The interaction of the immune system with skeletal muscle during respiratory viral infection of the elderly
File(s)
Author(s)
Sagawe, Johanna Sophie
Type
Thesis
Abstract
The population of the world is ageing. Respiratory syncytial virus (RSV) is emerging as a leading cause of severe respiratory tract infection in the elderly. Loss of muscle mass occurs naturally with age, but can be exacerbated by inflammation, inactivity, or chronic disease, leading to increased risk of morbidity and mortality. If and how RSV infection promotes muscle wasting in the elderly is unknown. This study has developed an aged mouse model to investigate muscle wasting after RSV infection. 12-week-old and 80-week-old female C57BL/6 mice were infected with the same dose of RSV A2. Compared to young mice, elderly mice displayed enhanced RSV disease, including increased weight loss, viral load, and cellular airway infiltration. Elderly, but not young, mice displayed signs of muscle wasting following RSV infection, including decreased tibialis anterior muscle weight, increased expression of muscle atrophy-promoting enzymes, decreased muscle fibre size, and a failure to upregulate muscle protein synthesis. Elderly mice also displayed an impaired antibody response as evidenced by decreased anti-RSV IgG titres, but this was not due to reduced numbers of RSV-specific Tfh cells or germinal centre B cells. Blocking GDF-15, a TGF-β superfamily cytokine associated with muscle wasting and loss of appetite, which was produced in the elderly lung following RSV infection, unexpectedly led to signs of enhanced muscle wasting in elderly mice infected with RSV, suggesting a tissue-protective effect of GDF-15. Blocking IL-6R did not have consistent effects in elderly mice infected with RSV, potentially due to counteracting effects on systemic inflammation, the antibody response, and skeletal muscle. These results demonstrate that RSV infection promotes muscle wasting in an age-dependent manner, potentially regulated by GDF-15. This model is a useful tool for mechanistic studies and could be used in the future for the development of vaccines and treatments for RSV for the elderly.
Version
Open Access
Date Issued
2020-06
Date Awarded
2021-01
Copyright Statement
Creative Commons Attribution NonCommercial NoDerivatives Licence
Advisor
Openshaw, Peter
Culley, Fiona
Sponsor
The Wellcome Trust
Publisher Department
National Heart & Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)