Accelarated immune ageing is associated with COVID-19 disease severity

Janet M Lord; Tonny Veenith; Jack Sullivan; Archana Sharma-Oates; Alex G Richter; Neil J Greening; Hamish J C McAuley; Rachael A Evans; Paul Moss; Shona C Moore; Lance Turtle; Nandan Gautam; Ahmed Gilani; Manan Bajaj; Louise V Wain; Christopher Brightling; Betty Raman; Michael Marks; Amisha Singapuri; Omer Elneima; Peter J M Openshaw; Niharika A Duggal; PHOSP-COVID Study collaborative group; ISARIC4C investigators

doi:10.1186/s12979-023-00406-z

Accelarated immune ageing is associated with COVID-19 disease severity

Immun Ageing. 2024 Jan 11;21(1):6. doi: 10.1186/s12979-023-00406-z.

Authors

Janet M Lord^{1

2

3}, Tonny Veenith³, Jack Sullivan¹, Archana Sharma-Oates⁴, Alex G Richter⁵, Neil J Greening⁶, Hamish J C McAuley⁶, Rachael A Evans⁶, Paul Moss⁵, Shona C Moore⁷, Lance Turtle⁷, Nandan Gautam⁸, Ahmed Gilani⁸, Manan Bajaj⁸, Louise V Wain^{6

9}, Christopher Brightling⁶, Betty Raman¹⁰, Michael Marks¹¹, Amisha Singapuri⁶, Omer Elneima⁶, Peter J M Openshaw¹², Niharika A Duggal¹³; PHOSP-COVID Study collaborative group; ISARIC4C investigators

