# Role of ZBP1 in pathogenesis of Salmonella biofilms

> **NIH AI R01** · RESEARCH INST OF FOX CHASE CAN CTR · 2026 · $834,784

## Abstract

PROJECT SUMMARY
Infections with enteric pathogens such as Salmonella, Campylobacter, Shigella, or Yersinia are leading causes
of morbidity and mortality worldwide. Although in most individuals the infection resolves, approximately 5% of
patients subsequently develop a painful chronic inflammatory condition known as Reactive Arthritis (ReA). How
Salmonella infections trigger ReA is not well understood. Using Salmonella enterica serovar Typhimurium (STm)
as a model organism, we discovered that a Salmonella protein, curli, is a dominant instigator of inflammation
following Salmonella infection. Curli is a secreted protein and major component of the STm biofilm in the
gastrointestinal tract. Curli fibrils bind extruded bacterial DNA within the biofilm. It is these curli:DNA complexes,
rather than curli alone, that are potent triggers of type I interferon, IL-17, and anti-double stranded DNA
autoantibody production, leading to ReA. Unknown, however, is why curli:DNA complexes are so inflammatory.
We report in this proposal the remarkable discovery that the DNA present within curli:DNA complexes is not
solely B-DNA, the classic right-handed (Watson-Crick) double-helix, but includes copious amounts of left-handed
Z-DNA as well. Z-form nucleic acids, such as Z-DNA and Z-RNA, were thought not to readily occur in nature,
until we showed last year that Z-RNA is indeed produced during virus infections and is a ligand for the
necroptosis-activating host sensor protein ZBP1. Our preliminary results now show that the Z-DNA within
curli:DNA complexes activates ZBP1 in intestinal epithelial cells (IECs) and fibroblasts, resulting in RIPK3-
dependent necroptosis of these cells. These findings allow us to put forward the hypothesis that Z-DNA within
curli:DNA fibrils in Salmonella biofilms activates ZBP1 to instigate RIPK3-dependent necroptosis in intestinal
epithelial cells (IECs) and other cell types. Necroptosis, in turn, causes cell loss and disrupts gut barrier integrity,
releasi

## Key facts

- **NIH application ID:** 11325302
- **Project number:** 5R01AI171568-04
- **Recipient organization:** RESEARCH INST OF FOX CHASE CAN CTR
- **Principal Investigator:** SIDDHARTH  BALACHANDRAN; Cagla  Tukel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** AI
- **Fiscal year:** 2026
- **Award amount:** $834,784
- **Award type:** 5
- **Project period:** 2023-05-11T00:00:00 → 2028-04-30T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11325302

## Citation

> US National Institutes of Health, RePORTER application 11325302, Role of ZBP1 in pathogenesis of Salmonella biofilms (5R01AI171568-04). Retrieved via AI Analytics 2026-06-30 from https://api.ai-analytics.org/grant/nih/11325302. Licensed CC0.

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