# Translation of evolution-guided insights for new models of human infectious disease

> **NIH NIH DP2** · UNIVERSITY OF WASHINGTON · 2024 · $484,105

## Abstract

SUMMARY
 Inflammasomes are cytosolic innate immune complexes that form in response to a variety of pathogen-
associated or stress-induced stimuli. Activated inflammasomes recruit Caspase-1, which initiates downstream
inflammatory signaling. Genetic deletion of inflammasome components in mice has demonstrated the critical
importance of inflammasomes during infection by viral, bacterial and eukaryotic pathogens. In addition, the
inappropriate activation of inflammasomes has been linked to numerous auto-inflammatory and auto-immune
diseases in humans.
 Host-pathogen coevolution is a major factor underlying the genetic and molecular determinants of cross-
species transmission and infectious disease. The antagonistic nature of host-pathogen interactions can drive
recurrent cycles of adaptation and counter-adaptation. These evolutionary ‘arms races’ drive rapid molecular
innovation. Thus, the unique history of pathogen encounters of each lineage has driven species-specific
adaptations. It should therefore not be surprising that laboratory mice are poor models of many human-specific
or human-adapted pathogens. In this proposal I outline my vision to leverage the species-specific nature of
host-pathogen interactions to develop improved models of human immunity and pathogenesis.
 Using a combination of evolution-guided and mechanism-focused approaches, I have made the following
discoveries: 1) the Dengue virus (DENV) protease NS2B3 activates the human (but not mouse) NLRP1
inflammasome. DENV is the first known pathogen that activates human NLRP1. This finding supports a
formerly unrecognized role for NLRP1 in host immunity and pathogenesis to DENV infection. 2) the enteric
bacterial pathogen Shigella antagonizes the human (but not mouse) NAIP/NLRC4 inflammasome. Based on
this finding, I have found that NLRC4-deficient mice are highly susceptible to enteric infection and. exhibit
hallmarks of intestinal inflammation. Thus, I have established the first mouse model of Shigellosis.
 This proposal seeks to boldly expand on these observations using innovative approaches to generate new
or significantly refine models of human infectious disease. I propose to 1) establish a new model of DENV
immunity and pathogenesis, and 2) advance the development of the Shigellosis mouse model. Both DENV and
Shigella are important human pathogens, which combined cause >200 million infections per year. Improved
DENV infection models is a clear but unmet need, and until my Shigellosis mouse model, mice were thought to
be refractory to Shigella enteric infection. Thus, the successful completion of the stated goals will significantly
impact human infectious disease research.

## Key facts

- **NIH application ID:** 10828745
- **Project number:** 5DP2AI154432-04
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Patrick S Mitchell
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $484,105
- **Award type:** 5
- **Project period:** 2021-05-06 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10828745

## Citation

> US National Institutes of Health, RePORTER application 10828745, Translation of evolution-guided insights for new models of human infectious disease (5DP2AI154432-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10828745. Licensed CC0.

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