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The spatio-temporal landscape of lung pathology in SARS-CoV-2 infection.

ABSTRACT: Recent studies have provided insights into the pathology and immune response to coronavirus disease 2019 (COVID-19) ^1-8 . However thorough interrogation of the interplay between infected cells and the immune system at sites of infection is lacking. We use high parameter imaging mass cytometry ⁹ targeting the expression of 36 proteins, to investigate at single cell resolution, the cellular composition and spatial architecture of human acute lung injury including SARS-CoV-2. This spatially resolved, single-cell data unravels the disordered structure of the infected and injured lung alongside the distribution of extensive immune infiltration. Neutrophil and macrophage infiltration are hallmarks of bacterial pneumonia and COVID-19, respectively. We provide evidence that SARS-CoV-2 infects predominantly alveolar epithelial cells and induces a localized hyper-inflammatory cell state associated with lung damage. By leveraging the temporal range of COVID-19 severe fatal disease in relation to the time of symptom onset, we observe increased macrophage extravasation, mesenchymal cells, and fibroblasts abundance concomitant with increased proximity between these cell types as the disease progresses, possibly as an attempt to repair the damaged lung tissue. This spatially resolved single-cell data allowed us to develop a biologically interpretable landscape of lung pathology from a structural, immunological and clinical standpoint. This spatial single-cell landscape enabled the pathophysiological characterization of the human lung from its macroscopic presentation to the single-cell, providing an important basis for the understanding of COVID-19, and lung pathology in general.

SUBMITTER: Rendeiro AF

PROVIDER: S-EPMC7605585 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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The spatio-temporal landscape of lung pathology in SARS-CoV-2 infection.

Rendeiro André Figueiredo AF Ravichandran Hiranmayi H Bram Yaron Y Salvatore Steven S Borczuk Alain A Elemento Olivier O Schwartz Robert Edward RE

medRxiv : the preprint server for health sciences 20201027

Recent studies have provided insights into the pathology and immune response to coronavirus disease 2019 (COVID-19)<sup>1-8</sup>. However thorough interrogation of the interplay between infected cells and the immune system at sites of infection is lacking. We use high parameter imaging mass cytometry<sup>9</sup> targeting the expression of 36 proteins, to investigate at single cell resolution, the cellular composition and spatial architecture of human acute lung injury including SARS-CoV-2. Thi ...[more]

PMID: 33140072

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Project description:BackgroundCoronavirus disease 2019 (COVID-19) caused by the enveloped RNA virus SARS-CoV-2 primarily affects the respiratory and gastrointestinal tracts. SARS-CoV-2 was isolated from fecal samples, and active viral replication was reported in human intestinal cells. The human gut also harbors an enormous amount of resident viruses (collectively known as the virome) that play a role in regulating host immunity and disease pathophysiology. Understanding gut virome perturbation that underlies SARS-CoV-2 infection and severity is an unmet need.MethodsWe enrolled 98 COVID-19 patients with varying disease severity (3 asymptomatic, 53 mild, 34 moderate, 5 severe, 3 critical) and 78 non-COVID-19 controls matched for gender and co-morbidities. All subjects had fecal specimens sampled at inclusion. Blood specimens were collected for COVID-19 patients at admission to test for inflammatory markers and white cell counts. Among COVID-19 cases, 37 (38%) patients had serial fecal samples collected 2 to 3 times per week from time of hospitalization until after discharge. Using shotgun metagenomics sequencing, we sequenced and profiled the fecal RNA and DNA virome. We investigated alterations and longitudinal dynamics of the gut virome in association with disease severity and blood parameters.ResultsPatients with COVID-19 showed underrepresentation of Pepper mild mottle virus (RNA virus) and multiple bacteriophage lineages (DNA viruses) and enrichment of environment-derived eukaryotic DNA viruses in fecal samples, compared to non-COVID-19 subjects. Such gut virome alterations persisted up to 30 days after disease resolution. Fecal virome in SARS-CoV-2 infection harbored more stress-, inflammation-, and virulence-associated gene encoding capacities including those pertaining to bacteriophage integration, DNA repair, and metabolism and virulence associated with their bacterial host. Baseline fecal abundance of 10 virus species (1 RNA virus, pepper chlorotic spot virus, and 9 DNA virus species) inversely correlated with disease COVID-19 severity. These viruses inversely correlated with blood levels of pro-inflammatory proteins, white cells, and neutrophils. Among the 10 COVID-19 severity-associated DNA virus species, 4 showed inverse correlation with age; 5 showed persistent lower abundance both during disease course and after disease resolution relative to non-COVID-19 subjects.ConclusionsBoth enteric RNA and DNA virome in COVID-19 patients were different from non-COVID-19 subjects, which persisted after disease resolution of COVID-19. Gut virome may calibrate host immunity and regulate severity to SARS-CoV-2 infection. Our observation that gut viruses inversely correlated with both severity of COVID-19 and host age may partly explain that older subjects are prone to severe and worse COVID-19 outcomes. Altogether, our data highlight the importance of human gut virome in severity and potentially therapeutics of COVID-19. Video Abstract.

Dataset Information

The spatio-temporal landscape of lung pathology in SARS-CoV-2 infection.

Publications

The spatio-temporal landscape of lung pathology in SARS-CoV-2 infection.

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