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Article: Accelarated immune ageing is associated with COVID-19 disease severity.

2024 Volume 21, Issue 1, Page(s) 6

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 ...

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 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.
Language	English
Publishing date	2024-01-11
Publishing country	England
Document type	Journal Article
ZDB-ID	2168941-6
ISSN	1742-4933
ISSN	1742-4933
DOI	10.1186/s12979-023-00406-z
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Article ; Online: Delayed mucosal anti-viral responses despite robust peripheral inflammation in fatal COVID-19.

Sidhu, Jasmin K / Siggins, Matthew K / Liew, Felicity / Russell, Clark D / Uruchurtu, Ashley S S / Davis, Christopher / Turtle, Lance / Moore, Shona C / Hardwick, Hayley E / Oosthuyzen, Wilna / Thomson, Emma C / Semple, Malcolm G / Baillie, J Kenneth / Openshaw, Peter J M / Thwaites, Ryan S

The Journal of infectious diseases

2023

Abstract: Background: While inflammatory and immune responses to SARS-CoV-2 infection in peripheral blood are extensively described, responses at the upper respiratory mucosal site of initial infection are relatively poorly defined. We sought to identify mucosal ... ...

Abstract	Background: While inflammatory and immune responses to SARS-CoV-2 infection in peripheral blood are extensively described, responses at the upper respiratory mucosal site of initial infection are relatively poorly defined. We sought to identify mucosal cytokine/chemokine signatures that distinguished COVID-19 severity categories, and relate these to disease progression and peripheral inflammation. Methods: We measured 35 cytokines and chemokines in nasal samples from 274 patients hospitalised with COVID-19. Analysis considered the timing of sampling during disease, as either the early (0-5 days post-symptom onset) or late (6-20 days post-symptom onset). Results: Patients that survived severe COVID-19 showed IFN-dominated mucosal immune responses (IFN-γ, CXCL10 and CXCL13) early in infection. These early mucosal responses were absent in patients that would progress to fatal disease despite equivalent SARS-CoV-2 viral load. Mucosal inflammation in later disease was dominated by IL-2, IL-10, IFN-γ, and IL-12p70, which scaled with severity but did not differentiate patients who would survive or succumb to disease. Cytokines and chemokines in the mucosa showed distinctions from responses evident in the peripheral blood, particularly during fatal disease. Conclusions: Defective early mucosal anti-viral responses anticipate fatal COVID-19 but are not associated with viral load. Early mucosal immune responses may define the trajectory of severe COVID-19.
Language	English
Publishing date	2023-12-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	3019-3
ISSN	1537-6613 ; 0022-1899
ISSN (online)	1537-6613
ISSN	0022-1899
DOI	10.1093/infdis/jiad590
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Article ; Online: Obesity Differs from Diabetes Mellitus in Antibody and T Cell Responses Post COVID-19 Recovery.

Ali, Mohammad / Longet, Stephanie / Neale, Isabel / Rongkard, Patpong / Chowdhury, Forhad Uddin Hassan / Hill, Jennifer / Brown, Anthony / Laidlaw, Stephen / Tipton, Tom / Hoque, Ashraful / Hassan, Nazia / Hackstein, Carl-Philipp / Adele, Sandra / Akther, Hossain Delowar / Abraham, Priyanka / Paul, Shrebash / Rahman, Md Matiur / Alam, Md Masum / Parvin, Shamima /

Hoque Mollah, Forhadul / Hoque, Md Mozammel / Moore, Shona C / Biswas, Subrata K / Turtle, Lance / de Silva, Thushan I / Ogbe, Ane / Frater, John / Barnes, Eleanor / Tomic, Adriana / Carroll, Miles W / Klenerman, Paul / Kronsteiner, Barbara / Chowdhury, Fazle Rabbi / Dunachie, Susanna J

Clinical and experimental immunology

2024

Abstract: Obesity and type 2 diabetes (DM) are risk factors for severe COVID-19 outcomes, which disproportionately affect South Asian populations. This study aims to investigate the humoral and cellular immune responses to SARS-CoV-2 in adult COVID-19 survivors ... ...

