These summaries were compiled by Washington University in St. Louis medical and graduate students. Please note that bioRxiv and medRxiv articles have yet to be peer reviewed.
Title (link)JournalPub. DateCategoryArticle highlightsProblem/BackgroundDesignGroups, for clinical studiesResults
The architecture of SARS-CoV-2 transcriptomeCellPre-proofBiologyTranscriptomic features and RNA modifications of SARS-CoV-2Expressions from open reading frames of SARS-CoV-2 have not been experimentally verified.Basic science1) Expression of gRNA and sgRNAs (S, 3a, E, M, 6, 7a, 7b, 8, and N) are confirmed, while ORF10 is questionable; 2) Frequenct detection of leader-body junctions suggests that SARS-CoV-2 also utilizes the Transcription-Regulatory Sequences (TRSs)-mediated template switching for positive strand mRNA synthesis like other coronaviruses; 3) Direct RNA sequencing indicates potential existence of 41 RNA modification sites (types unknown), with the ‘AAGAA-like’ motif modifications as the most prevalent.
COVID-19: a new virus, but an old cytokine release syndromeImmunityPre-proofBiologyACE2 sequestration by SARS-CoV-2 viral adhesion lead to the formation of an inflammatory positive feedback loop of NF-kB and STAT3 activation through the angiotensin 2 and angiotensin I receptor axis. This feedback loop potentiates the cytokine release syndrome during the acute respiratory distress syndrome of COVID-19 and may be a druggable pathway.Cytokine release syndrome is a consequence of COVID-19 disease with significant associated morbidity. This mini-review addresses what is known about the cascade of host-virus interactions that proceed from viral attachment to cells and lead to cytokine release.Basic scienceSARS-CoV-2 requires TMPRSS2 or Cathepsin B or L protease activity to infect ACE2+ cells through cleavage of viral S proteins. Sequestration of ACE2 by virus decreases inactivation of Angiotensin 2 (AngII). Increased pools of AngII activate the angiotensin receptor type 1 (AT1R) leading to NF-kB activation, directly or indirectly through disintegrin and ADAM17. ADAM17 also activates IL-6 signaling and STAT3 through production of soluble IL-6Ra. The concurrent activation of NF-kB and STAT3 creates the IL-6 amplifier, a common endpoint for several inflammatory and autoimmune disorders, that acts as an inflammatory postive feedback loop. This mechanism leading to cytokine release syndrome is thought to contribute strongly to acute respiratory distress syndrome in COVID-19 and is a potential druggable target.
High risk of thrombosis in patients in severe SARS-CoV-2 infection: a multicenter prospective cohort studyIntensive Care MedicinePre-printBiologyCompared to non-COVID-19 acute respiratory distress syndrome (ARDS) patients, COVID-19 ARDS is associated with significantly more pulmonary embolisms (11.7% vs. 2.1%, OR 6.2 [1.6-23.4], p <0.008) despite prophylactic anticoagulation.Do the pathologic sequelae of COVID-19 lead to increased thrombotic events in severe disease?Prospective cohort study150 COVID-19 intensive care unit patients were prospectively monitored for thrombotic events. These were compared to a historical cohort of non-COVID-19 patients..Primary end-points was the occurence of any thrombotic event. 64 thrombotic events were recorded in the COVID-19 cohort. Greater than 95% of patients had baseline elevations in D-dimer and fibrinogen. Pulmonary embolism was diagnosed a median of 5.5 days after ICU admission.
Infection and Rapid Transmission of SARS-CoV-2 in FerretsCell Host & MicrobeJournal Pre-proofBiologyInfected ferrets show elevated body temperature and viral replication. Both direct and indirect transmissions seen between ferrets.
Animal model for SARS-CoV-2 infection and transmission is neededBasic scienceFerrets with direct infection (6), direct contact (6), indirect contact (6), PBS control (6) were included in the study. Infected ferrets presented elevated body temperatures that went back to normal by 8 day-post-infection (dpi). Occasional cough and reduced activities detected, yet no body weight loss or fatalities. Viral RNA can be detected in nasal washes, saliva, fecal and urine samples before 8 dpi. After 12 dpi, high titers of neutralizing antibodies can be detected in direct infection and direct contact groups.
SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissuesCelljournal pre-proofBiologyACE2 and TMPRSS2 co-expression was detected in type II pneumocytes, ileal absorptive enterocytes, and nasal goblet secretory cells. ACE2 was found to be a human interferon-stimulated gene.Basic scienceUsing various scRNA-seq datasets, ACE2 and TMPRSS2 co-expressing cells were identified within type II pneumocytes, ileal enterocytes, and nasal goblet cells. ACE2 expression was associated with components of the INF signaling pathway. Type I INF, and to a lesser extend type II INF, induced ACE2 expression in a primary human upper airway basal cell culture, suggesting that ACE2 may be an interferon-stimulated gene.
A multibasic cleavage site in the spike protein of SARS-CoV-2 is essential for infection of human lung cellsMolecular Celljournal pre-proofBiologyThe authors report in this study that the cellular protease furin cleaves the SARS-CoV-2 spike protein and the S1/S2 site and is essential for S protein-mediated cell-cell fusion and entry into human lung cells.It is known that the SARS-CoV-2 S-protein has a S1/S2 cleavage site with multiple arginine residues (multibasic) unlike other closely related animal coronaviruses, but the role of this multibasic site in SARS-CoV-2 infection is not completely understood.Basic scienceUsing various combinations of viral pseudotypes of coronavirus spike (S) protein with different variations of the S1/S2 clevage site, the multibasic SARS-CoV-2 S1/S2 cleavage site is suggested to be needed for efficient cleavage by furin before it can be further cleaved by TMPRSS2 and further suggested to be required for cell-cell fusion as well as viral entry into human TMPRSS2+ Calu3 cells. Authors note that work will need to be extended into primary human respiratory epithelial cells, use real virus instead of the pseudotype they were using, and also that furin inhibition for prolonged periods could have unwanted toxic effects.
ACE-2 Expression in the Small Airway Epithelia of Smokers and COPD Patients: Implications for COVID-19Eur Respir JIn PressBiologyACE2 expression level is higher in airways of current smokers and those with COPD in COVID-19 patients.
Smoking status and ACE2 expressionBasic scienceACE2 protein level were measured from COVID-19 patients including 10 current smokers with COPD (FEV1/FVC 61±7%), 9 non-smoker controls (FEV1/FVC 85±2%), and 8 healthy current smokers (FEV1/FVC 78±6%). Increase in expression was seen in COPD (2.52±0.66) versus non-COPD subjects (1.70±0.51; p=7.62×10e-4) and smokers (2.77±0.91) versus non-smokers (1.78±0.39; p=0.024). The increased ACE2 expression pattern in smokers was confirmed in Cornell and BCCA cohorts.
Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivirScience5/1/20BiologyPartial double-stranded RNA template is inserted into the central channel of the RdRp where Remdesivir is covalently incorporated into the primer strand at the first replicated base pair and terminates chain elongationStrutural basis of remdesivir binding-derived RdRp inhibitionBasic scienceRdRp complex was formed by co-expressing nsp12 with nsp7 and nsp8 in insect cells, supplemented with additional nsp7 and nsp8, then purified. See highlights
SARS-CoV-2 Productively Infects Human Gut EnterocytesbioRxiv4/25/20BiologyBoth SARS-CoV and SARS-CoV-2 can infect enterocytes and enterocyte precursors with productive viral replication in a human small intestinal organoid model.GI symptoms, viral RNA in rectal swabs, and ACE2 expression in intestinal enterocytes suggest potential GI infection and fecal-oral transmission in COVID-19 patientsBasic scienceSARS-CoV and SARS-CoV-2 productively infected human small intestinal organoids, with enterocytes and enterocyte precursors appearing to be the primary viral target. Infection with SARS-CoV-2 elicited expression of xytokines and interferon stimulated genes.
MINERVA: A facile strategy for SARS-CoV-2 whole genome deep sequencing of clinical samplesbioRxiv4/25/20BiologySimplified sequencing library construction approach (MINERA) achieves high sensitivity, coverage and depth for viral genome sequencing from patient samplesA better approach for capturing viral genome together with metatranscriptome from patient sample is neededBasic scienceDirect tag RNA/cDNA hybrids with sequencing adapters combined with post-library target enrichment protocol reduces hands-on time to 100min from clinical sample to sequencing-ready library, or 190min if deeper viral genome coverage is required. This method can reach higher coverages at similar sequencing depth compared to traditional approach.
