# Inducible epithelial resistance: a program investigating mechanisms to protect against acute and chronic complications of pneumonia

> **NIH NIH R35** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $880,000

## Abstract

PROJECT SUMMARY-ABSTRACT
Pneumonias cause millions of deaths annually and cause chronic health complications in many survivors. Yet,
despite constant exposure of an immense surface area to the external environment, the lungs’ intrinsic
defenses clear most pathogens before infections are established. These mucosal defenses can be
therapeutically stimulated using a novel inhaled therapy comprised of a non-intuitive, synergistic synthetic
pattern recognition receptor agonist combination. This inducible resistance results in rapid intrapulmonary
pathogen killing and prevents death in mice from otherwise lethal pneumonias caused by bacterial, viral or
fungal pathogens. Lung epithelial cells are principal mediators of this response, and reliance on airway and
alveolar cells is fortuitous for patients with leukocyte-dependent immunocompromising conditions. The current
proposal supports a program investigating the mechanisms by which this phenomenon protects against acute
pneumonia and chronic lung disease, allowing greater understanding of native mucosal defenses, identifying
populations most likely to benefit, and promoting development of more efficacious interventions against
pneumonia. This program is designed to produce the greatest scientific advance and most robust training
environment, so rather than targeting pre-specified milestones, investigations align within four self-sustaining
enterprises that serially pursue testable hypotheses then iteratively build upon the generated data.
Enterprise 1 dissects the mechanisms of synergistic signaling that drive pneumonia protection to reveal how
optimized coincident detection can maximize the protective signal through novel sensors and amplifiers.
Enterprise 2 pursues the mechanisms of inducible reactive oxygen species production to explain how sensing
and signaling events promote coordinated generation of multisource antimicrobial volatile species.
Enterprise 3 addresses the effector mechanisms that achieve broad pathogen killing to better define the extent
of protection and investigate unexplored interactions of antimicrobial peptides and reactive oxygen species.
Enterprise 4 explores the mechanisms that promote durably induced immunomodulatory effects to determine
how inducible resistance exerts effects against asthma and immunopathology over extended time scales.
These efforts will identify critical signaling events and effector mechanisms of inducible resistance, reveal
unanticipated sensor interactions, facilitate discovery of more efficacious inducers of resistance, and expedite
the translation of this technology into the clinic to protect patients during periods of peak vulnerability.

## Key facts

- **NIH application ID:** 10125192
- **Project number:** 5R35HL144805-03
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Scott E. Evans
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $880,000
- **Award type:** 5
- **Project period:** 2019-03-05 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10125192

## Citation

> US National Institutes of Health, RePORTER application 10125192, Inducible epithelial resistance: a program investigating mechanisms to protect against acute and chronic complications of pneumonia (5R35HL144805-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10125192. Licensed CC0.

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