Abstract	Obesity and type 2 diabetes (DM) are risk factors for severe COVID-19 outcomes, which disproportionately affect South Asian populations. This study aims to investigate the humoral and cellular immune responses to SARS-CoV-2 in adult COVID-19 survivors with obesity and DM in Bangladesh. In this cross-sectional study, SARS-CoV-2-specific antibody and T cell responses were investigated in 63 healthy and 75 PCR-confirmed COVID-19 recovered individuals in Bangladesh, during the pre-vaccination first wave of the COVID-19 pandemic in 2020. In COVID-19 survivors, SARS-CoV-2 infection induced robust antibody and T cell responses, which correlated with disease severity. After adjusting for age, sex, DM status, disease severity, and time since onset of symptoms, obesity was associated with decreased neutralising antibody titers, and increased SARS-CoV-2 spike-specific IFN-γ response along with increased proliferation and IL-2 production by CD8+ T cells. In contrast, DM was not associated with SARS-CoV-2-specific antibody and T cell responses after adjustment for obesity and other confounders. Obesity is associated with lower neutralising antibody levels and higher T cell responses to SARS-CoV-2 post COVID-19 recovery, while antibody or T cell responses remain unaltered in DM.
Language	English
Publishing date	2024-04-20
Publishing country	England
Document type	Journal Article
ZDB-ID	218531-3
ISSN	1365-2249 ; 0009-9104 ; 0964-2536
ISSN (online)	1365-2249
ISSN	0009-9104 ; 0964-2536
DOI	10.1093/cei/uxae030
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Article ; Online: Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease.

Liew, Felicity / Efstathiou, Claudia / Fontanella, Sara / Richardson, Matthew / Saunders, Ruth / Swieboda, Dawid / Sidhu, Jasmin K / Ascough, Stephanie / Moore, Shona C / Mohamed, Noura / Nunag, Jose / King, Clara / Leavy, Olivia C / Elneima, Omer / McAuley, Hamish J C / Shikotra, Aarti / Singapuri, Amisha / Sereno, Marco / Harris, Victoria C /

Houchen-Wolloff, Linzy / Greening, Neil J / Lone, Nazir I / Thorpe, Matthew / Thompson, A A Roger / Rowland-Jones, Sarah L / Docherty, Annemarie B / Chalmers, James D / Ho, Ling-Pei / Horsley, Alexander / Raman, Betty / Poinasamy, Krisnah / Marks, Michael / Kon, Onn Min / Howard, Luke S / Wootton, Daniel G / Quint, Jennifer K / de Silva, Thushan I / Ho, Antonia / Chiu, Christopher / Harrison, Ewen M / Greenhalf, William / Baillie, J Kenneth / Semple, Malcolm G / Turtle, Lance / Evans, Rachael A / Wain, Louise V / Brightling, Christopher / Thwaites, Ryan S / Openshaw, Peter J M

Nature immunology

2024 Volume 25, Issue 4, Page(s) 607–621

Abstract: One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly ... ...

Abstract	One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood
MeSH term(s)	Humans ; Post-Acute COVID-19 Syndrome ; COVID-19 ; Biomedical Research ; Hospitalization ; Immunoglobulin G
Chemical Substances	Immunoglobulin G
Language	English
Publishing date	2024-04-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	2016987-5
ISSN	1529-2916 ; 1529-2908
ISSN (online)	1529-2916
ISSN	1529-2908
DOI	10.1038/s41590-024-01778-0
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Article ; Online: HLA-E-restricted SARS-CoV-2-specific T cells from convalescent COVID-19 patients suppress virus replication despite HLA class Ia down-regulation.

Yang, Hongbing / Sun, Hong / Brackenridge, Simon / Zhuang, Xiaodong / Wing, Peter A C / Quastel, Max / Walters, Lucy / Garner, Lee / Wang, Beibei / Yao, Xuan / Felce, Suet Ling / Peng, Yanchun / Moore, Shona / Peeters, Bas W A / Rei, Margarida / Canto Gomes, Joao / Tomas, Ana / Davidson, Andrew / Semple, Malcolm G /

Turtle, Lance C W / Openshaw, Peter J M / Baillie, J Kenneth / Mentzer, Alexander J / Klenerman, Paul / Borrow, Persephone / Dong, Tao / McKeating, Jane A / Gillespie, Geraldine M / McMichael, Andrew J

Science immunology

2023 Volume 8, Issue 84, Page(s) eabl8881

Abstract: Pathogen-specific ... ...

