Evaluation of SARS-CoV-2 entry, inflammation and new therapeutics in human lung tissue cells

• Published in: PLoS pathogens 2022-01, Vol.18 (1), p.e1010171
• Main Authors: Grau-Expósito, Judith, Perea, David, Suppi, Marina, Massana, Núria, Vergara, Ander, Soler, Maria José, Trinite, Benjamin, Blanco, Julià, García-Pérez, Javier, Alcamí, José, Serrano-Mollar, Anna, Rosado, Joel, Falcó, Vicenç, Genescà, Meritxell, Buzon, Maria J
• Format: Article
• Language: English
• Subjects: ACE2; Adult; Alveoli; Analysis; Angiotensin-converting enzyme 2; Animals; Anti-inflammatory agents; Antiviral activity; Antiviral agents; Antiviral Agents - pharmacology; Antiviral Agents - therapeutic use; Axl protein; Biology and life sciences; CD147 antigen; Cell culture; Cell differentiation; Cell suspensions; Cells, Cultured; Chlorocebus aethiops; Coronaviruses; COVID-19; COVID-19 - immunology; COVID-19 - pathology; COVID-19 Drug Treatment; Dendritic cells; Dosage and administration; Drug development; Drug Evaluation, Preclinical; Drug resistance; Drugs, Investigational - pharmacology; Drugs, Investigational - therapeutic use; Gene expression; HEK293 Cells; Host-pathogen interactions; Host-Pathogen Interactions - drug effects; Host-virus relationships; Humans; Infection control; Infections; Inflammation; Inflammation - pathology; Inflammation - therapy; Inflammation - virology; Lung - pathology; Lung - virology; Lungs; Medicine and health sciences; Methods; Neutrophils; Nonsteroidal anti-inflammatory drugs; Phosphatase; Physiology; Proteins; Pulmonary function tests; Research and Analysis Methods; SARS-CoV-2 - drug effects; SARS-CoV-2 - physiology; Severe acute respiratory syndrome coronavirus 2; Thoracic surgery; Vero Cells; Viral diseases; Viral infections; Virus Internalization - drug effects
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1010171

The development of physiological models that reproduce SARS-CoV-2 infection in primary human cells will be instrumental to identify host-pathogen interactions and potential therapeutics. Here, using cell suspensions directly from primary human lung tissues (HLT), we have developed a rapid platform for the identification of viral targets and the expression of viral entry factors, as well as for the screening of viral entry inhibitors and anti-inflammatory compounds. The direct use of HLT cells, without long-term cell culture and in vitro differentiation approaches, preserves main immune and structural cell populations, including the most susceptible cell targets for SARS-CoV-2; alveolar type II (AT-II) cells, while maintaining the expression of proteins involved in viral infection, such as ACE2, TMPRSS2, CD147 and AXL. Further, antiviral testing of 39 drug candidates reveals a highly reproducible method, suitable for different SARS-CoV-2 variants, and provides the identification of new compounds missed by conventional systems, such as VeroE6. Using this method, we also show that interferons do not modulate ACE2 expression, and that stimulation of local inflammatory responses can be modulated by different compounds with antiviral activity. Overall, we present a relevant and rapid method for the study of SARS-CoV-2.