# Regulation of Inflammatory Pathology in Invasive Aspergillosis

> **NIH NIH R21** · INDIANA UNIVERSITY INDIANAPOLIS · 2022 · $189,000

## Abstract

Abstract
Due to widespread use of immune suppressive therapies, the incidence of life-threatening lung
infections with fungal pathogens is increasing. Although protective immunity against Aspergillus
fumigatus (Af) and other fungal pathogens is critical for host survival, excessive inflammation can
also inhibit disease resolution. The potential to therapeutically target anti-inflammatory pathways to
facilitate the resolution of fungal infection and associated pathology is understudied, primarily due
to the difficulties of dissociating immune pathology from the pathologies directly linked to invasive
fungal growth. We recently observed an increase in mortality, immune pathology, and antifungal
inflammatory cytokine production in mice that lack the insulin-regulating cytokine adiponectin, thus
establishing a novel link between the known anti-inflammatory role for adiponectin and control of
excessive inflammation in fungal infection. Although most studies have focused on the role of
adipose-derived adiponectin, our data suggest that adiponectin levels are regulated locally in the
lung during IA. The role of non-adipose-tissue-derived adiponectin in controlling fungal infection-
induced inflammation is unknown. Similarly, it is unclear whether macrophages and other immune
cells are directly responsive to the immune-regulatory actions of adiponectin during IA. Using an
unbiased, systems biology approach to study the impact of adiponectin during IA, we identified
tristetraprolin (TTP) as a potential regulator. TTP is an RNA-binding and degrading protein known
to regulate the production of multiple cytokines. Importantly, we have developed an experimental
approach that allows us to separate immunopathology from fungal growth. With this approach we
can specifically interrogate the mechanisms by which adiponectin regulates excessive pulmonary
inflammation. Based on our results, our central hypothesis is that locally produced adiponectin
acts directly on macrophages via AdipoR1/R2 engagement to activate TTP and subsequent
cytokine degradation. In AIM 1, we will determine if adiponectin produced in non-adipose tissues
such as the lungs is critical for protection from IA. In AIM 2, we will determine if adiponectin protects
against inflammatory pathology in IA via AdipoR1/R2 on macrophages. We anticipate that these
studies will delineate mechanisms of adiponectin-mediated inhibition of lung immune pathology. Our
proposed work will identify novel targets with therapeutic potential and open new avenues of
research in the development of detrimental immunity to infection.

## Key facts

- **NIH application ID:** 10427455
- **Project number:** 5R21AI163574-02
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Steven P Templeton
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $189,000
- **Award type:** 5
- **Project period:** 2021-06-11 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10427455

## Citation

> US National Institutes of Health, RePORTER application 10427455, Regulation of Inflammatory Pathology in Invasive Aspergillosis (5R21AI163574-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10427455. Licensed CC0.

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