Since the start of the coronavirus pandemic early last year, scientists all over the world are still trying to better understand SARS-CoV-2, the virus that causes COVID-19. Although the more commonly known symptoms involve respiratory issues, there have been other long term problems observed in recovered patients. These consist of heart issues, fatigue, and neurological issues such as loss of taste and smell and “brain fog”.
To better understand this, Dr. Tariq Rana and a team of researchers at the UC San Diego School of Medicine are using stem cells to create lung and brain organoids to better understand how the virus interacts with the various organ systems and to better develop therapies that block infection. Organoids are 3D models made of cells that can be used to analyze certain features of the human organ being modeled. Although they are far from perfect replicas, they can be used to study physical structure and other characteristics.
The team’s lung and brain organoids produced molecules ACE2 and TMPRSS2, which sit like doorknobs on the outer surfaces of cells. SARS-CoV-2 is able to use these doorknobs to enter cells and establish infection.
Dr. Rana and his team then developed a pseudovirus, a noninfectious version of SARS-CoV-2, and attached a fluorescent label, allowing them to measure how effectively the virus binds in human lung and brain organoids as well as to evaluate the cells’ response. The team was surprised to see an approximately 10-fold higher SARS-CoV-2 infection in lung organoids compared to brain organoids. Additionally, treatment with TMPRSS2 inhibitors reduced infection levels in both organoids.
Besides differences in infection levels, the lung and brain organoids also differed in their responses to the virus. Infected lung organoids pumped out molecules intended to summon help from the immune system while infected brain organoids upped their production of molecules that plays a fundamental role in pathogen recognition and activation of the body’s own immune defenses.
In a news release from UC San Diego Health, Dr. Rana elaborates on the results of his study.
“We’re finding that SARS-CoV-2 doesn’t infect the entire body in the same way. In different cell types, the virus triggers the expression of different genes, and we see different outcomes.”
The next steps for Rana and his team is to develop SARS-CoV-2 inhibitors and test out how well they work in organoid models derived from people of a variety of racial and ethnic backgrounds that represent California’s diverse population. To carry out this research, CIRM awarded Dr. Rana a grant of $250,000, which is part of the $5 million in emergency funding for COVID-19 research that CIRM authorized at the beginning of the pandemic.
The full results of this study can be found in Stem Cell Reports.
The Stem Cellar 
SARS is an acute infectious disease that spreads mainly via the respiratory route. ACE2(Angiotensine-Converting Enzyme 2) has been identified as functional receptor for SARS-CoV-2 to enter into intracellular cell for viral replication. ACE2 is found in all human’s organs. These include oral and nasal, mucosal, nasapharnys, lung, stomach, small intestine, colon, skin, lymph nodes, thymus, bone marrow, spleen, liver, kidney and brain. The highest expression levels of ACE2 were found in small intestine, testes, kidney, heart, thyroid and adipose tissue. There was lowest of ACE2 levels in the blood, spleen, bone marrow, brain and blood vessels and muscle. However, lung, colon, livers, bladder and adrenal gland showed medium expression levels. The most remarkable finding was SAR-CoV-2 taking advantage of faster and easier route to cause predominantly infection in alveolar epithelium bronchiolar, epithelium, endothelium and smooth muscle cells of pulmonary vessel. Although SARS-CoV-2 may infect other tissues aside from the lung. They infect equally to persons with different sexes, ages and races. The difference host immunity response to virus infection may partially explain why males and females, young and old infected with these viruses have markedly distinct disease severity. Study in rat model indicated that, no gender-related difference of ACE2 levels in young-adult and middle-aged group. However, the elevated levels of ACE2 in young adults in comparison to aged groups suggested the predominant of SARS-CoV-2 attacks in this age group. In addition, mouse model revealed that, tissues involved in blood pressure homeostasis (lung, heart and kidney)express high levels of ACE2 enzyme. Therefore, the high levels of enzymatic activity in the lung may possibly participate in hypertension programming.
To note, the research to investigate the efficacy of SARS-CoV-2 inhibitors to block the infection of organoids models derived from people with various races and ethnic background must take account their age, stress conditions and gender.