# Multifunctional roles of an Orientia tsutsugamushi nucleomodulin

> **NIH AI F32** · VIRGINIA COMMONWEALTH UNIVERSITY · 2026 · $79,348

## Abstract

SUMMARY
Orientia tsutsugamushi is a genetically intractable obligate intracellular bacterium that causes scrub typhus, a
globally emerging infection with a high fatality rate. Disease progression depends on bacterial-driven modulation
of host antimicrobial responses that affords O. tsutsugamushi the ability to survive in leukocytes and endothelial
cells. The bacterial mechanisms responsible are largely unknown, highlighting a gap in our knowledge of host-
pathogen interactions that influence scrub typhus outcome. A family of eukaryotic-like effectors called Anks are
key O. tsutsugamushi virulence factors. Most consist of an N-terminal ankyrin repeat (AR) domain that mediates
protein-protein interactions with host targets and a C-terminal F-box that recruits the host SCF E3 ubiquitin ligase
complex to ubiquitinate the AR-bound proteins. The interacting partners and cellular processes that the Anks
modulate are mostly unknown. We discovered that O. tsutsugamushi Ank13 is a nucleomodulin. Gene
expression profiles in cells ectopically expressing Ank13 recapitulate many of those observed for O.
tsutsugamushi infected host cells, indicating that Ank13 contributes to the pathogen’s ability to modulate cellular
processes at the transcriptional level. Both infected and Ank13-expressing cells exhibit down-regulation of genes
involved in immune responses and other processes regulated by the Notch signaling pathway. A yeast two-
hybrid screen coupled with co-immunoprecipitation identified host MIB1 as an Ank13 binding partner. MIB1 is a
positive regulator of canonical Notch signaling. MIB1 levels are reduced in O. tsutsugamushi infected cells, and
this is phenocopied in cells ectopically expressing Ank13 or an Ank13 mutant with a functionally inactivated F-
box. These data suggest that Ank13 sequestration of MIB1 promotes its auto-ubiquitination and proteasomal
degradation during infection. Notch ligand surface presentation on infected cells is altered and Notch-related
gene ex

## Key facts

- **NIH application ID:** 11234250
- **Project number:** 5F32AI174656-03
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Paige  Allen
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** AI
- **Fiscal year:** 2026
- **Award amount:** $79,348
- **Award type:** 5
- **Project period:** 2023-12-10T00:00:00 → 2026-12-09T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11234250

## Citation

> US National Institutes of Health, RePORTER application 11234250, Multifunctional roles of an Orientia tsutsugamushi nucleomodulin (5F32AI174656-03). Retrieved via AI Analytics 2026-06-27 from https://api.ai-analytics.org/grant/nih/11234250. Licensed CC0.

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