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Background: Persistent radiological lung abnormalities are evident in many survivors of acute coronavirus disease 2019 (COVID-19). Consolidation and ground glass opacities are interpreted to indicate subacute inflammation whereas reticulation is thought to reflect fibrosis. We sought to identify differences at molecular and cellular level, in the local immunopathology of post-COVID inflammation and fibrosis. Methods: We compared single-cell transcriptomic profiles and T cell receptor (TCR) repertoires of bronchoalveolar cells obtained from convalescent individuals with each radiological pattern, targeting lung segments affected by the predominant abnormality. Results: CD4 central memory T cells and CD8 effector memory T cells were significantly more abundant in those with inflammatory radiology. Clustering of similar TCRs from multiple donors was a striking feature of both phenotypes, consistent with tissue localised antigen-specific immune responses. There was no enrichment for known SARS-CoV-2-reactive TCRs, raising the possibility of T cell-mediated immunopathology driven by failure in immune self-tolerance. Conclusions: Post-COVID radiological inflammation and fibrosis show evidence of shared antigen-specific T cell responses, suggesting a role for therapies targeting T cells in limiting post-COVID lung damage. [ABSTRACT FROM AUTHOR]

Background: Concerted efforts aim to reduce the burden of 6 months of anti-tuberculous treatment for tuberculosis (TB). Treatment cessation at 8 weeks is effective for most but incurs increased risk of disease relapse. We tested the hypothesis that blood RNA signatures or C-reactive protein (CRP) measurements discriminate 8-week sputum culture status, as a prerequisite for a biomarker to stratify risk of relapse following treatment cessation at this time-point., Methods: We identified blood RNA signatures of TB disease or cure by systematic review. We evaluated these signatures and CRP measurements in a pulmonary TB cohort, pre-treatment, at 2 and 8 weeks of treatment, and sustained cure after treatment completion. We tested biomarker discrimination of 8-week sputum culture status using area under the receiver operating characteristic curve (AUROC) analysis and, secondarily, assessed correlation of biomarker scores with time to culture positivity at 8 weeks of treatment., Results: 12 blood RNA signatures were reproduced in the dataset from 44 individuals with sputum culture-positive pulmonary TB. These normalised over time from TB treatment initiation. 11 out of 44 cases with blood RNA, CRP and sputum culture results were sputum culture-positive at 8 weeks of treatment. None of the contemporary blood RNA signatures discriminated sputum culture status at this time-point or correlated with bacterial load. CRP achieved modest discrimination with AUROC 0.69 (95% CI 0.52-0.87)., Conclusions: Selected TB blood RNA signatures and CRP do not provide biomarkers of microbiological clearance to support TB treatment cessation at 8 weeks. Resolution of blood transcriptional host responses in sputum culture-positive individuals suggests Mycobacterium tuberculosis may colonise the respiratory tract without triggering a detectable immune response., Competing Interests: Conflict of interest: C.J. Calderwood reports support for the present study from the National Institute for Health Research (Academic Clinical Fellowship), grants from the Wellcome Trust (225466/Z/22/Z), and support for attending meetings from the British Thoracic Society (Travel Award 2023). B. Oguti reports support for the present study from the National Institute for Health Research (Academic Clinical Fellowship, awarded via University College London). J.K. Roe reports patents held in relation to blood transcriptomic biomarkers of tuberculosis. R. Gupta reports support for the present study from the National Institute for Health Research (personal fellowship award). A.R. Martineau reports support for the present study from the British Lung Foundation, and patents held in relation to blood transcriptomic biomarkers of tuberculosis. M. Noursadeghi reports support for the present study from the Wellcome Trust and NIHR Biomedical Research Centre at University College London Hospitals NHS Trust, and patents held in relation to blood transcriptomic biomarkers of tuberculosis. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

Introduction: Ageing is associated with increased number of infections, decreased vaccine efficacy and increased systemic inflammation termed inflammageing. These changes are reflected by reduced recall responses to varicella zoster virus (VZV) challenge in the skin of older adults. Vitamin D deficiency is more common in the old and has been associated with frailty and increased inflammation. In addition, vitamin D increases immunoregulatory mechanisms and therefore has the potential to inhibit inflammageing., Objectives: We investigated the use of vitamin D 3 replacement to enhance cutaneous antigen-specific immunity in older adults (≥65 years)., Methods: Vitamin D insufficient older adults ( n = 18) were administered 6400IU of vitamin D 3 /day orally for 14 weeks. Antigen-specific immunity to VZV was assessed by clinical score assessment of the injection site and transcriptional analysis of skin biopsies collected from challenged injection sites pre- and post-vitamin D 3 replacement., Results: We showed that older adults had reduced VZV-specific cutaneous immune response and increased non-specific inflammation as compared to young. Increased non-specific inflammation observed in the skin of older adults negatively correlated with vitamin D sufficiency. We showed that vitamin D 3 supplementation significantly increased the response to cutaneous VZV antigen challenge in older adults. This enhancement was associated with a reduction in inflammatory monocyte infiltration with a concomitant enhancement of T cell recruitment to the site of antigen challenge in the skin., Conclusion: Vitamin D 3 replacement can boost antigen-specific immunity in older adults with sub-optimal vitamin D status., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Immunology.)