mutants representing
all 384 effectors and, in the process, a set of genetic tools to systematically interrogate effector
regulation and function. Collectively, these reagents will provide a foundation for numerous key
avenues of investigation and an invaluable resource to the research community. Such a
systems level approach to studying effectors is not only unprecedented but paramount to
characterizing a critical set of virulence factors in Legionella pathogenesis and thus the
development of new strategies to prevent and treat disease.

## Key facts

- **NIH application ID:** 10108037
- **Project number:** 1R03AI156526-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Tamara O'Connor
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $81,875
- **Award type:** 1
- **Project period:** 2020-11-23 → 2022-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10108037

## Citation

> US National Institutes of Health, RePORTER application 10108037, Developing a set of robust tools to interrogate Legionella effector function (1R03AI156526-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10108037. Licensed CC0.

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