# Identity, function and control of Francisella effectors encoded outside its pathogenicity island

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2021 · $688,713

## Abstract

Summary
The Francisella constitute a genus of Gram-negative bacteria that occupy intracellular niches within a wide
range of metazoan hosts. This group includes Francisella tularensis subsp. tularensis, a highly virulent human
pathogen that has been classified as a Tier 1 select agent due to its low infectious dose, aerosol route of
inoculation, and aggressive course of infection. Several studies have suggested that the key virulence factor of
these bacteria is the Francisella pathogenicity island (FPI), which encodes a variant of the bacterial type VI
secretion system (T6SS). However, the FPI is conserved among Francisella spp with diverse host ranges and
variable capacity to cause disease. In preliminary data accompanying this proposal, we demonstrate that
genes encoding substrate effector proteins of the FPI T6SS can be found at distal locations in the genome. We
further find that although these effectors are variably present in Francisella spp, they play important, direct
roles in promoting the virulence strategies of the bacteria that harbor them. These findings lead us to
hypothesize that the FPI-encoded T6SS serves as a versatile platform for the delivery of diverse effector
molecules encoded elsewhere within the genome. In our first aim we will define the molecular mechanism by
which one T6SS effector of F. tularensis, OpiA, facilitates intracellular replication. Importantly, the mode of
action of an FPI effector protein has not been identified to date. We show herein that OpiA is the founding
member of a family of bacterial phosphatidylinositol kinases with representatives in diverse pathogens
including Vibrio, Legionella, and Rickettsia spp. These data and additional preliminary findings suggest that
OpiA acts by manipulating host cell membrane trafficking. In our second aim, we seek to identify the proteins
required for targeting effectors to the T6SS in Francisella, as well as to define the mechanism by which the
secretory apparatus and its substrates are coordinately regulated. Finally, in the third aim we propose to
identify additional substrates of FPI-encoded T6SSs belonging to multiple F. tularensis subspecies and to
characterize their contribution to the pathogenesis of F. tularensis subsp. tularensis. Collectively, the proposed
research will provide insight into the virulence mechanisms of an important group of human and animal
pathogens.

## Key facts

- **NIH application ID:** 10187513
- **Project number:** 5R01AI145954-03
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** SIMON L DOVE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $688,713
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10187513

## Citation

> US National Institutes of Health, RePORTER application 10187513, Identity, function and control of Francisella effectors encoded outside its pathogenicity island (5R01AI145954-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10187513. Licensed CC0.

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