Abstract	Pathogen-specific CD8
MeSH term(s)	Humans ; SARS-CoV-2 ; COVID-19 ; CD8-Positive T-Lymphocytes ; Down-Regulation ; Histocompatibility Antigens Class II ; Virus Replication ; Antibodies ; HLA-E Antigens
Chemical Substances	Histocompatibility Antigens Class II ; Antibodies
Language	English
Publishing date	2023-06-30
Publishing country	United States
Document type	Journal Article
ISSN	2470-9468
ISSN (online)	2470-9468
DOI	10.1126/sciimmunol.abl8881
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Article: Procalcitonin Is Not a Reliable Biomarker of Bacterial Coinfection in People With Coronavirus Disease 2019 Undergoing Microbiological Investigation at the Time of Hospital Admission.

Relph, Katharine A / Russell, Clark D / Fairfield, Cameron J / Turtle, Lance / de Silva, Thushan I / Siggins, Matthew K / Drake, Thomas M / Thwaites, Ryan S / Abrams, Simon / Moore, Shona C / Hardwick, Hayley E / Oosthuyzen, Wilna / Harrison, Ewen M / Docherty, Annemarie B / Openshaw, Peter J M / Baillie, J Kenneth / Semple, Malcolm G / Ho, Antonia

Open forum infectious diseases

2022 Volume 9, Issue 5, Page(s) ofac179

Abstract: Admission procalcitonin measurements and microbiology results were available for 1040 hospitalized adults with coronavirus disease 2019 (from 48 902 included in the International Severe Acute Respiratory and Emerging Infections Consortium World Health ... ...

Abstract	Admission procalcitonin measurements and microbiology results were available for 1040 hospitalized adults with coronavirus disease 2019 (from 48 902 included in the International Severe Acute Respiratory and Emerging Infections Consortium World Health Organization Clinical Characterisation Protocol UK study). Although procalcitonin was higher in bacterial coinfection, this was neither clinically significant (median [IQR], 0.33 [0.11-1.70] ng/mL vs 0.24 [0.10-0.90] ng/mL) nor diagnostically useful (area under the receiver operating characteristic curve, 0.56 [95% confidence interval, .51-.60]).
Language	English
Publishing date	2022-05-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2757767-3
ISSN	2328-8957
ISSN	2328-8957
DOI	10.1093/ofid/ofac179
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Article ; Online: IgE-tailpiece associates with α-1-antitrypsin (A1AT) to protect IgE from proteolysis without compromising its ability to interact with FcεRI.

Quinn, Phyllis M / Dunne, David W / Moore, Shona C / Pleass, Richard J

Scientific reports

2016 Volume 6, Page(s) 20509

Abstract: ... that both the classical form of IgE (IgE-c) and IgE-tp interact with polymers of the serine protease inhibitor alpha-1 ...

Abstract	Several splice variants of IgE exist in human plasma, including a variant called IgE-tailpiece (IgE-tp) that differs from classical IgE by the replacement of two carboxy-terminal amino acids with eight novel residues that include an ultimate cysteine. To date, the role of the secreted IgE-tp isoform in human immunity is unknown. We show that levels of IgE-tp are raised in helminth-infected donors, and that both the classical form of IgE (IgE-c) and IgE-tp interact with polymers of the serine protease inhibitor alpha-1-antitrypsin (A1AT). The association of IgE-tp with A1AT polymers in plasma protects the antibody from serine protease-mediated degradation, without affecting the functional interaction of IgE-tp with important receptors, including FcεR1. That polymers of A1AT protect IgE from degradation by helminth proteases may explain why these common and normally non-disease causing polymorphic variants of A1AT have been retained by natural selection. The observation that IgE can be complexed with polymeric forms of A1AT may therefore have important consequences for our understanding of the pathophysiology of pulmonary diseases that arise either as a consequence of A1AT-deficiency or through IgE-mediated type 1 hypersensitivity responses.
MeSH term(s)	Helminthiasis/immunology ; Humans ; Immunoglobulin E/chemistry ; Immunoglobulin E/metabolism ; Protein Isoforms/metabolism ; Proteolysis ; Receptors, IgE/metabolism ; alpha 1-Antitrypsin/metabolism
Chemical Substances	Protein Isoforms ; Receptors, IgE ; alpha 1-Antitrypsin ; Immunoglobulin E (37341-29-0)
Language	English
Publishing date	2016-02-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/srep20509
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Article ; Online: Immunoglobulin M: Restrainer of Inflammation and Mediator of Immune Evasion by Plasmodium falciparum Malaria.

