Severe SARS-CoV-2 infection often leads to development of acute respiratory distress syndrome (ARDS), with profound pulmonary patho-histological changes post-mortem. In this study, we utilized the spatial transcriptomic approach to focus on ARDS regions in SARS-CoV-2 subjects compared to other forms of virus-induced ARDS (H1N1), providing insights into regional or cell-specific differential gene regulation. We analyzed specific ARDS regions and cells of interest utilizing 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 identified 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. Overall, these results challenge conventional wisdom and provide evidence for a more fibroproliferative ARDS phenotype in SARS-CoV-2 infection versus a more exudative inflammatory ARDS phenotype in H1N1 infection. This finding may explain the observation of COVID ARDS patients often displaying extended time requiring ventilator support. It is our hope that these pathways will improve our understanding of mechanisms leading to progressive worsening of gas exchange and increased mortality in SARS-CoV-2 related ARDS.  As a result, the potential for new therapeutic targets to alter the fibroproliferative response will present the potential to improve clinical outcomes in patients with progressive lung injury.

Learning Objectives:

1. Describe how spatial transcriptomics can be used to profile COVID-19 tissue autopsies.

2. Explain the differences seen in gene expression between SARS-CoV-2 infected lung samples and H1N1 infected lung samples.

3. Summarize the pathways involved in the fibroproliferative ARDS (Acute Respiratory Distress Syndrome) phenotype seen in SARS-CoV-2 infection.