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A Co-culture System Reveals a Cross-talk between Alveolar Epithelium and Pulmonary Microvascular Endothelium during SARS-CoV-2 Infection

ABSTRACT: SARS-CoV-2 seriously injures human alveoli and causes severe respiratory illness. Histopathologic evidences suggested alveolar-capillary barrier integrity is compromised in COVID-19 deaths, however, little is known about how it is disrupted. In this study, we investigated the effects of SARS-CoV-2 infection on alveolar epithelium and pulmonary microvascular endothelium, and tried to elucidate the cross-talk between them during viral infection. Under monoculture system, SARS-CoV-2 infection caused massive virus replication and dramatic organelles re-modeling in alveolar epithelial cells. While, as for pulmonary microvascular endothelial cells, direct viral exposure had little effect on them, but treatment with culture supernatant from infected epithelial cellls significantly damaged them, which suggested SARS-CoV-2 affected endothelium indirectly, possibly by substances released from infected alveolar epithelium. Then, we tested SARS-CoV-2 infection in an alveolar epithelium/endothelium co-culture system, and found viral infection caused global proteomic modulations and ultrastructual changes in both cell types. Especially for alveolar epithelial cells, viral infection elicited significant protein changes and structural reorganizations across many sub-cellular compartments. Among the affected organelles, mitochondrion seems to be a primary target organelle. In addition, based on proteomic analysis and EM clues, we tested several autophagy inhibitors, and discovered one of them, Daurisoline, could inhibit virus replication effectively in cells. Collectively, our study revealed the distinctive responses of alveolar epithelium and microvascular endothelium to SARS-CoV-2 infection, which will expand our understanding of COVID-19 and helpful for targeted drug development.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Peng Wang

LAB HEAD: Peng Wang

PROVIDER: PXD020470 | Pride | 2020-12-04

REPOSITORIES: pride

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			Action	DRS
	Mock-HPA-Coculture-1.zip	Other
	Mock-HPA-Coculture-2.zip	Other
	Mock-HPA-Coculture-3.zip	Other
	Mock-HULEC-Coculture-1.zip	Other
	Mock-HULEC-Coculture-2.zip	Other

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Project description:The coronavirus disease 2019 (COVID-19) pandemic has affected nearly 700 million and claimed more than 6 million lives. However, the large heterogeneity in disease susceptibility and severity of illness (SOI) remains poorly understood. A growing body of evidence suggests that alveolar epithelial cell type 2 (AT2), which constitute 10-15% of all alveolar cells and are critical for alveolar homeostasis, are the primary targets of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and damage to AT2s may directly contribute to disease severity and poor prognosis in COVID-19 patients. Our in-vitro modeling of SARS-CoV-2 infection, in well-characterized, highly uniform, (r2 at 95% CI = 0.92 ± 0.03), induced pluripotent stem cell (iPSC) derived AT2s from 10 participants of our Mexican American Family Study, showed interindividual variability in infection susceptibility and the post-infection cellular viral load. To understand the underlying mechanism of the AT2’s capacity to regulate SARS-CoV-2 infection and cellular viral load, we performed a systematic characterization of the pre- and post-SARS-CoV-2 challenged AT2 transcriptomes. A total of 1,393 genes were found significantly (Oneway ANOVA FDR corrected p ≤ 0.05; FC abs ≥ 2.0) differentially expressed (DE) between pre- and post-SARS-CoV-2 infection-challenged AT2 and suggest significant upregulation of viral infection-related cellular innate immune response pathways (p-value ≤ 0.05; activation z-score ≥ 3.5), whilst the cholesterol and xenobiotic related metabolic pathways were significantly downregulated (p-value ≤ 0.05; activation z-score ≤ - 3.5). Interestingly, pre-infection expression of 238 DE genes showed a high correlation with the post-infection SARS-CoV-2 viral load (FDR corrected p-value ≤ 0.05, and r2-absolute ≥ 0.57). The 85 genes whose expression was negatively correlated with the viral load showed significant enrichment in viral recognition and cytokine-mediated innate immune GO biological processes (p-value range: 4.65x10-10 to 2.24x10-6). The 153 genes whose expression was positively correlated with the viral load showed significant enrichment in cholesterol homeostasis, extracellular matrix, and MAPK/ERK pathway-related GO biological processes (p-value range: 5.06x10-5 to 6.53x10-4). Overall, our results strongly suggest that AT2s pre-infection innate immunity and metabolic state affects their susceptibility to SARS-CoV-2 infection and viral load.

Dataset Information

A Co-culture System Reveals a Cross-talk between Alveolar Epithelium and Pulmonary Microvascular Endothelium during SARS-CoV-2 Infection

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