Understanding TLR7 in COVID-19 Lung Injury
The goal of our project is to determine the role of toll-like receptor 7 (TLR7) signaling in the host response to SARS-CoV-2. Viral RNA is sensed by a range of intracellular pathogen recognition receptors, of which TLR7 is expressed in myeloid cells in the lung including alveolar macrophages. TLR7 signaling results in both type 1 interferon responses, which are essential for control of virus, and pro-inflammatory cytokine expression, including IL6. Using inhibitors and agonists of the TLR7 pathway, we will test whether TLR7 signaling should be activated or inhibited in SARS-CoV-2 infection and whether age and timing during infection affect outcomes.
University of California COVID Research Data Set (UC CORDS)
The University of California Health System, with 19 health professional schools, 5 academic medical centers, and 12 hospitals, has built a secure central data warehouse (UC Health Data Warehouse, or UCHDW) for operational improvement, promotion of quality patient care, and to enable the next generation of clinical research. The repository currently securely holds data on nearly 6 million patients seen since 2012, treated by nearly 100,000 health care providers in nearly 200 million encounters, with over 300 million procedures, more than 600 million medication orders, and with over 2 billion vital signs measurements and test results. Over 600,000 of these patients are primary care patients. De-identification of the data has already been completed to enable clinical research projects, under guidance from UC campus institutional reviews boards, privacy and compliance officers, and information security officers. This data is stored in the Observational Medical Outcomes Partnership (OMOP) open vendor-neutral data model, enabling a wide range of software tools and computational methods to be used consistently with other state and national efforts. Since the start of the COVID-19 pandemic, the University of California has tested 79,560 of its patients (as of this writing) finding the virus in 2,136 of them. We have created a standardized HIPAA Limited Data Set with the appropriate information to let researchers, clinicians, policy makers and journalists understand the impact and progression of COVID-19. Care practice data (medications, procedures, ventilators, laboratory data) and previous medical data is available on the over 700 patients admitted to date.
Atul Butte, Vivek Rudrapatna
The early identification of local trends in the COVID-19 pandemic is critical to inform public health interventions and estimate their impacts. In collaboration with Paul Bleicher, former CEO of OptumLabs, our group has developed a web dashboard of COVID-19 trends at the level of US counties. Our dashboard consists of various data visualization modalities to understand disease trajectories and important geospatial relationships as they relate to the implementation of various social distancing mandates.
Serum Antibody Analysis in COVID-19 Patients
Jason Cyster, Alex Marson, Maryls Fassett, Bryan Greenhouse
Antonia Gallman in the lab established in-house ELISA assay based on Florian Krammer lab protocol (now FDA-approved) for measuring antibody against Spike and RBD. Protein provided by Aashish Manglik and we worked on initial assay development with Bryan Greenhouse's team. Assay was used in comparative serology test study led by Marson team. Now working on a collaboration with Marlys Fassett (in the Ansel lab) and her team in dermatology to study a possible connection between COVID19 and a dermal disorder.
Expression and Regulation of SARS-CoV-2-related Genes in Human Airway Epithelial Cells
Human bronchial epithelial (HBE) cells are key targets of SARS-CoV-2. We are examining expression of a set of SARS-CoV-2-related host cell genes in these cells. We are also examining how cytokines that are important in viral pneumonia and in chronic airway diseases like asthma and COPD regulate these host cell genes.
Evaluation of Protective Immunity to SARS-CoV-2
We are able to provide collaborative support for studies that will benefit from assays of functional antibodies, including antibody-dependent enhancement and neutralizing activities.
Thiol-based Drugs to Inhibit SARS-CoV2
COVID-19 Impact on Maternal and Neonatal Immune Responses
Margaret Feeney, Stephanie Gaw, Mary Prahl
Through a collaboration with the PRIORITY study of COVID-19 in pregnant women based at UCSF, we are collecting and biobanking specimens including blood, placenta, breast milk, urine, and stool from COVID-19 positive pregnant mothers and their infants. Our research aims are: 1) To determine if SARS-CoV-2 is transmitted vertically during pregnancy and/or horizontally during breastfeeding. 2) To determine the maternal and neonatal inflammatory response to COVID-19 infection in utero and the clinical impact on maternal and neonatal outcomes.
