Revealing Tissue-Specific SARS-CoV-2 Infection and Host Responses using Human Stem Cell-Derived Lung and Cerebral Organoids

COVID-19 is primarily the lower respiratory tract infection caused by the pandemic coronavirus SARS-CoV-2. Apart from the respiratory tract, the virus has also become known for affecting other body parts in a way that is not well understood. The word “Long COVID” is now used to describe the long term consequences, such as extreme fatigue, loss of taste and “brain fog”, beyond initial illness.

Researchers at University of California San Diego School of Medicine used organoids grown from human induced pluripotent stem cells to model how the virus affects cells of different organ systems.

UC San Diego School of Medicine researchers found approximately 10-fold higher SARS-CoV-2 infection (green) in lung organoids (left), compared to brain organoids (right).

“SARS-CoV-2 does not infect the entire body in the same way” said Tariq Rana, PhD, professor and chief of the Division of Genetics in the Department of Pediatrics at UC San Diego School of Medicine and Moores Cancer Center. “In different cell types, the virus triggers the expression of different genes, and we see different outcomes”

As in many organs, ACE2 and TMPRSS2 molecules are expressed in lung and brain organoids. These molecules act as the binding targets on the outer surfaces of cells. SARS-CoV-2 binds to these molecules with its spike protein and initiates subsequent cell entrance events.

Rana and the team developed a non-infectious variant of the SARS-CoV-2 (pseudovirus), and labeled it with a green fluorescent protein (GFP). The fluorescent signal allowed them to quantity the binding of the virus’ spike protein to ACE2 receptors in the human lung and brain organoids. Unsurprisingly, approximately 10-fold more ACE2 and TMPRSS2 receptor binding was observed in lung organoids than the brain organoids.

Besides the differences in infection levels, it was the difference in immune responses shown by the lung and brain organoids that may help to explain the vast varieties of COVID symptoms. In lung organoids, SARS-CoV-2 induced cells to pump out molecules that summon interferons, cytokines and chemokines from the immune system. Infected brain organoids, on the other hand, increased the production of toll-like receptor molecules in recognizing pathogens and activating innate immunity. “It seems that the brain organoid reaction is another form of the immune response. Those molecules can also aid in programmed cell death.”

“The way we are seeing brain cells react to the virus may help explain some of the neurological effects reported by patients with COVID-19,” Rana said.

The team also verified their findings by replicating the study using live SARS-CoV-2 virus in a biosafety laboratory specifically designed to handle high-risk infectious microbes.

Rana’s team published their findings February 11, 2021 in Stem Cell Reports.

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