Collaborators

K Abel, H Adamali, D Adeloye, O Adeyemi, R Adrego, L A AguilarJimenez, S Ahmad, N Ahmad Haider, R Ahmed, N Ahwireng, M Ainsworth, B Al-Sheklly, A Alamoudi, M Ali, M Aljaroof, A M All, L Allan, R J Allen, L Allerton, L Allsop, P Almeida, D Altmann, M Alvarez Corral, S Amoils, D Anderson, C Antoniades, G Arbane, A Arias, C Armour, L Armstrong, N Armstrong, D Arnold, H Arnold, A Ashish, A Ashworth, M Ashworth, S Aslani, H Assefa-Kebede, C Atkin, P Atkin, R Aul, H Aung, L Austin, C Avram, A Ayoub, M Babores, R Baggott, J Bagshaw, D Baguley, L Bailey, J K Baillie, S Bain, M Bakali, M Bakau, E Baldry, D Baldwin, M Baldwin, C Ballard, A Banerjee, B Bang, R E Barker, L Barman, S Barratt, F Barrett, D Basire, N Basu, M Bates, A Bates, R Batterham, H Baxendale, H Bayes, M Beadsworth, P Beckett, M Beggs, M Begum, P Beirne, D Bell, R Bell, K Bennett, E Beranova, A Bermperi, A Berridge, C Berry, S Betts, E Bevan, K Bhui, M Bingham, K Birchall, L Bishop, K Bisnauthsing, J Blaikely, A Bloss, A Bolger, C E Bolton, J Bonnington, A Botkai, C Bourne, M Bourne, K Bramham, L Brear, G Breen, J Breeze, A Briggs, E Bright, S Brill, K Brindle, L Broad, A Broadley, C Brookes, M Broome, A Brown, A Brown, J Brown, J Brown, J S Brown, M Brown, M Brown, V Brown, T Brugha, N Brunskill, M Buch, P Buckley, A Bularga, E Bullmore, L Burden, T Burdett, D Burn, G Burns, A Burns, J Busby, R Butcher, A Butt, S Byrne, P Cairns, P C Calder, E Calvelo, H Carborn, B Card, C Carr, L Carr, G Carson, P Carter, A Casey, M Cassar, J Cavanagh, M Chablani, T Chalder, J D Chalmers, R C CHambers, F Chan, K M Channon, K Chapman, A Charalambou, N Chaudhuri, A Checkley, J Chen, Y Cheng, L Chetham, C Childs, E R Chilvers, H Chinoy, A Chiribiri, K Chong-James, G Choudhury, N Choudhury, P Chowienczyk, C Christie, M Chrystal, D Clark, C Clark, J Clarke, S Clohisey, G Coakley, Z Coburn, S Coetzee, J Cole, C Coleman, F Conneh, D Connell, B Connolly, L Connor, A Cook, B Cooper, J Cooper, S Cooper, D Copeland, T Cosier, M Coulding, C Coupland, E Cox, T Craig, P Crisp, D Cristiano, M G Crooks, A Cross, I Cruz, P Cullinan, D Cuthbertson, L Daines, M Dalton, P Daly, A Daniels, P Dark, J Dasgin, A David, C David, E Davies, F Davies, G Davies, G A Davies, K Davies, M J Davies, J Dawson, E Daynes, A De Soyza, B Deakin, A Deans, C Deas, J Deery, S Defres, A Dell, K Dempsey, E Denneny, J Dennis, A Dewar, R Dharmagunawardena, N Diar-Bakerly, C Dickens, A Dipper, S Diver, S N Diwanji, M Dixon, R Djukanovic, H Dobson, S L Dobson, A B Docherty, A Donaldson, T Dong, N Dormand, A Dougherty, R Dowling, S Drain, K Draxlbauer, K Drury, P Dulawan, A Dunleavy, S Dunn, C Dupont, J Earley, N Easom, C Echevarria, S Edwards, C Edwardson, H El-Taweel, A Elliott, K Elliott, Y Ellis, A Elmer, D Evans, H Evans, J Evans, R Evans, R I Evans, T Evans, C Evenden, L Evison, L Fabbri, S Fairbairn, A Fairman, K Fallon, D Faluyi, C Favager, T Fayzan, J Featherstone, T Felton, J Finch, S Finney, J Finnigan, L Finnigan, H Fisher, S Fletcher, R Flockton, M Flynn, H Foot, D Foote, A Ford, D Forton, E Fraile, C Francis, R Francis, S Francis, A Frankel, E Fraser, R Free, N French, X Fu, J Fuld, J Furniss, L Garner, J R Geddes, J George, P George, M Gibbons, M Gill, L Gilmour, F Gleeson, J Glossop, S Glover, N Goodman, C Goodwin, B Gooptu, H Gordon, T Gorsuch, M Greatorex, P L Greenhaff, W Greenhalf, A Greenhalgh, J Greenwood, H Gregory, R Gregory, D Grieve, D Griffin, L Griffiths, A-M Guerdette, B Guillen Guio, M Gummadi, A Gupta, S Gurram, E Guthrie, Z Guy, H Henson, K Hadley, A Haggar, K Hainey, B Hairsine, P Haldar, I Hall, L