# Mechanisms by which rickettsiae subvert autophagy pathway in macrophages

> **NIH NIH R21** · UNIVERSITY OF TEXAS MED BR GALVESTON · 2021 · $239,750

## Abstract

Tick-borne rickettsial diseases continue to cause severe illness and death in otherwise healthy adults and
children worldwide. The incidence rate of rickettsial diseases significantly increased in the past six years with
case fatality rate as high as 10%. Patients with rickettsial diseases respond well to doxycycline if the antibiotics
are administered early. However, doxycycline is not appropriate for patients in pregnancy or under age of 5
years old. Therefore, host-mechanisms based therapeutic interventions are urgently needed. Our long term
goal is to study the key host molecules by which obligately intracellular bacteria, rickettsiae, evolve to establish
their infection niche in mammalian host cells. These studies will provide insights into novel immune therapeutic
interventions. The objectives of this proposal are to reveal the mechanisms by which R. australis subvert
autophagy to facilitate infection in macrophages. The hypothesis to be tested in this proposal is that R.
australis modulates and exploits Atg5-dependent autophagy to facilitate infection via inhibiting the maturation
of autophagosomes and counteracting host immune controls in macrophages. We will evaluate the potential of
autophagy inhibition as a therapeutic strategy against life-threatening rickettsial infection by interrupting the
pathways involved in R. australis-induced Atg5-dependent autophagosomes. This project will study this
hypothesis utilizing two linked specific aims. Aim 1 will determine the mechanisms by which R. australis
induces and subverts Atg5-dependent autophagosomes for the benefit of their infection in macrophages. The
role of ULK1 in regulating rickettsiae-induced autophagosomes will be investigated. We will study the
involvement of MAVS/IRF7/ISG54 and GTPase Rab 25 in counteracting the antibacterial activity and
supporting infection in macrophages. Aim 2 will evaluate the potential of autophagy inhibition as a therapeutic
strategy against life-threatening rickettsial infection. We will employ the in vivo mouse model of rickettsial
infection to investigate the potential of targeting Atg5 (+) autophagosomes as immune-therapeutic
interventions by using specific inhibitors or stimulators of key molecules regulating autophagosomes. It is
believed that completion of the specific aims of this proposal may provide novel insights into immuno-
therapeutic strategies for treating fatal rickettsioses.

## Key facts

- **NIH application ID:** 10129150
- **Project number:** 1R21AI151904-01A1
- **Recipient organization:** UNIVERSITY OF TEXAS MED BR GALVESTON
- **Principal Investigator:** Rong Megan Fang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $239,750
- **Award type:** 1
- **Project period:** 2021-08-04 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129150

## Citation

> US National Institutes of Health, RePORTER application 10129150, Mechanisms by which rickettsiae subvert autophagy pathway in macrophages (1R21AI151904-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10129150. Licensed CC0.

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