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Obesity Is Associated with Attenuated Tissue Immunity in COVID-19.

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Rationale: Obesity affects 40% of U.S. adults, is associated with a proinflammatory state, and presents a significant risk factor for the development of severe coronavirus disease (COVID-19). To date, there is limited information on how obesity might affect immune cell responses in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Objectives: To determine the impact of obesity on respiratory tract immunity in COVID-19 across the human lifespan. Methods: We analyzed single-cell transcriptomes from BAL in three ventilated adult cohorts with (n = 24) or without (n = 9) COVID-19 from nasal immune cells in children with (n = 14) or without (n = 19) COVID-19, and from peripheral blood mononuclear cells in an independent adult COVID-19 cohort (n = 42), comparing obese and nonobese subjects. Measurements and Main Results: Surprisingly, we found that obese adult subjects had attenuated lung immune or inflammatory responses in SARS-CoV-2 infection, with decreased expression of IFN-α, IFN-γ, and TNF-α (tumor necrosis factor α) response gene signatures in almost all lung epithelial and immune cell subsets, and lower expression of IFNG and TNF in specific lung immune cells. Peripheral blood immune cells in an independent adult cohort showed a similar but less marked reduction in type-I IFN and IFNγ response genes, as well as decreased serum IFNα, in obese patients with SARS-CoV-2. Nasal immune cells from obese children with COVID-19 also showed reduced enrichment of IFN-α and IFN-γ response genes. Conclusions: These findings show blunted tissue immune responses in obese patients with COVID-19, with implications for treatment stratification, supporting the specific application of inhaled recombinant type-I IFNs in this vulnerable subset.



COVID-19, bronchoalveolar lavage, obesity, single-cell RNA sequencing, type-I interferon, Adult, Humans, Child, COVID-19, SARS-CoV-2, Leukocytes, Mononuclear, Pediatric Obesity, Lung, Interferon Type I

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Am J Respir Crit Care Med

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American Thoracic Society
MRC (MR/V006118/1)
Medical Research Council (MR/R015635/1)
Medical Research Council (MR/S035842/1)
European Commission Horizon 2020 (H2020) Societal Challenges (874656)
GB is funded by a Wellcome Strategic Scientific award (WT211276/Z/18/Z). ZKT and MRC are supported by a Medical Research Council Research Project Grant (MR/S035842/1). JRF and MRC are supported by the National Institute of Health Research (NIHR) Blood and Transplant Research Unit in Organ Donation, and NR, MM, GD and MRC by the NIHR Cambridge Biomedical Research Centre. MZN acknowledges funding from the Rutherford Fund Fellowship allocated by the Medical Research Council and the UK Regenerative Medicine Platforms 2 (MR/5005579/1). KBM acknowledges funding from Wellcome (WT211276/Z/18/Z and Sanger core grant WT206194), the Chan Zuckerberg Foundation (grants 2017-174169 and 2019-202654) and the European Union’s Horizon 2020 research and innovation programme under grant agreement No 874656. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. The CL3 for this research was partly funded by the NIHR AMR Research Capital Funding Scheme [NIHR200640]. We are grateful to the Evelyn Trust (20/75), Addenbrooke’s Charitable Trust, Cambridge University Hospitals (12/20A), the NIHR Cambridge Biomedical Research Centre, Rosetrees Trust (M944), Action Medical Research (GN2911) and the UKRI/NIHR through the UK Coronavirus Immunology Consortium (UK-CIC) for their financial support. RGW and AVM are funded by NIH NIAID U19AI35964. Collection of lavage samples in Cambridge was supported by a grant from LifeArc (900244). ACM is supported by a Clinician Scientist Fellowship from the Medical Research Council (MR/V006118/1). MRC and SAG by an NIHR Research Professorship RP-2017-08-ST2-002).