Hall, M Halling-Brown, R Hamil, A Hancock, K Hancock, N A Hanley, S Haq, H E Hardwick, E Hardy, T Hardy, B Hargadon, K Harrington, E Harris, V C Harris, E M Harrison, P Harrison, N Hart, A Harvey, M Harvey, M Harvie, L Haslam, M Havinden-Williams, J Hawkes, N Hawkings, J Haworth, A Hayday, M Haynes, J Hazeldine, T Hazelton, L G Heaney, C Heeley, J L Heeney, M Heightman, S Heller, M Henderson, L Hesselden, M Hewitt, V Highett, T Hillman, T Hiwot, L P Ho, A Hoare, M Hoare, J Hockridge, P Hogarth, A Holbourn, S Holden, L Holdsworth, D Holgate, M Holland, L Holloway, K Holmes, M Holmes, B Holroyd-Hind, L Holt, A Hormis, A Horsley, A Hosseini, M Hotopf, L Houchen-Wolloff, K Howard, L S Howard, A Howell, E Hufton, A D Hughes, J Hughes, R Hughes, A Humphries, N Huneke, E Hurditch, J Hurst, M Husain, T Hussell, J Hutchinson, W Ibrahim, F Ilyas, J Ingham, L Ingram, D Ionita, K Isaacs, K Ismail, T Jackson, J Jacob, W Y James, W Jang, C Jarman, I Jarrold, H Jarvis, R Jastrub, B Jayaraman, R G Jenkins, P Jezzard, K Jiwa, C Johnson, S Johnson, D Johnston, C J Jolley, D Jones, G Jones, H Jones, H Jones, I Jones, L Jones, M G Jones, S Jones, S Jose, T Kabir, G Kaltsakas, V Kamwa, N Kanellakis, S Kaprowska, Z Kausar, N Keenan, S Kelly, G Kemp, S Kerr, H Kerslake, A L Key, F Khan, K Khunti, S Kilroy, B King, C King, L Kingham, J Kirk, P Kitterick, P Klenerman, L Knibbs, S Knight, A Knighton, O Kon, S Kon, S S Kon, S Koprowska, A Korszun, I Koychev, C Kurasz, P Kurupati, C Laing, H Lamlum, G Landers, C Langenberg, D Lasserson, L Lavelle-Langham, A Lawrie, C Lawson, C Lawson, A Layton, A Lea, O C Leavy, D Lee, J-H Lee, E Lee, K Leitch, R Lenagh, D Lewis, J Lewis, K E Lewis, V Lewis, N Lewis-Burke, X Li, T Light, L Lightstone, W Lilaonitkul, L Lim, S Linford, A Lingford-Hughes, M Lipman, K Liyanage, A Lloyd, S Logan, D Lomas, N I Lone, R Loosley, H Lota, W Lovegrove, A Lucey, E Lukaschuk, A Lye, C Lynch, S MacDonald, G MacGowan, I Macharia, J Mackie, L Macliver, S Madathil, G Madzamba, N Magee, M M Magtoto, N Mairs, N Majeed, E Major, F Malein, M Malim, G Mallison, W D-C Man, S Mandal, K Mangion, C Manisty, R Manley, K March, S Marciniak, P Marino, M Mariveles, E Marouzet, S Marsh, B Marshall, M Marshall, J Martin, A Martineau, L M Martinez, N Maskell, D Matila, W Matimba-Mupaya, L Matthews, A Mbuyisa, S McAdoo, H McAllister-Williams, A McArdle, P McArdle, D McAulay, G P McCann, J McCormick, W McCormick, P McCourt, L Mcgarvey, C McGhee, K Mcgee, J McGinness, K McGlynn, A McGovern, H McGuinness, I B McInnes, J McIntosh, E McIvor, K McIvor, L McLeavey, A McMahon, M J McMahon, L McMorrow, T Mcnally, M McNarry, J McNeill, A McQueen, H McShane, C Mears, C Megson, S Megson, P Mehta, J Meiring, L Melling, M Mencias, D Menzies, M Merida Morillas, A Michael, C Miller, L Milligan, C Mills, G Mills, N L Mills, L Milner, S Misra, J Mitchell, A Mohamed, N Mohamed, S Mohammed, P L Molyneaux, W Monteiro, S Moriera, A Morley, L Morrison, R Morriss, A Morrow, A J Moss, K Motohashi, N Msimanga, E Mukaetova-Ladinska, U Munawar, J Murira, U Nanda, H Nassa, M Nasseri, A Neal, R Needham, P Neill, S Neubauer, D E Newby, H Newell, T Newman, J Newman, A Newton-Cox, T Nicholson, D Nicoll, A Nikolaidis, C M Nolan, M J Noonan, C Norman, P Novotny, J Nunag, L Nwafor, U Nwanguma, J Nyaboko, C O'Brien, K O'Donnell, D O'Regan, L O'Brien, N Odell, G Ogg, O Olaosebikan, C Oliver, Z Omar, L Orriss-Dib, L Osborne, R Osbourne, M Ostermann, C Overton, J Owen, J Oxton, J Pack, E Pacpaco, S Paddick, S Painter, A Pakzad, S Palmer, P Papineni, K Paques, K Paradowski, M Pareek, D Parekh, H Parfrey, C Pariante, S