A preliminary study on the reproductive toxicity of GS-5734 on male micebioRxiv4/23/20BiologyHigh dosage of GS-5734 (Remdesivir) may induce testicular toxicity and result in deterioration of sperm parameters in miceWhat's the biological impact of Remdesivir on the mammalian reproductive system?Basic science28 adult male mice split into four groups, treated with intraperitoneal injection of GS-5734 for 10 days at 0, 10, 50, 150µg/mouse respectively.
GS-5734 treatment presented dose-dependent sperm count and motility reduction coupled with abnormality increase in male mice
COVID-19 Critical Illness Pathophysiology Driven by Diffuse Pulmonary Thrombi and Pulmonary Endothelial Dysfunction Responsive to ThrombolysismedRxiv4/22/20BiologyAbnormal coagulation in COVID-19 may lead to pulmonary thrombi which disrupt oxygenation and respiratory function.Abnormal coagulation and gas exchange with preserved lung mechanics has been noted in COVID-19. Do thrombi in the pulmonary vasculature contribute to COVID-19 pathogenesis?Basic science4 patients with severe COVID-19 pneumonia, respiratory filure, and shock.Tissue plasminogen activator was administered to pre-terminal patients. Three of four patients survived with one patients demonstrating a clear temporal link to their improved status. Three patients had a decreased need for vasopressors.
Explanation for COVID‐19 infection neurological damage and reactivationsTransbound Emerg Dis4/22/20BiologyCOVID-19 reactivation might due to neurological infection in latency state
What are the possible explanations for COVID-19 reactivation?Ideas, editorials, reviews or opinionsReports regarding COVID-19 reactivation and neurological symptoms might seem disputable, but they do resemble that from the Nipah virus infections. One potential explanation that links neurological symptoms and reaction would be that virus might evade immune attack through neuron infections, granting them the ability to reactivate later.
COVID-19 diagnosis and study of serum SARS-CoV-2 specific IgA, IgM and IgG by a quantitative and sensitive immunoassaymedRxiv4/22/20BiologyReceptor binding domain (RBD) specific immunoglobulins have improved sensitivity/specificity for SARS-CoV-2 compared to nucleocapsid protein (NP) and CT/qPCR. Serum IgA levels against the RBD may distinguish levels of COVID-19 severity.With qPCR and CT scan based diagnosis having a sensitivity of around 70%, improved methods for detecting COVID-19 are needed. Can serum immunoglobulins be used to diagnose and monitor COVID-19 disease?Basic science216 sera samples from 87 qPCR confirmed COVID-19 patients and 483 sera samples from SARS-CoV-2 negative or health controls.Detecting serum immunoglobulins against the receptor binding domain of the SARS-CoV-2 spike protein with a chemiluminescent immunoassay led to a sensitivity/specificity in detecting SARS-CoV-2 of >90%. Detection of anti-RBD IgA alone had a sensitivity of 98.6% and a specificity of 98.1%. Serum IgA contentrations tracked with disease severity.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the central nervous systemTrends in Neurosciences4/22/20BiologySARS-CoV-2 is associated with neurological alterations in COVID-19 patients, presenting with severe clinical manifestationsSystematic reviewShould consider include CSF testing, cognitive testing to monitor neurological conditions of COVID-19 patients.
Histopathology and Ultrastructural Findings of Fatal COVID-19 InfectionsmedRxiv4/21/20BiologyBesides sigificant pathology in the lungs, diffuse organ damage is associated with fatal COVID-19 with pathology identified in the kidney, trachea, heart, GI tract, and brain.What is the whole body pathology associated with COVID-19?Basic sciencePost-mortem analysis of 12 fatal COVID-19 cases from Washington StateVirus was identified in type I and II pneumocytes by EM in the kidney, trachea, large intestines and heart. Histologic pathology was noted in the lungs, liver, heart, trachea, spleen, brain, stomach, and kidneys. Gross pathology noted in the lungs, liver, heart, spleen, kidney, and brain.
