Recurrent pulmonary infections and their impact on neurological decline in A-T

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Research Project information

Principal researcher:  Professor Margot Mayer-Proschel and Professor Michael O’Reilly
Institute:  University of Rochester, New York
Cost: £246,691 over 36 months
Completion date: March 2024

Project Overview
A-T is a multi-organ disease, yet neurological pathologies (one of the main problems in A-T) are for the most part studied in isolation from other organs.

Professors Mayer-Proschel and O’Reilly wanted to study whether lung infections exacerbate neurological decline.  The team recognized this was a poorly understood and investigated correlation and aimed to understand better the role of peripheral insults and inflammation to the brain in patients with A-T.

Three aims were clearly set out and the team used a mouse model to:

  • Undertake cellular analysis of the effect of a single lung infection (Influenza A)
  • Undertake cellular analysis of the impact of recurrent respiratory infections on lung and brain pathology
  • Characterise the functional changes after the respiratory infections

Research Methods and Outcome
The mice were exposed to viral or bacterial lung infections and their lung and motor function tested. They found that the mice were highly sensitive to recurrent peripheral viral infections which impacted their lung function. In addition, they failed to boost their antibody response after a primary infection rendering them highly vulnerable to recurrent infections.  The peripheral infections did not only affect lung function but exacerbated motor defects in a significant manner. Young animals exposed to a peripheral viral or bacterial challenge developed highly reproducible motor defects that were consistent with ataxic traits.

What next?
The researchers have established relevant behavioural endpoints that can be used to test efficiency of therapeutic drugs in the future. They aim to start the process of identifying potential drugs.  If drugs are identified, they will then need to be tested to see if they prevent or revert the neurological decline that occurs in A-T.  This work may ultimately assist in the development of new therapeutic approaches

Publications
Warren R, Dylag AM, Behan M, Domm W, Yee M, Mayer-Pröschel M, Martinez-Sobrido L, O’Reilly MA. Ataxia telangiectasia mutated is required for efficient proximal airway epithelial cell regeneration following influenza A virus infection. Am J Physiol Lung Cell Mol Physiol. 2022 Apr 1;322(4):L581-L592. doi: 10.1152/ajplung.00378.2021. Epub 2022 Feb 23. PubMed PMID: 35196880; PubMed Central PMCID: PMC8993527.