When news of a novel pathogenic coronavirus reached us, we knew that it was an “all hands on deck” situation. Two other coronaviruses, SARS and MERS, had already proven highly contagious and deadly.
We identified four areas where we could contribute:
We are developing a rapid CRISPR-based testing platform in collaboration with Nobel Laureate Dr. Jennifer Doudna and Dr. Dan Fletcher of UC Berkeley. This new diagnostic uses a mobile phone to deliver quantitative results within 5 to 30 min. Because it does not need to be sent to a lab, it can be used practically anywhere. This makes it ideal for places that require fast, frequent testing: doctors’ offices, airports, schools, theaters, stadiums — and also in remote locations, far from any lab or hospital. Ultimately, the test may even be used at home.
Our system takes advantage of a CRISPR enzyme that detects the virus’s RNA genome and of the incredible quality of modern smartphone cameras. Because it does not require amplification and reverse transcription of the virus’s genome, our assay indicates viral load — how much virus the sample contains. Current PCR and antigen tests are not able to do this
Thanks to help from the Gladstone Institutes’ facilities department and the UCSF biosafety team, we now have lab space at Gladstone that meets the requirements for a Biosafety Level 3 lab, certified for airborne pathogens. The BSL-3 lab opened in July 2020 and is a shared facility among trained virologists at Gladstone Institutes. Before its opening, Ott lab members trained with UCSF professor Anita Sil and her team in the BSL-3 lab on the UCSF Parnassus campus.
The BSL-3 lab allows us to investigate the effects of live SARS-CoV-2 on human cells or organoids. As access to the BSL-3 lab is limited to trained personnel, we have engaged in many collaborations to make live SARS-CoV-2 experiments accessible to the local research community. We currently focus on viral variants of SARS-CoV-2, especially replication, infectivity and sensitivity to neutralizing antibodies, in collaboration with a large Bay Area-wide consortium that includes UCSF’s Charles Chiu and Raul Andino.
For years, we have championed the concept of targeting the host-virus interface as a promising strategy toward antiviral therapies. We have already applied this concept to influenza and hepatitis viruses. With SARS-CoV-2, we are taking it one step further and searching for host-directed therapies with pan-viral potential by identifying host factors shared by multiple coronaviruses, in collaboration with Drs. Nevan Krogan and Andreas Puschnik.
We were part of a large international consortium that helped identify pre-approved compounds that interfere with human host factors for SARS-CoV-2. These compounds could lead to the rapid development of new drug treatments for COVID-19. In addition, we have identified host pathways shared between SARS-CoV-2 and two coronaviruses responsible for common colds. These shared pathways will help guide the development of therapies that could stem future coronavirus epidemics.
We routinely use primary human cells and organoids—miniature organs derived from stem cells—to model the infection of human tissues by live viruses.
Lungs are the primary site of SARS-CoV-2’s entry into the human body, and the organ that suffers the brunt of COVID-19 pathology. Much of our work investigates SARS-CoV-2 infection of different types of airway cells and organoids derived from adult progenitor or induced pluripotent stem cells.
But the COVID-19 pathology manifests in many other organs. In a series of collaborations, we have shown for example that heart cells are uniquely damaged by SARS-CoV-2 infection and that astrocytes, and not neurons, are viral targets in the brain. We have also helped uncover a role for androgen in regulating the SARS-CoV-2 receptor ACE2 in heart cells and lung organoids, which may explain in part men’s greater susceptibility than women’s to COVID-19 .