Pleass, Richard J / Moore, Shona C / Stevenson, Liz / Hviid, Lars

Trends in parasitology

2015 Volume 32, Issue 2, Page(s) 108–119

Abstract: Immunoglobulin M (IgM) is an ancient antibody class that is found in all vertebrates, with the exception of coelacanths, and is indispensable in both innate and adaptive immunity. The equally ancient human malaria parasite, Plasmodium falciparum, formed ... ...

Abstract	Immunoglobulin M (IgM) is an ancient antibody class that is found in all vertebrates, with the exception of coelacanths, and is indispensable in both innate and adaptive immunity. The equally ancient human malaria parasite, Plasmodium falciparum, formed an intimate relationship with IgM with which it co-evolved. In this article, we discuss the association between IgM and human malaria parasites, building on several recent publications that implicate IgM as a crucial molecule that determines both host and parasite survival. Consequently, a better understanding of this association may lead to the development of improved intervention strategies.
MeSH term(s)	Animals ; Host-Parasite Interactions ; Humans ; Immune Evasion/immunology ; Immunoglobulin M/immunology ; Inflammation/immunology ; Malaria, Falciparum/immunology ; Plasmodium falciparum/immunology
Chemical Substances	Immunoglobulin M
Language	English
Publishing date	2015-11-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2036227-4
ISSN	1471-5007 ; 1471-4922
ISSN (online)	1471-5007
ISSN	1471-4922
DOI	10.1016/j.pt.2015.09.007
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Article ; Online: CD4+ and CD8+ T cells and antibodies are associated with protection against Delta vaccine breakthrough infection: a nested case-control study within the PITCH study.

Neale, Isabel / Ali, Mohammad / Kronsteiner, Barbara / Longet, Stephanie / Abraham, Priyanka / Deeks, Alexandra S / Brown, Anthony / Moore, Shona C / Stafford, Lizzie / Dobson, Susan L / Plowright, Megan / Newman, Thomas A H / Wu, Mary Y / Carr, Edward J / Beale, Rupert / Otter, Ashley D / Hopkins, Susan / Hall, Victoria / Tomic, Adriana /

Payne, Rebecca P / Barnes, Eleanor / Richter, Alex / Duncan, Christopher J A / Turtle, Lance / de Silva, Thushan I / Carroll, Miles / Lambe, Teresa / Klenerman, Paul / Dunachie, Susanna

mBio

2023 Volume 14, Issue 5, Page(s) e0121223

Abstract: Importance: Defining correlates of protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine breakthrough infection informs vaccine policy for booster doses and future vaccine designs. Existing studies demonstrate humoral ... ...

Abstract	Importance: Defining correlates of protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine breakthrough infection informs vaccine policy for booster doses and future vaccine designs. Existing studies demonstrate humoral correlates of protection, but the role of T cells in protection is still unclear. In this study, we explore antibody and T cell immune responses associated with protection against Delta variant vaccine breakthrough infection in a well-characterized cohort of UK Healthcare Workers (HCWs). We demonstrate evidence to support a role for CD4+ and CD8+ T cells as well as antibodies against Delta vaccine breakthrough infection. In addition, our results suggest a potential role for cross-reactive T cells in vaccine breakthrough.
MeSH term(s)	Humans ; Case-Control Studies ; Breakthrough Infections ; Antibodies ; CD8-Positive T-Lymphocytes ; SARS-CoV-2 ; Vaccines ; CD4-Positive T-Lymphocytes ; Antibodies, Viral ; Antibodies, Neutralizing
Chemical Substances	Antibodies ; Vaccines ; Antibodies, Viral ; Antibodies, Neutralizing
Language	English
Publishing date	2023-09-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2557172-2
ISSN	2150-7511 ; 2161-2129
ISSN (online)	2150-7511
ISSN	2161-2129
DOI	10.1128/mbio.01212-23
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Article ; Online: Plasma steroid concentrations reflect acute disease severity and normalise during recovery in people hospitalised with COVID-19.

