# Interaction of the Burkholderia type VI secretion system with innate host defenses

> **NIH NIH R21** · UNIVERSITY OF WASHINGTON · 2020 · $163,804

## Abstract

Melioidosis is a tropical infection caused by inoculation, inhalation, or ingestion of the Gram-negative soil
saprophyte and Tier 1 select agent Burkholderia pseudomallei (Bps). Pneumonia is a common manifestation of
infection, is frequently associated with septic shock, and confers a two-fold increase in mortality. Bps is
intrinsically resistant to many common antibiotics. The standard therapies to which Bps is susceptible are
ceftazidime and carbapenems yet patients may take days to defervesce once on treatment and need extended
courses of therapy. Treatments for melioidosis have not changed substantially in decades and the case fatality
rate in northeast Thailand has remained at 40% since 1989. New therapies are urgently needed; yet to develop
effective therapies it is essential to advance understanding of the pathogen's ability to persist, especially in the
lung. The multiple PIs of this application offer expertise in pulmonary host defenses (West) and in Burkholderia
virulence factors (Schwarz). Together, these investigators have studied both Bps and the closely related
bacterium Burkholderia thailandensis (Bt), a surrogate organism to Bps that is avirulent in humans and exempt
from select agent restrictions. Bt/Bps, facultative intracellular bacteria, enter a wide variety of cell types and
can escape the endosome into the cytosol. The type III secretion system (T3SS) is involved in cellular invasion
and endosomal escape. Bt/Bps can induce cell-cell fusions in a type VI secretion system (T6SS)-mediated
fashion that may facilitate intercellular spread. Bps can enter primary alveolar macrophages and bronchial
epithelial cells in vitro, yet replication in alveolar macrophages is contained whereas replication in bronchial
epithelial cells is unrestricted. However, the extent of intracellular parasitism by Bt/Bps, the cells that Bt/Bps
infects in the lung, and the effect of T3SS and T6SS on these host-pathogen interactions have not been
studied in vivo. The central hypothesis of this project is that Bps differentially parasitizes, replicates, and
spreads intercellularly in specific pulmonary cell types in vivo; these processes are variably dependent on
T3SS or T6SS, and they impede successful treatment. It is critical to test this hypothesis in order to develop
new cell- or pathogen-targeted therapies for this infection. This will be accomplished using a novel dual
fluorescent Bt reporter construct that signals when the bacterium is located within the cytoplasm of the host
cell. The aims of the project are: 1) Determine whether specific cell types are differentially parasitized by Bt in
the lung in vivo; 2) Determine whether T3SS and T6SS alter intracellular localization and the specific cells
parasitized by Bt in the lung in vivo; 3) Determine whether standard treatment for melioidosis successfully kills
intracellular Bt in the lung in vivo. The scientific value of this project is that it will advance understanding of the
specific host cells par...

## Key facts

- **NIH application ID:** 9844443
- **Project number:** 5R21AI137430-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Sandra Schwarz
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $163,804
- **Award type:** 5
- **Project period:** 2019-01-04 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9844443

## Citation

> US National Institutes of Health, RePORTER application 9844443, Interaction of the Burkholderia type VI secretion system with innate host defenses (5R21AI137430-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9844443. Licensed CC0.

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