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Pre-Infection Innate Immunity Attenuates SARS-CoV-2 Infection and Viral Load in iPSC-Derived Alveolar Epithelial Type 2 Cells

Kumar et al., Cells, doi:10.3390/cells13050369
Feb 2024  
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In vitro study showing interindividual variability in iPSC-derived alveolar epithelial type 2 cells' susceptibility to SARS-CoV-2 infection and postinfection viral load. Results indicate AT2s mount an antiviral interferon response, though this alone did not control viral replication. Notably, genes involved in cholesterol homeostasis and lipid metabolism were positively correlated with subsequent SARS-CoV-2 infection and viral load, whereas antiviral immunity genes were negatively correlated.
The cholesterol synthesis enzyme SOAT2 and cholesterol transporters MTTP and APOB were among lipid metabolism genes linked to higher infection, suggesting basal cholesterol levels in AT2s may impact SARS-CoV-2 infectivity. Overall, findings indicate AT2s’ pre-infection innate immunity and metabolic state, particularly cholesterol homeostasis pathways, influence COVID-19 severity by affecting cellular susceptibility to infection and viral replication.
Higher cholesterol levels in lung cells may be associated with increased clustering of the ACE2 receptor with lipid rafts, which facilitate more efficient SARS-CoV-2 viral entry.
Yuan et al. showed that HCQ disrupts the association of ACE2 receptors with both lipid rafts (GM1 clusters) and PIP2 clusters, inhibiting viral docking and entry. They demonstrated that HCQ had the strongest effect on disrupting ACE2 receptor clustering in cells with high cholesterol levels.
High cholesterol drives ACE2 association with rafts/endosomes, enabling more efficient SARS-CoV-2 infection. HCQ blocks this by separating ACE2 receptors from lipid rafts and clusters, showing greater efficacy for higher cholesterol levels.
Kumar et al., 21 Feb 2024, peer-reviewed, 9 authors. Contact: (corresponding author),,,,,,,,
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
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Pre-Infection Innate Immunity Attenuates SARS-CoV-2 Infection and Viral Load in iPSC-Derived Alveolar Epithelial Type 2 Cells
Satish Kumar, Jose Granados, Miriam Aceves, Juan Peralta, Ana C Leandro, John Thomas, Sarah Williams-Blangero, Joanne E Curran, John Blangero
Cells, doi:10.3390/cells13050369
A large portion of the heterogeneity in coronavirus disease 2019 (COVID-19) susceptibility and severity of illness (SOI) remains poorly understood. Recent evidence suggests that SARS-CoV-2 infection-associated damage to alveolar epithelial type 2 cells (AT2s) in the distal lung may directly contribute to disease severity and poor prognosis in COVID-19 patients. Our in vitro modeling of SARS-CoV-2 infection in induced pluripotent stem cell (iPSC)-derived AT2s from 10 different individuals showed interindividual variability in infection susceptibility and the postinfection cellular viral load. To understand the underlying mechanism of the AT2 ′ s capacity to regulate SARS-CoV-2 infection and cellular viral load, a genome-wide differential gene expression analysis between the mock and SARS-CoV-2 infection-challenged AT2s was performed. The 1393 genes, which were significantly (one-way ANOVA FDR-corrected p ≤ 0.05; FC abs ≥ 2.0) differentially expressed (DE), suggest significant upregulation of viral infection-related cellular innate immune response pathways (p-value ≤ 0.05; activation z-score ≥ 3.5), and significant downregulation of the cholesterol-and xenobiotic-related metabolic pathways (p-value ≤ 0.05; activation z-score ≤ -3.5). Whilst the effect of post-SARS-CoV-2 infection response on the infection susceptibility and postinfection viral load in AT2s is not clear, interestingly, pre-infection (mock-challenged) expression of 238 DE genes showed a high correlation with the postinfection SARS-CoV-2 viral load (FDR-corrected p-value ≤ 0.05 and r 2absolute ≥ 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: 4.65 × 10 -10 to 2.24 × 10 -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: 5.06 × 10 -5 to 6.53 × 10 -4 ). Overall, our results strongly suggest that AT2s' pre-infection innate immunity and metabolic state affect their susceptibility to SARS-CoV-2 infection and viral load.
Conflicts of Interest: The author declares no conflicts of interest.
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