10-fold higher Covid-19 infection found in human lung organoids than brain organoids: Study

Researchers at the University of California San Diego School of Medicine are using stem cell-derived organoids to study how the virus interacts with various organs in the host’s body.

Stem cell-derived organoids are small balls of human cells that look and act like mini-organs in a laboratory dish.

The study, published in the Stem Cell Reports, revealed that like many organs, lung and brain organoids produce the molecules ACE2 and TMPRSS2, which sit like doorknobs on the outer surfaces of cells. SARS-CoV-2 grabs these doorknobs with its spike protein as a means to enter cells and infect host cells.

"We're finding that SARS-CoV-2 doesn't infect the entire body in the same way," said Tariq Rana, Ph.D., 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," he added.

Study design

The team developed a pseudovirus -- a non-infectious version of SARS-CoV-2 -- and labeled it with a green fluorescent protein, or GFP. This is a bright molecule derived from jellyfish that helps researchers visualize the inner workings of cells.

The fluorescent label allowed them to quantify the binding of the virus' spike protein to ACE2 receptors in human lung and brain organoids and evaluate the cells' responses.

Findings

The team found 10-fold more ACE2 and TMPRSS2 receptors and correspondingly much higher viral infection in lung organoids, as compared to brain organoids. Treatment with viral spike protein or TMPRSS2 inhibitors reduced infection levels in both organoids.

"We saw dots of fluorescence in the brain organoids, but it was the lung organoids that really lit up," Rana said.

The team wrote that besides differences in infectivity levels, the lung and brain organoids also differed in their responses to the virus. SARS-CoV-2-infected lung organoids pumped out molecules intended to summon help from the immune system -- interferons, cytokines, and chemokines.

While infected brain organoids upped their production of other molecules, such as TLR3, a member of the toll-like receptor family that plays a fundamental role in pathogen recognition and activation of innate immunity.

"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 researchers mentioned that though organoids are not exact replicas of human organs, but they provide an important tool for studying diseases and testing potential therapies.