Parker, J Parmar, S Patale, B Patel, M Patel, S Patel, D Pattenadk, M Pavlides, S Payne, L Pearce, J E Pearl, D Peckham, J Pendlebury, Y Peng, C Pennington, I Peralta, E Perkins, Z Peterkin, T Peto, N Petousi, J Petrie, P Pfeffer, J Phipps, J Pimm, K Piper Hanley, R Pius, H Plant, S Plein, T Plekhanova, M Plowright, K Poinasamy, O Polgar, L Poll, J C Porter, J Porter, S Portukhay, N Powell, A Prabhu, J Pratt, A Price, C Price, C Price, D Price, L Price, L Price, A Prickett, J Propescu, S Prosper, S Pugmire, S Quaid, J Quigley, J Quint, H Qureshi, I N Qureshi, K Radhakrishnan, N M Rahman, M Ralser, A Ramos, H Ramos, J Rangeley, B Rangelov, L Ratcliffe, P Ravencroft, A Reddington, R Reddy, A Reddy, H Redfearn, D Redwood, A Reed, M Rees, T Rees, K Regan, W Reynolds, C Ribeiro, A Richards, E Richardson, M Richardson, P Rivera-Ortega, K Roberts, E Robertson, E Robinson, L Robinson, L Roche, C Roddis, J Rodger, A Ross, G Ross, J Rossdale, A Rostron, A Rowe, A Rowland, J Rowland, M J Rowland, S L Rowland-Jones, K Roy, M Roy, I Rudan, R Russell, E Russell, G Saalmink, R Sabit, E K Sage, T Samakomva, N Samani, C Sampson, K Samuel, R Samuel, A Sanderson, E Sapey, D Saralaya, J Sargent, C Sarginson, T Sass, N Sattar, K Saunders, R M Saunders, P Saunders, L C Saunders, H Savill, W Saxon, A Sayer, J Schronce, W Schwaeble, J T Scott, K Scott, N Selby, M G Semple, M Sereno, T A Sewell, A Shah, K Shah, P Shah, M Shankar-Hari, M Sharma, C Sharpe, M Sharpe, S Shashaa, A Shaw, K Shaw, V Shaw, A Sheikh, S Shelton, L Shenton, K Shevket, A Shikotra, J Short, S Siddique, S Siddiqui, J Sidebottom, L Sigfrid, G Simons, J Simpson, N Simpson, C Singh, S Singh, S J Singh, D Sissons, J Skeemer, K Slack, A Smith, D Smith, S Smith, J Smith, L Smith, M Soares, T S Solano, R Solly, A R Solstice, T Soulsby, D Southern, D Sowter, M Spears, L G Spencer, F Speranza, L Stadon, S Stanel, N Steele, M Steiner, D Stensel, G Stephens, L Stephenson, M Stern, I Stewart, R Stimpson, S Stockdale, J Stockley, W Stoker, R Stone, W Storrar, A Storrie, K Storton, E Stringer, S Strong-Sheldrake, N Stroud, C Subbe, C L Sudlow, Z Suleiman, C Summers, C Summersgill, D Sutherland, D L Sykes, R Sykes, N Talbot, A L Tan, L Tarusan, V Tavoukjian, A Taylor, C Taylor, J Taylor, A Te, H Tedd, C J Tee, J Teixeira, H Tench, S Terry, S Thackray-Nocera, F Thaivalappil, B Thamu, D Thickett, C Thomas, D C Thomas, S Thomas, A K Thomas, T Thomas-Woods, T Thompson, A A R Thompson, T Thornton, M Thorpe, R S Thwaites, J Tilley, N Tinker, G F Tiongson, M Tobin, J Tomlinson, C Tong, M Toshner, R Touyz, K A Tripp, E Tunnicliffe, A Turnbull, E Turner, S Turner, V Turner, K Turner, S Turney, H Turton, J Ugoji, R Ugwuoke, R Upthegrove, J Valabhji, M Ventura, J Vere, C Vickers, B Vinson, E Wade, P Wade, T Wainwright, L O Wajero, S Walder, S Walker, S Walker, E Wall, T Wallis, S Walmsley, J A Walsh, S Walsh, L Warburton, T J C Ward, K Warwick, H Wassall, S Waterson, E Watson, L Watson, J Watson, J Weir McCall, C Welch, H Welch, B Welsh, S Wessely, S West, H Weston, H Wheeler, S White, V Whitehead, J Whitney, S Whittaker, B Whittam, V Whitworth, A Wight, J Wild, M Wilkins, D Wilkinson, B Williams, N Williams, N Williams, J Williams, S A Williams-Howard, M Willicombe, G Willis, J Willoughby, A Wilson, D Wilson, I Wilson, N Window, M Witham, R Wolf-Roberts, C Wood, F Woodhead, J Woods, D G Wootton, J Wormleighton, J Worsley, D Wraith, C Wrey Brown, C Wright, L Wright, S Wright, J Wyles, I Wynter, M Xu, N Yasmin, S Yasmin, T Yates, K P Yip, B Young, S Young, A Young, A J Yousuf, A Zawia, L Zeidan, B Zhao, B Zheng, O Zongo

