Investigators

Principal Investigator

Dr Alan Chen-Yu Hsu (Singapore)

Co-Investigators

Dr Jemma Mayall (Australia)
Dr Jay Horvat (Australia)
Dr Kai Sen Tan (Singapore)
Dr Peter Wark (Australia)

Project term

1 January 2024 – 31 December 2025

Project Summary

Background

Iron is essential for many biological processes. To maintain tissue homeostasis, iron levels are tightly regulated by systems that control iron absorption, systemic transport and cellular uptake, storage, and release. Loss of iron homeostasis in either direction leads to cellular dysfunction and pathognomonic changes. It is well established that, to survive and replicate, pathogenic bacteria have evolved strategies to source host iron and to counter these microbial strategies, host organisms have evolved immune-mediated mechanisms that reduce iron availability to pathogens, particularly at mucosal sites, which are frequently the front line of defence. More recently, links have been reported between iron levels and metabolism and the severity of viral infections. However, it is currently unknown if respiratory viral infections alter iron metabolism, or if altered iron metabolism or availability in the cells and tissues of the respiratory tract directly increase susceptibility to infections or resultant disease.

Innovative approach

By combining new applications of unique tools, interventions, and models, and collaborations with world-leading experts in respiratory immunobiology, iron biology, and respiratory viral infection, this team has established a collaborative research program between Singapore and Australia to:
Investigate how seasonal and potentially pandemic influenza A virus (IAV) infections affect host iron metabolism and whether iron metabolism can be therapeutically targeted for the treatment of both seasonal and potentially pandemic IAV infection and infection-induced disease.
We have collected world-first pilot data to show that influenza A virus (IAV) infection alters iron metabolism in the airways and systemically, and that iron levels and iron-related metabolic processes play a crucial role in host defence, and in determining IAV-induced disease outcomes. We show that iron uptake processes are down-regulated in whole lung and airway epithelial cells (AECs) during IAV infection. Significantly, increased iron levels in AECs increase IAV replication. Most importantly we show that depleting transferrin receptor 1 (TFR1)-mediated cellular iron uptake in the airways reduces viral load and protects against IAV-induced disease in in vivo mouse model of IAV infection.
This APSR Multi-Society Research Project will extend upon these preliminary data to determine, for the first time, how seasonal and potentially pandemic IAV infections affect iron metabolism and validate the efficacy of TFR1-targeting therapies for the treatment of seasonal and potentially pandemic IAV infections and pathology in primary human airway epithelial cells cultured at the air-liquid interface.

Hypotheses

Both seasonal and potentially pandemic IAV infections induce changes in iron metabolism in airways cells. These responses alter iron availability, modulate cell function and play an important role in determining the pathological outcomes of respiratory viral infection. Targeting these processes can be used to treat IAV infections and their devastating effects.
To address these hypotheses, this APSR grant will:
Aim 1. Comprehensively characterise how seasonal and potentially pandemic IAV infections affect iron metabolism in fully differentiated human airway epithelial cells.
Aim 2. Determine if targeting iron metabolism therapeutically, influences host defence and IAV-induced pathology.