How the Broad community is responding to COVID-19

Cells taken from patients at the time of diagnosis who later developed severe COVID-19 show a muted antiviral response, study finds.

An international collaboration uncovers several genetic markers associated with SARS-CoV-2 infection and COVID-19 severity.

One type of white blood cell is abundant in severe infection and strongly curtails the immune response.

Peptides encoded by unexplored regions of the SARS-CoV-2 genome provoke strong immune responses compared to other known peptides.

Findings could help researchers identify mechanisms that cause severe disease.

Single-cell analysis of autopsy samples from COVID-19 patients shows how the lungs repeatedly tried, and failed, to repair themselves.

A study of antibody-producing B cells from patients who recovered from COVID-19 reveals a new cross-reactive antibody and what makes some B cells more effective at neutralizing the virus.

Study suggests blocking folate metabolism with oral, prophylactic drugs could reduce viral replication in infected cells.

The COVID-19 Host Genetics Initiative (HGI) is the largest genome-wide association study in history in terms of study participants (>2 million individuals) and number of collaborators (> 2,000 scientists), and is studying the role of genetics in SARS-CoV-2 infection and COVID-19 severity. The researchers conducted three genome-wide association meta-analyses comprising 49,562 COVID-19 patients from 46 studies across 19 countries worldwide. They report 15 genome-wide significant loci associated with SARS-CoV-2 infection or severe manifestations of COVID-19, and identified smoking and body mass index as causal risk factors for severe COVID-19.

A team of scientists from the Broad Institute, Massachusetts General Hospital, Harvard Medical School, Brigham and Women’s Hospital, Beth Israel Deaconess Medical Center, and the Wyss Institute surveyed gene expression programs induced by SARS-CoV-2 infection in tissues from severe cases. The researchers leveraged the Terra workspace to build and analyze an atlas of more than 100,000 single cells and nuclei collected from lung, kidney, liver, and heart tissues of SARS-CoV-2 infected autopsy donors. The scientists profiled those samples by single-cell or single-nucleus RNA sequencing, with spatial RNA profiling of distinct lung regions for context. The lung atlas, accessible on the Broad’s Single-Cell Portal, is the first in a series of data releases covering different organs.

Hasmik Keshishian, Randy Melanson, Eric Lander, and Steven Carr joined collaborators at Stanford and the University of Würzburg to profile the host proteins that interact with SARS-CoV-2 RNA, known as the virus's host interactome. Through a combination of proteomic, functional genetic, and pharmacologic studies, they identified 18 host proteins that bind viral RNA -- two of which interfere with viral replication -- and 20 compounds that block interactome proteins.

Expansion of a July 2020 Genome Wide Association Study (GWAS) by the COVID-19 Host Genetics Initiative provides robust evidence for seven genomic regions associated with severe COVID-19. The latest GWAS strengthened evidence that COVID-19 severity could be attributed to disruption in the immune system. An analysis associating chromosomal regions with patients experiencing severe COVID-19 symptoms successfully identified regions on chromosomes 3, 6, 9, 12, 19, and 21 harboring genes which regulate immunity or play a role in lung diseases, and one additional signal on chromosome 3 associated with COVID-19 partial-susceptibility. These findings further explain the potential genetic etiology for the development of severe COVID-19.

Age is the dominant risk factor for infectious diseases, but the mechanisms linking the two are incompletely understood. Age-related mosaic chromosomal alterations (mCAs) detected from blood-derived DNA genotyping are structural somatic variants associated with aberrant leukocyte cell counts, hematological malignancy, and mortality. Whether mCAs represent independent risk factors for infection is unknown. Seyedeh Zekavat, Pradeep Natarajan and colleagues used genome-wide genotyping of blood DNA to show that mCAs predispose to diverse infectious diseases. Their results link mCAs with impaired immunity and predisposition to infections, and also have important implications for the COVID-19 pandemic, relating to individual preventive strategies and evaluating immunization responses.