Affiliations

¹ MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, Office 6, University of Birmingham Research Labs, Institute of Inflammation and Ageing, Queen Elizabeth Hospital, Birmingham, UK.
² NIHR Birmingham Biomedical Research Centre, University Hospital Birmingham and University of Birmingham, Birmingham, UK.
³ NIHR Surgical Reconstruction and Microbiology Research Centre, University Hospital Birmingham, Birmingham, UK.
⁴ School of Biosciences, University of Birmingham, Birmingham, UK.
⁵ Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.
⁶ Institute for Lung Health, NIHR Leicester Biomedical Research Centre, Glenfield Hospital, University of Leicester, Leicester, UK.
⁷ NIHR Health Protection Research Unit in Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK.
⁸ Queen Elizabeth Hospital, University Hospital Birmingham NHS Foundation Trust, Birmingham, UK.
⁹ Department of Population Health Sciences, University of Leicester, Leicester, UK.
¹⁰ Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
¹¹ London School of Hygiene and Tropical Medicine, University of London, London, UK.
¹² National Heart and Lung Institute, Imperial College London, London, UK.
¹³ MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, Office 6, University of Birmingham Research Labs, Institute of Inflammation and Ageing, Queen Elizabeth Hospital, Birmingham, UK. [email protected].

Abstract

Background: The striking increase in COVID-19 severity in older adults provides a clear example of immunesenescence, the age-related remodelling of the immune system. To better characterise the association between convalescent immunesenescence and acute disease severity, we determined the immune phenotype of COVID-19 survivors and non-infected controls.

Results: We performed detailed immune phenotyping of peripheral blood mononuclear cells isolated from 103 COVID-19 survivors 3-5 months post recovery who were classified as having had severe (n = 56; age 53.12 ± 11.30 years), moderate (n = 32; age 52.28 ± 11.43 years) or mild (n = 15; age 49.67 ± 7.30 years) disease and compared with age and sex-matched healthy adults (n = 59; age 50.49 ± 10.68 years). We assessed a broad range of immune cell phenotypes to generate a composite score, IMM-AGE, to determine the degree of immune senescence. We found increased immunesenescence features in severe COVID-19 survivors compared to controls including: a reduced frequency and number of naïve CD4 and CD8 T cells (p < 0.0001); increased frequency of EMRA CD4 (p < 0.003) and CD8 T cells (p < 0.001); a higher frequency (p < 0.0001) and absolute numbers (p < 0.001) of CD28^-ve CD57^+ve senescent CD4 and CD8 T cells; higher frequency (p < 0.003) and absolute numbers (p < 0.02) of PD-1 expressing exhausted CD8 T cells; a two-fold increase in Th17 polarisation (p < 0.0001); higher frequency of memory B cells (p < 0.001) and increased frequency (p < 0.0001) and numbers (p < 0.001) of CD57^+ve senescent NK cells. As a result, the IMM-AGE score was significantly higher in severe COVID-19 survivors than in controls (p < 0.001). Few differences were seen for those with moderate disease and none for mild disease. Regression analysis revealed the only pre-existing variable influencing the IMM-AGE score was South Asian ethnicity ([Formula: see text] = 0.174, p = 0.043), with a major influence being disease severity ([Formula: see text] = 0.188, p = 0.01).

Conclusions: Our analyses reveal a state of enhanced immune ageing in survivors of severe COVID-19 and suggest this could be related to SARS-Cov-2 infection. Our data support the rationale for trials of anti-immune ageing interventions for improving clinical outcomes in these patients with severe disease.

Abstract

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