Influenza, but not SARS-CoV-2, infection induces a rapid interferon response that wanes with age and diminished tissue-resident memory CD8+ T cells
Clinical & Translational Immunology (2021)
Thi HO Nguyen1 , Julie L McAuley1 , Youry Kim1 , Ming ZM Zheng1 , Nicholas A Gherardin 1,2 , Dale I Godfrey 1,2, Damian FJ Purcell 1 , Lucy C Sullivan 1,3, Glen P Westall 3,4, Patrick C Reading 1,5, Katherine Kedzierska & Linda M Wakim1
1.Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC, Australia
2. Australian Research Council Centre of Excellence for Advanced Molecular Imaging, University of Melbourne, Melbourne, VIC, Australia
3. Lung Transplant Service, Alfred Hospital, Melbourne, VIC, Australia
4. Department of Medicine, Monash University, Melbourne, VIC, Australia
5. WHO Collaborating Centre for Reference and Research on Influenza, Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
This work was supported by National Health and Medical Research Council of Australia (LMW). KK is supported by Australian NHMRC Investigator Fellowship (#1173871) and the University of Melbourne Dame Kate Campbell Fellowship. THON is supported by NHMRC EL1 Fellowship (#1194036). This study was also supported by the Medical Research Future Fund (#2005544). The Melbourne WHO Collaborating Centre for Reference and Research on Influenza is supported by the Australian Government Department of Health.
Tissues from deceased organ donors were obtained following written informed consent from the next of kin. The study was approved by the University of Melbourne Human Ethics Committee
Respiratory pathogen – an agent that causes disease of the respiratory system
Pulmonary – relating to the lungs
Influenza – a disease caused by virus infecting the respiratory tract (including the lungs)
Trm – Tissue resident memory T cells – cells that persist long term in tissue without recirculating
SARS-CoV-2 – severe acute respiratory syndrome coronavirus 2. SARS-CoV-2 is the strain of coronavirus that causes the COVID-19 disease.
Attrition – weaking, wearing down.
In order to understand why respiratory pathogens impact older people disproportionately the research used human lung tissue (from donors aged 22-68 years) to assess how immune cells in the lungs change throughout life and how they respond to the respiratory viruses influenza and SARS-Cov-2. It is noted that older people are highly susceptible to respiratory pathogens and pulmonary infections which can be as a result of decline in their immune systems
Lung samples from deceased organ donors were obtained via the Alfred Hospital’s Lung Tissue Biobank using a cohort of 8 organ donors aged 22–68 years, with tissues banked between 2015 and 2019. The lung tissue was infected ex vivo with either influenza virus or SARS-CoV-2 to observe the tissue response to the infection via virus stimulation assay, flow cytometry and RNA extraction.
It was noted that influenza infection in the lungs of elderly donors did not result in a robust antiviral response but waned due to the loss of local memory of a specific immune cell in the lungs, namely the CD8+ cells. It was noted that the tissue infected with SARS-CoV-2 did not generate a rapid antiviral response in either the adult or the elderly tissue.
It is, however, noted that SARS-CoV-2 is a pathogen for which all donors’ tissue had not been immunologically exposed.
The results showed that pathogen-specific CD8+ lung Trm (tissue resident memory T-cell subset) provides an immediate response following virus re-exposure. The attrition of these lung Trm that occurs with advanced age, or their absence in those who have not been immunologically exposed to the virus SARS-CoV-2, however results in a diminished early antiviral response.
The researchers note that “A better understanding of age-associated changes that occur in the lung immune cell landscape will allow for the development of strategies that boost or preserve tissue-bound memory CD8+ T cells, this will enhance local antiviral immune responses and in turn improve the capacity of the elderly to combat respiratory infections”.
This case studies demonstrates the alternatives available that are human-relevant and humane. This is particularly relevant for respiratory viruses which may affect humans and animals in different ways, notwithstanding that animal models will not parallel human ageing or human lifespans. It also highlights the need for human biobanks where collections of human biological samples can be stored for use in research, thereby giving researchers access to a large human-relevant dataset.
Please note that this research is not animal-free and used both foetal calf serums and mouse monoclonal antibodies. There are valid alternatives for both.
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