Colchicine Coronavirus SARS-CoV-2 Trial (ColCorona)
SAR-Cov-2 induced cytokine storm is associated with disease severity and outcomes (Chen JCI 2020 and Pederson SF JCI 2020); antiviral agents alone may not be sufficient to stop cytokine storm and pulmonary destruction and targeted immunomodulation may be beneficial. Colchicine inhibits the NLRP3 inflammasome (Martinez G et al Atherosclerosis 2018). Thus, small-molecule inhibitors of NLRP3 inflammasomes might prove useful in the treatment of COVID-19. Colchicine may have direct anti-inflammatory effects by inhibiting key inflammatory signaling networks known as the inflammasome and pro-inflammatory cytokines. Of note, the mechanism of action of colchicine is very different from that of non-steroidal anti-inflammatory drugs. The latter agents inhibit cyclooxygenase and may occasionally shift the use of arachidonic acid towards lipoxygenase, resulting in the production of pro-inflammatory leukotrienes. ColCorona is a randomized, double-blind, placebo-controlled, multi-center study. Following signature of the informed consent form, approximately 250 subjects from UCSF meeting all inclusion and no exclusion criteria will be randomized to receive either colchicine or placebo (1:1 allocation ratio) for 30 days. Follow-up phone and video assessments will occur following randomization for evaluation of the occurrence of any trial endpoints or other adverse events.
Max Krummel, Mark Ansel, David Erle, Matthew Spitzer, Prescott Woodruff, Jimmie Ye
COMET is a UCSF study that is collecting biological samples of blood, respiratory secretions, and viral shedding in nasal secretions from COVID-19 coronavirus patients in order to identify immunophenotypic features for the development of effective therapeutic interventions. The COMET study is closely aligned with the multi-center IMPACC study funded by the NIH’s National Institute of Allergy and Infectious Diseases (NIAID), and eligible participants from COMET will be included in IMPACC.
Test Performance Evaluation of Commercially Available Coronavirus Disease 2019 (COVID-19) Serological Assays
Antibody tests for prior exposure to SARS-CoV-2 virus are urgently needed. We are performing head-to-head comparisons of commercially available lateral flow assays (also known as rapid serology tests) and ELISA immunoassays. Importantly, we include an evaluation of test performance by time from symptom onset. Our goal is to provide an ongoing resource for reliable tests to inform the scientific and medical community, policy makers, and the general public.
Infectious SARS-CoV-2 Study
The Ott Lab is currently working with infectious SARS-CoV-2. We are interested in studying viral replication and pathogenesis in different target tissues such as the lung and gut using organoid technology and single-cell RNA sequencing. We are also working on rapid and sensitive point-of-care detection of SARS-CoV-2 in biological samples using CRISPR technology.
Cell-Based Assay to Study and Inhibit CoV-2 RNA Dependent RNA Polymerase
B. Matja Peterlin, Koh Fujinaga
We are setting up a dual luciferase reporter system to study the mechanism of COV2 RNA dependent RNA polymerase. We have extensive expertise with RNA polymerases and possess many compounds that block their effects. With COV2 RdR Pol, we will study effects of the enzyme itself, contribution of viral helicase and other proteins to its fidelity and speed, making informative mutations to attentuate viral replication leading to an effective vaccine.
COVID-19 and Host Immunogenetics
The SARS-CoV-2 pandemic pose an imminent threat to humanity. Most individuals infected with SARS-CoV-2 contain infection and do not develop COVID-19. The host immune response to SARS-CoV-2 infection to be elucidated. We hypothesize that certain polymorphisms of host immune genes render susceptibility to COVID-19. Moreover, we determine if certain KIR-HLA gene combinations provide resistance to COVID-19 in solid organ transplant recipients, the most vulnerable population with chronic comorbidities and active immunosuppression. Data from these investigations will provide insights into the mechanisms of host immunity to SARS-CoV-2, and will offer a framework for developing biomarker to distinguish those susceptible to COVID-19.
Jeroen Roose, Mark Looney, Max Krummel, David Erle, Matthew Spitzer, Erin Gordon
RapidPath is a collaborative research program at UCSF that aims to test SARS-COV-2 therapeutic candidates, and to understand the innate, cellular and humoral immune responses to SARS-CoV-2 infection. It will consolidate the expertise of multiple PIs to identify optimal in vitro systems (airway organoids, lung slices, lung cell lines), to develop reagents and assays for virus characterization (infection, replication, pathogenesis, and transmission.
