New Data on Genetic Expression In Severe COVID-19, Pre-Existing Immune Response

July 31, 2020 | Research continues to uncover the underlying biology of SARS-CoV-2 and reveal some surprises. A German team found that 35% of their healthy controls had pre-existing SARS-CoV-2 cross-reactive T cells, and several groups are narrowing down the gene expression signatures that might explain why COVID-19 is so severe in some patients.

Literature Updates

In a preprint made available by Nature (peer reviewed and accepted for publication, but not copy edited or typeset), a German team from Charité - Universitätsmedizin Berlin and the Max Planck Institute for Molecular Genetics detected SARS-CoV-2 S-reactive CD4+ T cells in 83% of 18 patients with COVID-19 but also in 35% of the 68 healthy controls. “The role of pre-existing SARS-CoV-2 cross-reactive T cells for clinical outcomes remains to be determined in larger cohorts,” the authors write. “However, the presence of S-cross-reactive T cells in a sizable fraction of the general population may affect the dynamics of the current pandemic, and has important implications for the design and analysis of upcoming COVID-19 vaccine trials.” DOI: 10.1038/s41586-020-2598-9

A German team has characterized the papain-like protease PLpro that is implicated in evading host anti-viral immune responses. They have just published biochemical, structural and functional characterization of the SARS-CoV-2 PLpro (SCoV2-PLpro) in Nature and outlined differences to SARS-CoV PLpro (SCoV-PLpro) in controlling host interferon (IFN) and NF-κB pathways. While SCoV2-PLpro and SCoV-PLpro share 83% sequence identity, they exhibit different host substrate preferences. In particular, SCoV2-PLpro preferentially cleaves the ubiquitin-like protein ISG15, whereas SCoV-PLpro predominantly targets ubiquitin chains. Their results highlight a dual therapeutic strategy in which targeting of SCoV2-PLpro can suppress SARS-CoV-2 infection and promote anti-viral immunity. DOI: 10.1038/s41586-020-2601-5

Analyses of lung fluid cells from 19 COVID-19 patients and 40 controls conducted on Oak Ridge National Laboratory’s Summit supercomputer fastest supercomputer point to gene expression patterns that may explain the runaway symptoms produced by the body's response to SARS-CoV-2. The computational analyses suggest that genes related to one of the body's systems responsible for lowering blood pressure—the bradykinin system—appear to be excessively "turned on" in the lung fluid cells of those with the virus. The results were published in eLife. Based on their analyses, the team posits that bradykinin—the compound that dilates blood vessels and makes them permeable—is overproduced in the body of COVID-19 patients; related systems either contribute to overproduction or cannot slow the process. Excessive bradykinin leads to leaky blood vessels, allowing fluid to build up in the body's soft tissues. DOI: 10.7554/eLife.59177

In a new published study in Cell Discovery, researchers from Nanjing University and two other groups from Wuhan Institute of Virology and the Second Hospital of Nanjing present a novel finding that absorbed miRNA MIR2911 in honeysuckle decoction (HD) can directly target SARS-CoV-2 genes and inhibit viral replication. The authors posit that drinking HD may accelerate the negative conversion of COVID-19 patients. By reconstructing the evolutionary history of SARS-CoV-2, an international research team of Chinese, European and U.S. scientists has discovered that the lineage that gave rise to the virus has been circulating in bats for decades and likely includes other viruses with the ability to infect humans. They published their findings in Nature Microbiology. The team used three different bioinformatic approaches to identify and remove the recombinant regions within the SARS-CoV-2 genome. Next, they reconstructed phylogenetic histories for the non-recombinant regions and compared them to each other to see which specific viruses have been involved in recombination events in the past. They were able to reconstruct the evolutionary relationships between SARS-CoV-2 and its closest known bat and pangolin viruses. DOI: 10.1038/s41564-020-0771-4

In a paper published in Nature Microbiology, an international team from Germany, Switzerland, and the US showed that lymphocyte antigen 6 complex, locus E (LY6E) potently restricts infection by multiple CoVs, including SARS-CoV, SARS-CoV-2 and MERS-CoV. Mechanistic studies revealed that LY6E inhibits CoV entry into cells by interfering with spike protein-mediated membrane fusion. These findings advance our understanding of immune-mediated control of CoV in vitro and in vivo—knowledge that could help inform strategies to combat infection by emerging CoVs, the authors write. DOI: 10.1038/s41564-020-0769-y

