# Role of alterations in the ATII cell lipidome in influenza pathogenesis

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2020 · $745,184

## Abstract

Influenza is a highly contagious acute respiratory disease which is of major concern to public health. Severe
influenza can trigger acute respiratory distress syndrome (ARDS), for which treatment options are limited. The
objective of this proposal is to characterize a novel host determinant that can serve as a target for new drugs to
prevent or attenuate development of ARDS in influenza. Alveolar type II (ATII) cells are the site of influenza A
virus replication in the distal lung and essential to normal lung function. ATII cells synthesize phospholipids,
which are essential for both ATII cell mitochondrial respiration and surfactant function. However, effects of in
vivo infection on the ATII cell surfactant lipidome, and their consequences for mitochondrial respiration have
not been investigated. Preliminary studies indicate that influenza infection of C57BL/6 mice results in impaired
production of CDP-choline and CDP-ethanolamine, which are liponucleotide precursors for de novo synthesis
of the major phospholipids (phosphatidylcholine, phosphatidylglycerol, and phosphatidyl- ethanolamine).
Development of ARDS is also associated with abnormalities in carbohydrate and fatty acid metabolism, as well
as mitochondrial dysfunction and dysmorphology. However, inhibition of CDP-choline synthesis is not a result
of reduced expression of CCT-, which catalyzes its production. Influenza-induced ARDS, but not viral
replication, is attenuated by post-infection treatment with exogenous liponucleotides. The hypothesis of this
proposal is that influenza A virus inhibits ATII cell liponucleotide synthesis, which results in impaired
phospholipid generation, reduced surfactant function, altered mitochondrial respiration, and progression to
ARDS. This hypothesis will be tested in three complementary Specific Aims, which will show that: 1) Treatment
with exogenous lipoNTs attenuates ARDS and improves surfactant function in influenza-infected mice; 2)
Disruption of ATII cell Plipid synthesis results in mitochondrial dysfunction, altered energy metabolism, and
ATII cell apoptosis; and 3) Impaired ATII cell lipoNT synthesis results from phosphorylation of liponucleotide
synthesis enzymes by MAP kinases. Studies will use clinically-relevant measures of ARDS severity and state-
of-the-art assays to determine effects of influenza infection on mitochondrial respiration. The goal will be to
show a causal relationship between impaired ATII cell phospholipid synthesis, mitochondrial dysfunction, and
development of ARDS in influenza-infected mice. Completion of these Aims will generate fundamental new
information regarding the role of altered ATII cell lipid metabolism in the pathogenesis of influenza-induced
ARDS. It will also provide proof-of-concept that parenteral liponucleotide supplementation can delay onset or
reduce severity of influenza-induced ARDS, which will transform our current approach to its treatment.

## Key facts

- **NIH application ID:** 9917813
- **Project number:** 5R01HL137090-04
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** IAN CHRISTOPHER DAVIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $745,184
- **Award type:** 5
- **Project period:** 2017-07-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9917813

## Citation

> US National Institutes of Health, RePORTER application 9917813, Role of alterations in the ATII cell lipidome in influenza pathogenesis (5R01HL137090-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9917813. Licensed CC0.

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