The cellular mechanisms underlying severe COVID-19 are poorly understood. As part of the COVID-19 Acute Cohort Study, Michael Filbin, Arnav Mehta, Nir Hacohen, Marcia Goldberg, and others analyzed several thousand proteins in the plasma of 306 COVID-19 patients and 78 symptomatic controls over time. The effort uncovered host immune and non-immune proteins not previously linked to COVID-19, identified proteins associated with survival, and mapped tissue damage in severe disease. The study showed that infection upregulates monocyte/macrophage, plasmablast, and T cell effector proteins, and revealed that disease severity in lung tissue is driven by inflammatory myeloid cell phenotypes and cell-cell interactions with lung epithelial cells and T cells.

In a study led by institute scientist John Doench, Craig Wilen (Yale School of Medicine), and colleagues, the authors performed a genome-wide CRISPR screen in a primate cell line. They identified known SARS-CoV-2 host factors including the receptor ACE2 and CTSL and also discovered genes involved in diverse biological processes including chromatin remodeling, histone modification, cellular signaling, and RNA regulation. The findings reveal potential therapeutic targets for SARS-CoV-2 and enhance the understanding of COVID-19 pathogenesis.

T cell-mediated immunity may be important in combating SARS-CoV-2 infection, but researchers don’t know which peptides from the virus are presented to the immune system to activate T cells. Shira Weingarten-Gabbay, Susan Klaeger, Mohsan Saeed (Boston University) and their team have identified SARS-CoV-2 peptides that were presented on class I human leukocyte antigen (HLA-I) in two infected human cell lines. They found that 30 percent of the peptides are from previously unexplored coding regions in the SARS-CoV-2 genome and are thus not likely captured by current vaccines under development. The team estimates that a pool of 24 endogenously presented peptides would provide one or more peptides for presentation by at least one HLA allele in 99% of the human population. The findings will help facilitate selection of peptides for immune monitoring and vaccine development.

Bacterial sepsis shares some clinical manifestations with severe SARS-CoV-2 infection. A team of scientists at the Broad Institute and Massachusetts General Hospital, including Miguel Reyes, Michael Filbin, Marcia Goldberg, Paul Blainey, and Nir Hacohen, previously discovered an expanded CD14+ monocyte state, MS1, in patients with bacterial sepsis. In new work, they show that expression of the MS1 program is associated with sepsis mortality and up-regulated in monocytes from patients with severe COVID-19. The work highlights the utility of regulatory myeloid cells in sepsis prognosis, and the role of systemic cytokines in severe bacterial and SARS-CoV-2 infections.

Corrie Painter, Nicole Persky, Kerstin Lindblad-Toh, Elinor Karlsson, and collaborators tapped the NCBI Protein database and other datasets to compare the structure of ACE2 (the SARS-CoV-2 receptor) in 410 vertebrate species, including 252 mammals. They identified 47 mammals that have a high or very high likelihood of being reservoirs or intermediate hosts for SARS-CoV-2.

Fan Zhang, Soumya Raychaudhuri, and collaborators in the AMP RA/SLE Consortium compared gene expression profiles representing more than 300,000 immune cells from patients with COVID-19, rheumatoid arthritis, Crohn's disease, ulcerative colitis, lupus, and interstitial lung disease, looking for shared immune cell states. Their findings suggest that TNF-ɑ and IFN-γ may both drive inflammatory macrophage states in COVID-19 that could be targeted with available therapies.

Ayshwarya Subramanian, Aviv Regev, Anna Greka and their colleagues studied single human kidney cells to look for associations between the expression of ACE2, which SARS-CoV-2 binds to, and the use of drugs such as ACE inhibitors (ACEi), which are used to treat hypertension, heart and kidney disease. These drugs target the renin-angiotensin-aldosterone system (RAAS), of which ACE2 is a member. The team found an increase in ACE2 expression with the use of these drugs in certain cell types, but the association was confounded in this small cohort by the underlying disease. Assessing if increased ACE2 expression is beneficial or harmful in settings of disease or RAAS blockade requires further mechanistic investigation and studies in larger patient cohorts.