# Dysfunction of Innate Immunity in Asthma

> **NIH NIH U19** · UNIVERSITY OF ARIZONA · 2020 · $1,395,363

## Abstract

Asthma is disease manifested by chronic inflammation exacerbated by environmental insults such as
allergens, infectious agents and irritants. The innate and adaptive host responses recognize and eradicate the
effect of these insults to restore tissue integrity and homeostasis. In our proposal, we focus on the critical
innate immune factors surfactant protein A (SP-A), a lipid constituent of surfactant, palmitoyl-oleoyl-
phosphatidylglycerol (POPG) and Toll-like receptor interacting protein (Tollip). We show that these
mediators each perform critical negative regulatory functions that synergize to offer protection from type 2
inflammation and viral exacerbations. SP-A modulates inflammation associated with type 2 inflammation and
viral infections but exhibits genetic heterogeneity altering its function. Tollip, a 30 kDa adaptor protein that is
also genetically heterogeneous, is recognized as a negative regulator of toll-like receptor (TLR) signaling. A
phospholipid contained in surfactant, POPG is known to play a critical role in regulating innate immunity by
inhibiting activation of multiple TLRs. Our central hypothesis to be tested is that dysfunction of SP-A,
Tollip and POPG occurs as a consequence of genetic polymorphisms and degradative events which
significantly alter their function in the setting of asthma and viral infection, leading to exacerbations
and persistence of inflammation. With an underpinning of innate immune dysfunction, the projects utilize
distinct but overlapping clinically relevant models of exacerbations in asthma (rhinovirus (RV), respiratory
syncytial virus (RSV)), type 2 inflammation (IL-13 exposure, HDM animal models) from distinct molecular
perspectives (SP-A, Tollip, POPG), effectively creating a network rather than linear approach to understanding
the mechanism(s) of innate immune dysfunction in type 2 inflammation and asthma exacerbations. This
program proposes three interrelated projects: Project 1 will determine how SP-A suppresses allergic
inflammation through disruption of IL-13-dependent signaling pathways, but due to genetic heterogeneity, its
function is impaired in asthma. Specific SP-A peptides can rescue this dysfunction, offering a novel
therapeutic approach for asthma. Project 2 will determine the relationship between genetically determined
variations in Tollip expression and airway responses to viral infections in the setting of type 2 inflammation.
Project 3 will critically test the activity of POPG and SP-A as novel endogenous molecular mechanisms for
disrupting infections due to RV and RSV, two viruses known to exacerbate asthma. We also include two
cores: an Administrative Core and a Clinical Core, both which serve all projects equally and are responsible
for the scientific, advisory, fiscal, human subject and data management/statistical aspects of the program. In
this U19 program, we propose novel mechanisms of innate immune dysfunction and potential treatments that
not only modulate the resolutio...

## Key facts

- **NIH application ID:** 9971434
- **Project number:** 5U19AI125357-05
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Monica Kraft
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,395,363
- **Award type:** 5
- **Project period:** 2016-07-01 → 2021-08-23

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9971434

## Citation

> US National Institutes of Health, RePORTER application 9971434, Dysfunction of Innate Immunity in Asthma (5U19AI125357-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9971434. Licensed CC0.

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