# Pathogenic Mechanisms of Vascular Dysfunction in Scrub Typhus

> **NIH NIH R01** · UNIVERSITY OF TEXAS MED BR GALVESTON · 2024 · $468,000

## Abstract

ABSTRACT
Scrub typhus is a life-threatening disease caused by Orientia tsutsugamushi (Ot), an LPS-negative bacterium
that replicates preferentially in endothelial cells (EC) and phagocytes. While one million people are infected
yearly, with about one third of world population at risk of infection, effective strategies for infection control are
lacking. Information on disease pathogenesis and immune dysregulation is very limited. To address these
challenges, we have developed four different mouse models of scrub typhus that recapitulate clinical outcomes
in humans. This grant support has led to the first reports that i) Mincle (a phagocyte C-type lectin receptor, CLR)
can sense Ot Karp strain and synergize with TNFα to drive M1/Th1-skewed responses; ii) sustained
lung/brain/kidney inflammation and progressive loss of Tie2 (a key receptor for EC function and survival) are
hallmarks of lethal Karp infection, correlating with activation of endogenous damage-associated molecular
patterns (DAMPs); and iii) the concordance of “type 1-skewed/type 2-repressed immune signatures” is evident
for severe scrub typhus in both inbred (C57BL/6) and outbred (CD-1) mouse models. In contrast, the Ot Gilliam-
induced non-pathogenic outcome seems to be linked to distinct CLR and innate immune signatures. The
objective of this study is to define pathogenic mechanisms of vascular dysfunction and shared markers or
therapeutic targets for severe scrub typhus. Our central hypothesis is that innate immune programs induced by
Ot Karp or Gilliam infection in target cells shape pathogenic or protective adaptive immunity, vascular function,
and clinical outcomes. This hypothesis will be tested in two cohesive Specific Aims. Aim 1 will delineate
mechanisms by which CLR-like, pathogen-associated molecular patterns (PAMPs) drive innate immune
programs and distinct clinical outcomes in inbred mice. We will use two Ot strains to examine 1) innate immune
signatures in inflamed lung/spleen/brain tissues, focusing on CLR- and TGFβ-regulated pathways; 2) infection-
triggered M1/M2 polarization and their impact on EC activation/survival/death; 3) functional diversity of dendritic
cell (DC) subsets during infection and T cell-priming. Aim 2 will examine whether/how differential alarmin
responses, especially those regulated by the IL-33 and CD24 pathways, determine acute tissue injury, vascular
dysfunction, and host mortality. 1) To define disease “shared” immune signatures and vascular markers beyond
Tie2, we will assess transcriptomics of lung/brain/kidney during severe disease stages and use perfused lungs
for 30-color spectrum flow cytometry. 2) To examine alarmin-associated regulation, we will use Karp/Gilliam-
infected inbred mice, soluble CD24Fc (a known repressor for DAMP, but not PAMP, pathways), and knockout
mice. 3) We will use peripheral blood samples from all four models for cell RNAseq and serum Olink proteomic
profiling. Validation of blood- and tissue-derived immune signatu...

## Key facts

- **NIH application ID:** 10881321
- **Project number:** 2R01AI132674-05A1
- **Recipient organization:** UNIVERSITY OF TEXAS MED BR GALVESTON
- **Principal Investigator:** Yuejin Liang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $468,000
- **Award type:** 2
- **Project period:** 2018-08-02 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10881321

## Citation

> US National Institutes of Health, RePORTER application 10881321, Pathogenic Mechanisms of Vascular Dysfunction in Scrub Typhus (2R01AI132674-05A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10881321. Licensed CC0.

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