Human Lung Stem Cell-Based Alveolospheres Provide Insights into SARS-CoV-2-Mediated Interferon Responses and Pneumocyte Dysfunction

Katsura, Hiroaki; Sontake, Vishwaraj; Tata, Aleksandra; Kobayashi, Yoshihiko; Edwards, Caitlin E.; Heaton, Brook E.; Konkimalla, Arvind; Asakura, Takanori; Mikami, Yu; Fritch, Ethan J.; Lee, Patricia; Heaton, Nicholas S.; Boucher, Richard C.; Randell, Scott H.; Baric, Ralph S.; Tata, Purushothama Rao

doi:10.1016/j.stem.2020.10.005

Cited by 319 publications

(410 citation statements)

References 80 publications

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“…Our findings suggest that developing astrocytes are particularly vulnerable to SARS-CoV-2, however another recent study indicates that adult astrocytes may also be susceptible to infection and that other coronavirus receptors, like CD147, are abundant in mature astrocytes ( 11 , 30 ). We observe an increase in CD147 expression upon infection, suggesting a potential positive feedback loop, as observed in case of ACE2 in lung alveolosphere infection ( 34 ). Glial vulnerability to SARS-CoV-2 may extend across the lifetime but can be particularly consequential at early stages of brain development.…”

Section: Discussionsupporting

confidence: 68%

Tropism of SARS-CoV-2 for Developing Human Cortical Astrocytes

Andrews

Mukhtar

Eze

et al. 2021

Preprint

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) readily infects a variety of cell types impacting the function of vital organ systems, with particularly severe impact on respiratory function. It proves fatal for one percent of those infected. Neurological symptoms, which range in severity, accompany a significant proportion of COVID-19 cases, indicating a potential vulnerability of neural cell types. To assess whether human cortical cells can be directly infected by SARS-CoV-2, we utilized primary human cortical tissue and stem cell-derived cortical organoids. We find significant and predominant infection in cortical astrocytes in both primary and organoid cultures, with minimal infection of other cortical populations. Infected astrocytes had a corresponding increase in reactivity characteristics, growth factor signaling, and cellular stress. Although human cortical cells, including astrocytes, have minimal ACE2 expression, we find high levels of alternative coronavirus receptors in infected astrocytes, including DPP4 and CD147. Inhibition of DPP4 reduced infection and decreased expression of the cell stress marker, ARCN1. We find tropism of SARS-CoV-2 for human astrocytes mediated by DPP4, resulting in reactive gliosis-type injury.

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Section: Discussionsupporting

confidence: 68%

Tropism of SARS-CoV-2 for Developing Human Cortical Astrocytes

Andrews

Mukhtar

Eze

et al. 2021

Preprint

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“…ACE2 correlated genes in this cell population were enriched for regulators of the immune response ( Fig. 2e), with several of these genes found to be upregulated in alveolosphere cultures infected with SARS-CoV-2 36 . In addition to alterations in the cytokine microenvironment, changes in cellular immune populations were also identi ed in the COPD samples, dysregulation of several genes in in ammatory pathways (AREG, CCL3, CXCL8, SOCS1), and high levels of cytotoxic and exhaustion-related genes in CD4 and CD8 T Cells from COPD lungs.…”

Section: Discussionmentioning

confidence: 95%

“…1, Supplementary Table 3). SARS-CoV-2 utilizes the host ACE2, and other putative factors such as BSG, NRP1 and HSPA5, as entry receptor and TMPRSS2, CTSL or FURIN as priming proteases to facilitate cellular entry [33][34][35][36][37][38][39][40] . Consistent with prior reports analyzing normal lung tissue 33,34,41 , ACE2 and TMPRSS2 are expressed predominantly in epithelial cell types ( Fig.…”

Section: Expression Pro Le Of Sars-cov-2 Associated Receptors and Facmentioning

confidence: 99%

Chronic lung diseases are associated with gene expression programs favoring SARS-CoV-2 entry and severity

Bui

Winters

Chung

et al. 2020

Preprint

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Patients with chronic lung disease (CLD) have an increased risk for severe coronavirus disease-19 (COVID-19) and poor outcomes. Here, we analyzed the transcriptomes of 605,904 single cells isolated from healthy and CLD lungs to identify molecular characteristics of lung cells that may account for worse COVID-19 outcomes in patients with chronic lung diseases. We observed a similar cellular distribution and relative expression of SARS-CoV-2 entry factors in control and CLD lungs. CLD epithelial cells expressed higher levels of genes linked directly to the efficiency of viral replication and innate immune response. Additionally, we identified basal differences in inflammatory gene expression programs that highlight how CLD alters the inflammatory microenvironment encountered upon viral exposure to the peripheral lung. Our study indicates that CLD is accompanied by changes in cell-type-specific gene expression programs that prime the lung epithelium for and influence the innate and adaptive immune responses to SARS-CoV-2 infection.

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“…We also found that CTLVtotal was negatively correlated with absolute consolidation volume. A previous experimental study reported interferon-mediated inflammatory responses, loss of surfactant proteins, and apoptosis of pneumocytes in infected alveolospheres [ 20 ]. Histological studies have reported diffuse alveolar damage in patients with ARDS caused by SARS-CoV-2 [ 21 – 23 ].…”

Section: Discussionmentioning

confidence: 99%

Pulmonary vascular enlargement and lesion extent on computed tomography are correlated with COVID-19 disease severity

et al. 2021

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Purpose To assess the relationships among pulmonary vascular enlargement, computed tomography (CT) findings quantified with software, and coronavirus disease (COVID-19) severity. Materials and methods Ultra-high-resolution (UHR) CT images of 87 patients (50 males, 37 females; median age, 63 years) with COVID-19 confirmed using real-time polymerase chain reaction were analyzed. The maximum subsegmental vascular diameter was measured on CT. Total CT lung volume (CTLV total) and lesion extent (ratio of lesion volume to CTLV total) of ground-glass opacities, reticulation, and consolidation were measured using software. Maximum pulmonary vascular diameter and lesion extent were analyzed using Spearman's correlation analysis. Logistic regression analysis was performed on CT results to predict disease severity. We also assessed changes in these measures on follow-up scans in 16 patients. Results All 23 patients with severe and critical illness had vascular enlargement (> 4 mm). Pulmonary vascular enlargement (odds ratio 3.05, p = 0.018) and CT lesion extent (odds ratio 1.07, p = 0.002) were independent predictors of disease severity after adjustment for age and comorbidities. On follow-up CT, vascular diameter and CT lesion volume decreased (p = 0.001, p = 0.002; respectively), but CTLV total did not change significantly. Conclusion Subsegmental vascular enlargement is a notable finding to predict acute COVID-19 disease severity.

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Human Lung Stem Cell-Based Alveolospheres Provide Insights into SARS-CoV-2-Mediated Interferon Responses and Pneumocyte Dysfunction

Cited by 319 publications

References 80 publications

Tropism of SARS-CoV-2 for Developing Human Cortical Astrocytes

Tropism of SARS-CoV-2 for Developing Human Cortical Astrocytes

Chronic lung diseases are associated with gene expression programs favoring SARS-CoV-2 entry and severity

Pulmonary vascular enlargement and lesion extent on computed tomography are correlated with COVID-19 disease severity

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