Modeling SARS-CoV-2 infection and its individual differences with ACE2-expressing human iPS cells

Area of Science:

• Virology
• Genetics
• Stem Cell Biology

Background:

• Genetic variations significantly influence COVID-19 susceptibility and disease severity.
• Induced pluripotent stem (iPS) cells preserve an individual's genetic makeup, making them valuable for in vitro disease modeling.
• The SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), is crucial for viral entry into host cells.

Purpose of the Study:

• To investigate the utility of human ACE2-iPS cells for modeling SARS-CoV-2 infection in vitro.
• To explore individual differences in SARS-CoV-2 infection susceptibility and viral production using patient-derived iPS cells.
• To identify potential genetic factors, including sex-based differences, contributing to COVID-19 outcomes.

Main Methods:

• Generation of human iPS cells expressing the ACE2 receptor (ACE2-iPS cells).
• Infection of ACE2-iPS cells with SARS-CoV-2.
• Analysis of viral replication markers, including nucleocapsid protein expression, viral particle budding, and progeny virus production.
• Comparative SARS-CoV-2 infection experiments using ACE2-iPS/embryonic stem (ES) cells from eight individuals, stratified by sex.

Main Results:

• Human ACE2-iPS cells successfully supported SARS-CoV-2 infection, demonstrating viral replication.
• Confirmed presence of SARS-CoV-2 nucleocapsid protein, viral budding, and production of new viral particles within infected ACE2-iPS cells.
• Significant differences in viral production were observed between male and female iPS/ES cells, with male cells exhibiting higher production.

Conclusions:

• ACE2-iPS cells serve as a robust in vitro model to study individual variations in SARS-CoV-2 infection.
• The study demonstrates the feasibility of using iPS cells to investigate the impact of genetic differences on COVID-19.
• Observed sex-based differences in viral production suggest a role for genetic factors in differential COVID-19 outcomes.