Researchers at Yale tracked the progress of 113 patients admitted to Yale New Haven Hospital for COVID-19 and analyzed the varying immune system responses they exhibited during their hospital stay. They found an association between early, elevated cytokines and worse disease outcomes. Following an early increase in cytokines, COVID-19 patients with moderate disease displayed a progressive reduction in type-1 (antiviral) and type-3 (antifungal) responses, the authors wrote. In contrast, patients with severe disease maintained these elevated responses throughout the course of disease and saw an increase in multiple type 2 (anti-helminths) effectors including, IL-5, IL-13, IgE and eosinophils. They published their findings in Nature. DOI: 10.1038/s41586-020-2588-y

Using cohort of 782 COVID-19 positive patients and 7,025 COVID-19 negative patients, a team of researchers in Israel identified that low plasma vitamin D levels appears to be an independent risk factor for COVID-19 infection and hospitalization. The research was published in The FEBS Journal. The mean plasma vitamin D level was significantly lower among those who tested positive than negative for COVID‐19. DOI: 10.1111/febs.15495

Dutch researchers have identified a genetic link to severe COVID-19 disease among healthy, young men. In two separate families with severely sick young me, the researchers found mutations in the gene encoding for the Toll-like receptor 7. “Rare putative loss-of-function variants of X-chromosomal TLR7 were identified that were associated with impaired type I and II IFN responses,” the authors write in JAMA. “These preliminary findings provide insights into the pathogenesis of COVID-19.” DOI: 10.1001/jama.2020.13719

Loss of smell is the main neurological symptom of COVID-19, but the underlying mechanism has been unclear. New research published in Science Advances suggests that olfactory sensory neurons are not vulnerable to SARS-CoV-2 infection because they do not express ACE2, a key protein that the virus uses to enter human cells. Instead, loss of smell stems from infection of nonneuronal supporting cells in the nose and forebrain. DOI: 10.1126/sciadv.abc5801

A global research team has identified 21 existing drugs that stop the replication of SARS-CoV-2, the virus that causes COVID-19 at safe human doses. They found the drugs by analyzing 12,000 clinical-stage or FDA-approved small molecules for their ability to block the replication of SARS-CoV-2. Their findings will be published in Nature. DOI: 10.1038/s41586-020-2577-1

Researchers at King Abdullah University of Science and Technology (KAUST) used comparative pangenomic analysis of all sequenced reference Betacoronaviruses to determine that the envelope protein E is shared between SARS and SARS-CoV-2. They suggest E protein as an alternative therapeutic target to be considered for further studies to reduce complications of SARS-CoV-2 infections in COVID-19. The spike (S) protein of SARS-CoV-2 has been the prime target of vaccine work thus far, and while the S proteins from SARS and SARS-CoV-2 are similar, structural differences in the receptor binding domain (RBD) preclude the use of SARS-specific neutralizing antibodies to inhibit SARS-CoV-2. The KAUST team looked elsewhere for similarities, using comparative pangenomic analysis complemented with functional and structural analyses, and found that among all core gene clusters present in these viruses, the envelope protein E shows a variant cluster shared by SARS and SARS-CoV-2 with two completely-conserved key functional features, namely an ion-channel, and a PDZ-binding motif (PBM). The work was published in Frontiers in Cellular and Infection Molecular Biology. DOI: 10.3389/fcimb.2020.00405

In a study published in JAMA Cardiology, German researchers looked at 100 patients aged 45-53 who had recovered from COVID-19 (67 at home; 33 had been hospitalized) and had no pre-existing heart conditions. Cardiac MRI after recovery showed 78% with some “cardiac involvement”; 60% of those showed ongoing myocardial inflammation. “Our findings reveal that significant cardiac involvement occurs independently of the severity of original presentation and persists beyond the period of acute presentation, with no significant trend toward reduction of imaging or serological findings during the recovery period,” the authors write. “Our findings may provide an indication of potentially considerable burden of inflammatory disease in large and growing parts of the population and urgently require confirmation in a larger cohort.” DOI: 10.1001/jamacardio.2020.3557

In a separate JAMA Cardiology publication also from German researchers, a study of 39 autopsy cases of patients with COVID-19 found that cardiac infection with SARS-CoV-2 was found to be frequent but not associated with myocarditis-like influx of inflammatory cells into the myocardium. DOI: 10.1001/jamacardio.2020.3551

Researchers at the University of Texas, Austin, have engineered the spike protein of the SARS-CoV-2 virus—a critical component of potential COVID-19 vaccines—to be more environmentally stable and generate larger yields in the lab. They characterized 100 structure-guided spike designs and identified 26 individual substitutions that increased protein yields and stability. Testing combinations of beneficial substitutions resulted in the identification of HexaPro, a variant with six beneficial proline substitutions exhibiting ~10-fold higher expression than its parental construct and the ability to withstand heat stress, storage at room temperature, and three freeze-thaw cycles. They published their findings in Science. DOI: 10.1126/science.abd0826