Devine, Kerri / Russell, Clark D / Blanco, Giovanny R / Walker, Brian R / Homer, Natalie Z M / Denham, Scott G / Simpson, Joanna P / Leavy, Olivia C / Elneima, Omer / McAuley, Hamish J C / Shikotra, Aarti / Singapuri, Amisha / Sereno, Marco / Saunders, Ruth M / Harris, Victoria C / Houchen-Wolloff, Linzy / Greening, Neil J / Lone, Nazir I / Thorpe, Mathew /

Greenhalf, William / Chalmers, James D / Ho, Ling-Pei / Horsley, Alex / Marks, Michael / Raman, Betty / Moore, Shona C / Dunning, Jake / Semple, Malcolm G / Andrew, Ruth / Wain, Louise V / Evans, Rachael A / Brightling, Christopher E / Kenneth Baillie, John / Reynolds, Rebecca M

Clinical endocrinology

2024 Volume 100, Issue 4, Page(s) 317–327

Abstract: Objective: Endocrine systems are disrupted in acute illness, and symptoms reported following coronavirus disease 2019 (COVID-19) are similar to those found with clinical hormone deficiencies. We hypothesised that people with severe acute COVID-19 and ... ...

Abstract	Objective: Endocrine systems are disrupted in acute illness, and symptoms reported following coronavirus disease 2019 (COVID-19) are similar to those found with clinical hormone deficiencies. We hypothesised that people with severe acute COVID-19 and with post-COVID symptoms have glucocorticoid and sex hormone deficiencies. Design/patients: Samples were obtained for analysis from two UK multicentre cohorts during hospitalisation with COVID-19 (International Severe Acute Respiratory Infection Consortium/World Health Organisation [WHO] Clinical Characterization Protocol for Severe Emerging Infections in the UK study), and at follow-up 5 months after hospitalisation (Post-hospitalisation COVID-19 study). Measurements: Plasma steroids were quantified by liquid chromatography-mass spectrometry. Steroid concentrations were compared against disease severity (WHO ordinal scale) and validated symptom scores. Data are presented as geometric mean (SD). Results: In the acute cohort (n = 239, 66.5% male), plasma cortisol concentration increased with disease severity (cortisol 753.3 [1.6] vs. 429.2 [1.7] nmol/L in fatal vs. least severe, p < .001). In males, testosterone concentrations decreased with severity (testosterone 1.2 [2.2] vs. 6.9 [1.9] nmol/L in fatal vs. least severe, p < .001). In the follow-up cohort (n = 198, 62.1% male, 68.9% ongoing symptoms, 165 [121-192] days postdischarge), plasma cortisol concentrations (275.6 [1.5] nmol/L) did not differ with in-hospital severity, perception of recovery, or patient-reported symptoms. Male testosterone concentrations (12.6 [1.5] nmol/L) were not related to in-hospital severity, perception of recovery or symptom scores. Conclusions: Circulating glucocorticoids in patients hospitalised with COVID-19 reflect acute illness, with a marked rise in cortisol and fall in male testosterone. These findings are not observed 5 months from discharge. The lack of association between hormone concentrations and common post-COVID symptoms suggests steroid insufficiency does not play a causal role in this condition.
MeSH term(s)	Humans ; Male ; Female ; COVID-19 ; Hydrocortisone ; Acute Disease ; Aftercare ; Patient Discharge ; Glucocorticoids/therapeutic use ; Steroids/therapeutic use ; Patient Acuity ; Testosterone
Chemical Substances	Hydrocortisone (WI4X0X7BPJ) ; Glucocorticoids ; Steroids ; Testosterone (3XMK78S47O)
Language	English
Publishing date	2024-01-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	121745-8
ISSN	1365-2265 ; 0300-0664
ISSN (online)	1365-2265
ISSN	0300-0664
DOI	10.1111/cen.15012
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