Severe COVID-19 is associated with deep and sustained multifaceted cellular immunosuppression.
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ABSTRACT:
SUBMITTER: Jeannet R
PROVIDER: S-EPMC7276497 | biostudies-literature | 2020 Sep
REPOSITORIES: biostudies-literature
Publications
Severe COVID-19 is associated with deep and sustained multifaceted cellular immunosuppression.
Jeannet Robin R Daix Thomas T Formento Rémy R Feuillard Jean J François Bruno B
Intensive care medicine 20200608 9
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Project description:The objective of this study was to elucidate the pathophysiology that underlies severe COVID-19 by assessing the histopathology and the in situ detection of infectious SARS-CoV-2 and viral capsid proteins along with the cellular target(s) and host response from twelve autopsies. There were three key findings: 1) high copy infectious virus was limited mostly to the alveolar macrophages and endothelial cells of the septal capillaries; 2) viral spike protein without viral RNA localized to ACE2+ endothelial cells in microvessels that were most abundant in the subcutaneous fat and brain; 3) although both infectious virus and docked viral spike protein was associated with complement activation, only the endocytosed pseudovirions induced a marked up-regulation of the key COVID-19 associated proteins IL6, TNF alpha, IL1 beta, p38, IL8, and caspase 3. Importantly, this microvasculitis was associated with characteristic findings on hematoxylin and eosin examination that included endothelial degeneration and resultant basement membrane zone disruption and reduplication. It is concluded that serious COVID-19 infection has two distinct mechanisms: 1) a microangiopathy of pulmonary capillaries associated with a high infectious viral load where endothelial cell death releases pseudovirions into the circulation, and 2) the pseudovirions dock on ACE2+ endothelial cells most prevalent in the skin/subcutaneous fat and brain that activates the complement pathway/coagulation cascade resulting in a systemic procoagulant state as well as the expression of cytokines that produce the cytokine storm. The data predicts a favorable response to therapies based on either removal of circulating viral proteins and/or blunting of the endothelial-induced response. Highlights • SARS-CoV-2 causes serious disease via two distinct mechanisms• One mechanism is damage to the alveolar wall (microangiopathy) associated with high viral copy numbers• The other mechanism is circulating viral capsid proteins that dock on ACE2+ endothelia• The ACE2+ endothelia are most prominent in the subcutaneous fat and brain• Endocytosis of viral capsid protein by endothelia induces cell death, cytokine expression, and complement activation (endothelialitis)
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Project description:Transient lymphocytopenia is frequently observed in acute phase of coronavirus disease 2019 (COVID-19). It remains a concern whether impairment of cellular immunity may be retained after COVID-19. Here, we demonstrate by extensive lymphocyte profiling in 44 adults after mild COVID-19 that cellular immunity is not fundamentally altered in convalescent patients. Except for increased activated CD8+ lymphocytes, total counts of B, T, and NK cells and their subsets did not differ significantly between patients after COVID-19 and healthy controls after a median of 27 days (range 13-45) suggesting no residual cellular immune deficiency after recovery from mild COVID-19.
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Project description:Early in the COVID-19 pandemic, type 2 diabetes (T2D) was marked as a risk-factor for severe disease. Inflammation is central to the aetiology of both conditions where immune responses influence disease course. Identifying at-risk groups through immuno-inflammatory signatures can direct personalised care and help develop potential targets for precision therapy. This observational study characterised immunophenotypic variation associated with COVID-19 severity in T2D. Broad-spectrum immunophenotyping quantified 15 leukocyte populations in circulation from a cohort of 45 hospitalised COVID-19 patients with and without T2D. Lymphocytopenia, of CD8+ lymphocytes, was associated with severe COVID-19 and intensive care admission in non-diabetic and T2D patients. A morphological anomaly of increased monocyte size and monocytopenia of classical monocytes were specifically associated with severe COVID-19 in patients with T2D requiring intensive care. Over-expression of inflammatory markers reminiscent of the type-1 interferon pathway underlaid the immunophenotype associated with T2D. These changes may contribute to severity of COVID-19 in T2D. These findings show characteristics of severe COVID-19 in T2D as well as provide evidence that type-1 interferons may be actionable targets for future studies.
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Project description:As a primary target of SARS-CoV-2, lung exhibits heterogeneous histopathological changes following infection. However, comprehensive insight into their protein basis with spatial resolution remains deficient, which hinders further understanding of COVID-19-related pulmonary injury. Here, we generated a region-resolved proteomic atlas of hallmark pathological pulmonary structures by integrating histological examination, laser microdissection, and ultrasensitive proteomics. Over 10,000 proteins were quantified across 71 post-mortem specimens. We identified a spectrum of pathway dysregulations in alveolar epithelium, bronchial epithelium, and blood vessels comparing with non-COVID-19 controls, providing evidence for transitional-state pneumocyte hyperplasia. Additionally, our data revealed the region-specific enrichment of functional markers in bronchiole mucus plug, pulmonary fibrosis, airspace inflammation, and alveolar type 2 cells, uncovering their distinctive features. Furthermore, we detected increased protein expression associated with viral entry and inflammatory response across multiple regions, suggesting potential therapeutic targets. Collectively, this study provides a unique perspective for deciphering COVID-19-caused pulmonary dysfunction by spatial proteomics.
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