Viral load dynamics and disease severity in patients infected with SARS-CoV-2 in Zhejiang province, China, January-March 2020: retrospective cohort study.BMJ4/21/20BiologyRespiratory viral RNA load correlates with severity of disease. Respiratory viral RNA load peaks in the third week of symptoms in severe COVID-19 patients compared to the second week in milder patients. Viral RNA in stool persists longer and peaks later than in respiratory or serum samples.Do viral RNA loads correspond to COVID-19 disease progression?Case reports/series96 consecutively admitted, SARS-CoV-2 confirmed patients in Zhejiang, China from 1/19 to 3/20See highlights
Structural basis for potent neutralization of betacoronaviruses by single-domain camelid antibodiesCell4/20/20BiologyCamelid antibodies generated against SARS-CoV-1 can neutralize SARS-CoV-2.Can antibodies generated against the spike protein of other betacoronaviruses neutralize SARS-CoV-2?Basic scienceAntibodies derived from llamas injected with coronavirus spike proteins can neutralize MERS-CoV and SARS-CoV-1 viruses. Cross-reactivity of the SARS-CoV-1-generated antibody can cross-react with SARS-CoV-2 spike protein, and this antibody present as a chimeric llama-human IgG fusion can neutralize SARS-CoV-2 virus.
Comparative pathogenesis of COVID-19, MERS, and SARS in a nonhuman primate modelScience4/17/20BiologyCynomolgus macaques are permissive to SARS-CoV-2 infection, shed virus for a prolonged period of time and display COVID-19-like diseaseDifference of SARS-CoV, MERS, SARS-CoV-2 infection in non-human primate modelBasic scienceYoung and aged cynomolgus macaques inoculated with low passage clinical isolate of SARS-CoV-2 showed similar viral shedding and tissue and cell tropism as rhesus macaques, yet no transient respiratory disease and weight loss. SARS-CoV-2 infected animals also showed Diffuse Alveolar Aamage (DAD) that has been reported in human COVID-19 patients. SARS-CoV and SARS-CoV-2 infected both type I and type II pneumocytes, with the damage in type I possibly resulting in pulmonary edema, and formation of hyaline membranes.
Endothelial cell infection and endotheliitis in COVID-19The Lancet4/17/20BiologyPathologic reports detail immune cell infiltrates and cell death in vasculature throughout the body. SARS-CoV-2 can infect human endothelial organoids, potentially through ACE2 receptors expressed on these cell types.Given the rates of cardiovascular complications in COVID-19, how does SARS-CoV-2 interact with endothelium and other vasculature?Case reports/seriesThree patients with pre-existing vascular disease and COVID-19. Pathologic resection specimens from kidney, small bowel, heart, lung, and liver showed mononuclear or lymphocytic infiltrates into the vasculature. Apoptotic bodies or necrosis were also found with a similar organ distribution. Electron microscopy identified viral inclusion bodies in the peritubular space and viral particles in the endothelial cells of one patient's transplant recipient kidney.
Comparative pathogenesis of COVID-19, MERS, and SARS in a nonhuman primate modelScience4/17/20BiologyThe non-human primate cynomolgus macaques are permissive to SARS-CoV-2 infection. Viral shedding can be detected from both upper and lower respiratory tract in the absence of clinical signs. Histologic findings in the lungs are consistent with human COVID-19 cases, with detectable SARS-CoV-2 antigen in both type I and II pneumocytes, similar to SARS-CoV manifestations in this animal model. Novel animal model for testing preventive and therapeutic interventions for use in humansBasic scienceA non-human primate model (cynomolgus macaques) was used to characterize SARS-CoV-2 infection. Both young and old animals acquired infection without overt clinical signs after being inoculated with a clinical isolate. SARS-CoV-2 shedding peaked early, and was prolonged in the upper respiratory tract of aged animals. Histological findings are typical of respiratory coronavirus infections, with injury to both type I and II pneumocytes.
