The prevalence of “long COVID” underscores significant gaps in understanding how lungs respond to viral infections, notably SARS-CoV-2, which primarily infects lung cells upon entry. Researchers from the University of California San Diego, led by Sandra Leibel MD MSc, alongside international collaborators, have expanded this understanding by revealing that SARS-CoV-2 infects a broader array of lung cells than previously recognized.
Their study highlighted the critical role of Pulmonary Surfactant Protein-B (SP-B) in responding to SARS-CoV-2, enhancing viral resistance, reducing systemic inflammatory cytokines, and preventing apoptosis. Administering exogenous surfactant showed promising therapeutic benefits against viral infection.1
In an interview with Contagion, Leibel discussed the study’s findings on SARS-CoV-2 entry routes, including ACE2-mediated pathways and noncanonical routes. She emphasized the potential of FDA-approved endocytosis blockers, such as apilimod, in lung organoids (LOs) to inhibit viral entry via these alternative pathways. She explains,
“Our gene and protein data suggested that SARS-CoV-2 might be entering lung cells via a noncanonical route such as macropinocytosis, independent of ACE2,” Leibel discusses potential adjunctive therapies using FDA-approved endocytosis blockers in lung organoids, adding, “We tested the effects of inhibiting macropinocytosis with the FDA-approved PIKfyve inhibitor apilimod, finding that it effectively blocked the uptake of macropinosome markers in lung cells and significantly reduced infection rates. Apilimod's efficiency in blocking infection indicates that SARS-CoV-2 uses both noncanonical endocytotic and canonical receptor-mediated entry routes.”
Apilimod, under investigation for treating cancer, ALS, dementia, and viral infections, successfully prevented SARS-CoV-2 from entering cells through alternative pathways lacking traditional entry points.2
Key Takeaways
- The study underscores gaps in understanding how the lungs respond to viral infections, revealing that SARS-CoV-2 infects a broader range of lung cells than previously recognized.
- Pulmonary SP-B plays a role in enhancing viral resistance, reducing systemic inflammatory cytokines, and preventing apoptosis in response to SARS-CoV-2 infection.
- Insights into SARS-CoV-2 entry routes, including noncanonical pathways like macropinocytosis, could lead to new therapeutic strategies using FDA-approved endocytosis blockers in lung organoids.
SARS-CoV-2 demonstrated a broader ability to infect various lung cell types through canonical and noncanonical pathways. The virus also triggered an innate immune response in pulmonary epithelial cells, inducing interferons, cytokines, and chemokines independently of immune system cells. In LOs, viral replication led to mitochondrial apoptosis mediated by Bcl-xL, which may contribute to the persistent inflammatory patterns seen in long COVID.
Researchers employed an in vitro human lung system to conduct detailed single-cell analyses of pulmonary cell responses to various strains of SARS-CoV-2. They utilized induced pluripotent stem cells to create three-dimensional LOs that mimic lung tissue, which were then infected to observe viral responses. Leibel further explores the role of SP-B in enhancing viral resistance, reducing systemic inflammatory cytokines, and preventing apoptosis during SARS-CoV-2 infection in the LOs model.
“We showed that a part of the intrapulmonary antiviral host defense system is orchestrated by SP-B, known for reducing alveolar surface tension. SARS-CoV-2 infection dynamically altered SP gene expression in LOs, with the greatest infectivity in SP-B-deficient LOs. Restoring SP-B function in these LOs via CRISPR-Cas9, rSP-B, or exogenous surfactant restored their ability to suppress viral entry and prevent viral-induced apoptosis. Although the mechanism is unclear, previous work has shown that persistent viral infection could lead to surfactant depletion, enabling viral spread and inflammatory cell death, particularly if too many surfactant secreting cells die.”
The implications of Bcl-xL-mediated mitochondrial apoptosis in SARS-CoV-2-infected lung cells underscore its role in persistent inflammation and lung dysfunction observed in long COVID, influencing potential therapeutic strategies.
“SARS-CoV-2 infection induces endoplasmic reticulum stress, triggering apoptosis via caspase activation, as observed in human lung cells,” Leibel explains. “Inhibition of Bcl-xL induced apoptosis in lung cells, suggesting a role for restricting viral dissemination. Rapid induction of apoptosis using Bcl-xL reduced virus dissemination by targeting infected cells early in the viral life cycle, suggesting that apoptosis can serve as a self-defense mechanism if triggered before significant viral replication occurs.”
Future investigations will focus on elucidating SP-B's protective mechanisms and exploring its potential as a predictive marker for severe COVID-19 outcomes. The team aims to enhance understanding of how lung cells autonomously respond to viral threats and optimize COVID-19 treatment strategies effectively.
Leibel concludes, “These findings confirm what other investigators have shown, and there are ongoing clinical trials testing the efficacy of apilimod. If shown to be efficacious, it can be used as an adjuvant therapy along with inhibitors of viral replication that are currently being used.”
References
Leibel S, McVicar R, Murad R, et. Al. A therapy for suppressing canonical and noncanonical SARS-CoV-2 viral entry and an intrinsic intrapulmonary inflammatory response. PNAS. Published July 19, 2024. Accessed July 25, 2024. https://www.pnas.org/doi/10.1073/pnas.2408109121
Mini lungs make major COVID-19 discoveries possible. EurekAlert. Published July 23, 2024. Accessed July 25, 2024. https://www.eurekalert.org/news-releases/1052334
