Abstract
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.
Highlights
One antiviral against SARS-CoV-2, remdesivir, has been approved for the treatment of COVID-19 in adults and pediatric patients (12 years of age and older) requiring hospitalization [1,2]
The early stages of laboratory identification of therapeutics against pathogens is usually based on the use of immortalized cell lines, as exemplified by many studies screening antivirals against SARS-CoV-2
We show that human lung tissue (HLT) preserves lung cell composition, including the main SARS-CoV-2 cellular target, namely alveolar type-2 cells, as well as the proteins required for viral entry into the cells: ACE2, CD147, TMPRSS2 and AXL
Summary
One antiviral against SARS-CoV-2, remdesivir, has been approved for the treatment of COVID-19 in adults and pediatric patients (12 years of age and older) requiring hospitalization [1,2]. The development of Acute Respiratory Distress Syndrome in severe COVID-19 patients has been linked to dysregulated inflammatory responses. In this regard, treatment with the glucocorticoid dexamethasone decreased 28-day mortality among patients receiving invasive mechanical ventilation, but little benefit was observed in patients without respiratory support [6]. Treatment with the glucocorticoid dexamethasone decreased 28-day mortality among patients receiving invasive mechanical ventilation, but little benefit was observed in patients without respiratory support [6] Despite these major advances in treatment options for COVID-19, the rapid identification of new antivirals that could be transferred into the clinic is still of paramount importance, with the potential emergence of drugresistant variants
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
