Spatial mapping of SARS-CoV-2 and H1N1 lung injury identifies differential transcriptional signatures

Camilla Margaroli,Paul Benson,Nirmal S Sharma,Matthew C Madison,Sarah W Robison,Nitin Arora,Kathy Ton,Yan Liang,Liang Zhang,Rakesh P Patel,Amit Gaggar

doi:10.1016/j.xcrm.2021.100242

Abstract

SummarySevere SARS-CoV-2 infection often leads to the development of acute respiratory distress syndrome (ARDS), with profound pulmonary patho-histological changes post-mortem. It is not clear whether ARDS from SARS-CoV-2 is similar to that observed in influenza H1N1, another common viral cause of lung injury. Here, we analyze specific ARDS regions of interest utilizing a spatial transcriptomic platform on autopsy-derived lung tissue from patients with SARS-CoV-2 (n = 3), H1N1 (n = 3), and a dual infected individual (n = 1). Enhanced gene signatures in alveolar epithelium, vascular tissue, and lung macrophages identify not only increased regional coagulopathy but also increased extracellular remodeling, alternative macrophage activation, and squamous metaplasia of type II pneumocytes in SARS-CoV-2. Both the H1N1 and dual-infected transcriptome demonstrated an enhanced antiviral response compared to SARS-CoV-2. Our results uncover regional transcriptional changes related to tissue damage/remodeling, altered cellular phenotype, and vascular injury active in SARS-CoV-2 and present therapeutic targets for COVID-19-related ARDS.

Highlights

Report ll diagnosed with Acute respiratory distress syndrome (ARDS) and confirmed SARS-CoV-2 or H1N1 infection (Table S1)
The selected ARDS regions, which delineated the transcriptional response of the total lung tissue, demonstrated differences in transcriptome expression between the SARS-CoV-2 versus both H1N1 alone and dual viral infection regions (Figures 1D and 1E)
Immune activation pathways were found to predominate in the H1N1 (Figure 1F) and dual-infected regions (Figure 1G), SARS CoV-2 regions demonstrated increased expression of epithelial-to-mesenchymal transition (EMT), coagulation, and extracellular matrix (ECM) pathways

Summary

Introduction

Acute respiratory distress syndrome (ARDS) has been observed following respiratory viral infections, most notably during H1N1 influenza pandemics[1] and during the current COVID-19 pandemic caused by the the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2).[2,3] Both SARS-CoV-2 and H1N1-mediated ARDS have been characterized by increased lung inflammation and increased disease-related morbidity and mortality.[4,5,6] there has been recent evidence suggesting that SARS-CoV-2 patients have extended hospitalizations in subjects with ARDS compared to influenza-induced ARDS,[7] indicating that the cellular processes that drive this pathology may differ between these two important viral causes of lung injury.Post-mortem lung and vascular tissues from SARS-CoV-2 subjects have shown profound morphological changes,[8,9] with diffuse alveolar damage, induction of fibrotic responses in the lung epithelium,[10] and presence of vascular congestion and thrombi.[8,11] temporal and spatial heterogeneity of lung responses to SARS-CoV-2 have been reported,[12] including differential expression of interferon gamma in patients with high viral load. Acute respiratory distress syndrome (ARDS) has been observed following respiratory viral infections, most notably during H1N1 influenza pandemics[1] and during the current COVID-19 pandemic caused by the the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2).[2,3] Both SARS-CoV-2 and H1N1-mediated ARDS have been characterized by increased lung inflammation and increased disease-related morbidity and mortality.[4,5,6] there has been recent evidence suggesting that SARS-CoV-2 patients have extended hospitalizations in subjects with ARDS compared to influenza-induced ARDS,[7] indicating that the cellular processes that drive this pathology may differ between these two important viral causes of lung injury. The transcriptional alterations identified while preserving the tissue architecture and within the lungs of SARSCoV-2 ARDS subjects compared to other viral forms of ARDS remain poorly defined. We analyzed the histological and transcriptional response of key structural and immune cells, while preserving the tissue architecture of the lung, in ARDS patients infected with SARS-CoV2, H1N1, and an individual who was infected with both viruses

Methods

Results

Discussion

Conclusion