Host immune responses against SARS-CoV-2
Nadia Roan, Sulggi Lee, Eliver Ghosn, Joshua Vasquez
The COVID-19 Host Immune Response Pathogenesis (CHIRP) study is a prospective longitudinal cohort study designed to evaluate clinical, demographic, behavioral, immunologic, and genetic risk factors associated with COVID-19 acquisition and severity. We are using multi-omics single-cell analytical approaches to longitudinally characterize host immune responses, including defining the features of SARS-CoV-2-specific T and B cell responses during asymptomatic, mild, and severe cases of COVID-19. The study will ultimately include 300 longitudinal specimens from over 60 acute COVID-19 positive individuals and their contacts in an outpatient setting and includes individuals with varying degrees of COVID-19 disease severity (asymptomatic to severe disease). Participants are recruited from referrals from the San Francisco Department of Public Health, the Zuckerberg San Francisco General Hospital and University of California, San Francisco as well as from other outside hospital clinical systems.
Potential Role of FcRn for Infection of Lung Alveolar Epithelial Cells by Antibody Coated SARS-CoV-2
Dean Sheppard, Hal Chapman, Bryan Greenhouse, Tien Peng, Oren Rosenberg, Shoshana Zha
Alveolar epithelial injury and alveolar flooding are central features of fatal lung disease in COVID-19, but the mechanisms of viral infection of alveolar epithelial cells are unclear. These cells express little or no ACE2, the most studied receptor that facilitates viral entry. Respiratory failure in COVID-19 is usually quite delayed and nearly all patients who develop respiratory failure are already generating antibodies to SARS-CoV2. The low pH of alveolar lining fluid would enhance binding of antibody coated virus to FcRn, the major receptor that mediates bidirectional transport of IgG across mucosal epithelia. We are therefore examining the roles that this receptor and low lumenal pH play in alveolar epithelial cell infection by SARS-CoV2.
Transcriptomics-based Drug Repositioning Pipeline Identifies Therapeutic Candidates for COVID-19
Marina Sirota, Chaz Langelier
The COVID-19 pandemic caused by the SARS-CoV-2 virus has had far-reaching detrimental effects worldwide. Given the current lack of effective remedies, drug repositioning is one method to substantially speed up the discovery of therapeutics to help mitigate the effects of COVID-19. Here, we are leveraging a transcriptomics-based computational drug repositioning pipeline to identify existing drugs that could potentially be therapeutic in for COVID-19. This pipeline utilizes a rank-based pattern-matching method, leveraging gene expression data for both diseases and drugs, in order to identify disease-drug pairs with opposite transcriptional effects. Previously, this approach has been successfully applied to a variety of complex diseases, including dermatomyositis, inflammatory bowel syndrome, cancer and preterm birth. Using this method, we predicted drug hits for three different SARS-CoV-2 transcriptomic signatures from both cell line data and patient samples from public data and are currently extending these methods to UCSF patient data.
Development of a Rapid, High-throughput Diagnostic Antibody Test for COVID-19
Serologic assays are needed to determine SARS-CoV-2 seroprevalence, but poor specificity can overestimate exposures. Here, we built a pan-human coronavirus proteome-wide programmable phage display assay (VirScan) to profile coronavirus antigens specifically enriched by 20 COVID-19 patient serum IgG. With ReScan, a new diagnostic development workflow which combines the isolation of phage expressing the most immunogenic peptides with paper-based microarrays manufactured via acoustic liquid handling, we identified 9 candidate antigens from a library of 534 SARS-CoV-2 peptides. These arrays could form the basis of a multiplexed COVID-19 serologic assay with enhanced specificity. ReScan has broad applicability for serologic assay development.
Single-cell Genomics of Peripheral Blood Mononuclear in Patients with COVID-19
Jimmie Ye, Spyros Darmanis
We aim to understand the immunopathology of COVID-19 and study the molecular composition and activation status of the immune system in peripheral blood. Through multiplexed single-cell genomics approaches, we are gaining an understanding of the compositional as well as functional changes experienced after SARS-CoV-2 infection in as many patient samples as possible. Our cohort thus far is primarily inpatient, and we welcome opportunities to collaborate, including looking at patient subsets that may be missed in other cohorts and comparing the single-cell signatures in blood with other tissues or profiling techniques.
See the Office of Research COVID-19 page for a full listing of related projects at UCSF