# Targeting extracellular tRNA-derived RNA fragments (tRFs) to protect against fatal rickettsiosis

> **NIH NIH R21** · UNIVERSITY OF TEXAS MED BR GALVESTON · 2021 · $197,500

## Abstract

Rickettsioses represent devastating human infections. These arthropod-borne diseases are caused by
obligatory intracellular bacteria of the genus Rickettsia (R.). A vaccine is not available for rickettsioses.
Disseminated vascular endothelial cell (EC) infection and EC barrier dysfunction are the central pathophysiologic
features of human lethal spotted fever group rickettsial (SFGR) infections. Typically, infection with SFGR is
controlled by appropriate broad-spectrum antibiotic therapy if diagnosed early. Nevertheless, SFGR infections
present with nonspecific signs and symptoms rendering early clinical diagnosis difficult. Untreated or
misdiagnosed SFGR infections are frequently associated with severe morbidity and mortality. Comprehensive
understanding of rickettsial pathogenesis is urgently needed for the development of novel prophylactics and
post-infection (p.i.) therapeutics. We reported that, upon SFGR, RNase-mediated tRNA cleavage occurs and a
specific subset of tRNA-derived RNA fragments (tRFs) are induced. Among them, 5'-end fragment from
tRNAGlyGCC is the most prominently induced tRF, termed as tRFGlyGCC. We found that tRFGlyGCC exhibits
trans-silencing activity in a sequence-specific manner and induces EC barrier dysfunction. Several lines of new
evidence from our preliminary studies suggest that Exos derived from R. parkeri-infected human umbilical vein
EC (HUVEC) (RCExos) at 72hr p.i. or Exos derived from plasma of 2LD50 R. parkeri-nfected mice (RMExos)
on day 4 p.i. can induce dysfunction of normal recipient human brain microvascular ECs (BMECs) in a
tRFGlyGCC-dependent manner. Compared with naked format, bovine serum albumin-nanoparticlized anti-
tRFGlyGCC oligonucleotides (BSAanti-tRFGlyGCCs) in normal media with sera can maintain BMEC barrier
functions after exposure to RCExos. These findings suggest that RCExos/RMExos-packed tRFGlyGCC may
induce normal recipient EN dysfunction during SFGRs.
 Our goal in this proposal is to seek more experimental evidence to support our central hypothesis that
targeting identified SFGR-induced tRFGlyGCC in exosomes can provide protection against SFGR by
maintaining recipient EC barrier function. To test this hypothesis, we will pursue three Specific Aims: (1)
biochemically corroborate that RCExos/RMExos-packed tRFGlyGCC alters the recipient EC barrier structure(s),
(2) biomechanically corroborate that RCExos/RMExos-packed tRFGlyGCC causes the recipient EC barrier
dysfunction, and (3) evaluate whether targeting Exos-packed tRFGlyGCC with anti-tRFGlyGCC nanoparticles
can protect against lethal rickettsial infection by maintain the endothelial barrier function. We will test our
hypothesis by employing cutting-edge approaches (FluidFM technology, size-exclusion chromatography, and
formulation of nanoparticles for optimizing delivery of anti-tRFGlyGCC into ECs). Outcomes will provide deeper
insights into the biomechanical and molecular mechanisms of SFGR infection, ultimately leading to the
identifi...

## Key facts

- **NIH application ID:** 10200652
- **Project number:** 5R21AI154211-02
- **Recipient organization:** UNIVERSITY OF TEXAS MED BR GALVESTON
- **Principal Investigator:** Bin Gong
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $197,500
- **Award type:** 5
- **Project period:** 2020-06-23 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10200652

## Citation

> US National Institutes of Health, RePORTER application 10200652, Targeting extracellular tRNA-derived RNA fragments (tRFs) to protect against fatal rickettsiosis (5R21AI154211-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10200652. Licensed CC0.

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