Visualizing speech-generated oral fluid droplets with laser light scatteringNEJM4/15/20BiologyIn this small study, speaking the phrase "Stay healthy" was sufficient to produce droplets. Production of droplets went to baseline when the participant wore a damp cloth over their mouth.In sight of potential airborne and droplet spread of SARS-CoV-2, does normal speech produce droplets that may be infectious? Do face coverings change the production of droplets?Basic scienceSee highlights
The usual anaerobic bacterial suspects extracted from a global metagenomic database of Covid19 patients from Peru, Cambodia, China, Brazil and the US - Prevotella, Veillonella, Capnocytophaga, Fusobacterium, Oribacterium and Bacteroides should be monitored for colonizationOSF Preprints4/14/20BiologyAnaerobic bacteria are enriched in COVID-19 metagemoic datasetsBasic scienceCommon opportunistic anaerobic bacteria found from global metagenomic Covid19 dataset: Prevotella, Veillonella, Capnocytophaga, Fusobacterium, Oribacterium, Bacteroides
Comparative dynamic aerosol efficiencies of three emergent coronaviruses and the unusual persistence of SARS-CoV-2 in aerosol suspensionsmedRxiv4/13/20BiologySARS-CoV-2 remains replication-competent and virion integrity up to 16hrs in aerosol suspensions Dynamics and long-term persistence of SARS-CoV-2 viral particles in aerosols is unknownBasic scienceIn Collison 3-jet generated aerosols, SARS-CoV-2 showed improved short-term aerosol efficiency than SARS-CoV and MERS-CoV. In static aerosol suspensions, SARS-CoV-2 can be detected by RT-PCR up to 16 hrs without much decay, with its morphologies, size and aspect ratios remain stable.
The SARS-CoV-2 receptor-binding domain elicits a potent neutralizing response without antibody-dependent enhancementbioRxiv4/12/20BiologyAntibodies specific for the receptor binding domain (RBD) the SARS-CoV-2 S protein are strongly neutralizing and don't seem to result in antibody-dependent enhancement of future viral infections unlike antibodies produced to the SARS-CoV-1 S protein or those produced against Zika.Do neutralizing antibodies produced in response to Sars-Cov-2 have the potential for antibody dependent enhancement?Basic scienceSee highlights
Isolation, sequence, infectivity and replication kinetics of SARS-CoV-2bioRxiv4/12/20BiologyTwo SARS-COV-2 isolates were collected from a patient in Canada. Here, researchers sequenced and determined the replication kinetics for the virus in human T cells.Since the virus has spread globally, it will likely pick up mutations. Therefore, it is important to isolate coronavirus from patients and analyze their ability to infect multiple human cell types to determine whether new variants have appeared.Basic scienceCoronavirus was found to replicate efficiently in Vero E6 and Calu-3 cells; however, human cell lines (THP-1-derived cell lines) and peripheral blood mononuclear cells did not support replication. In addition, the complete genomes for the two SARS-COV-2 isolates were published.
Testing the association between blood type and COVID-19 infection, intubation, and deathmedRxiv4/11/20BiologyThere seems to be a higher proportion of A+ COVID-19 patients than O blood type.There may be a possible association between blood type and COVID-19 infectionCase reports/series1559 patients tested for COVID-19 (682 of which are positive) at New York Presbyterian hospitalBlood groups A are assoicated with increased odds of testing positive (1.338 95% CI [1.072-1.672]) and blood groups O are assocated with decreased odds of testing positive (.804 95% CI [.654-.987]).
Phenotype of SARS-CoV-2-specific T-cells in COVID-19 patients with acute respiratory distress syndromemedRxiv4/11/20BiologyThe virus induces a strong and specfic T cell response of both CD4s and CD8s. CD4s primarily have a Th1 cytokine profile, but also produce Th2 cytokines as well. It doesn't appear that T cells are responsible for the increaseed levels of IL-6 induced cytokine storm. They can be an important component of immunity in addition to neutralizing antibodies.What is the T cell response like in patients with ARDS?Basic sciencesee highlights
Structure of the RNA-dependent RNA polymerase from COVID-19 virusScience4/10/20BiologyCryo-EM structure of SARS-CoV-2 full-length nsp12 in complex with cofactors nsp7 and nsp8 at 2.9-Å resolutionBasic scienceOverall architecture of the COVID-19 virus nsp12-nsp7-nsp8 complex is similar to that of SARS-CoV. With more residues resolved, this study identified residues A4-T28 and Y69-R249 as the complete coronaviral NiRAN domain, and an additional N-terminal β-hairpin (D29 to K50) in the structure. A model of how remdesivir could bind to nsp12 is proposed.
Highly pathogenic coronavirus N protein aggravates lung injury by MASP-2-mediated complement over-activationmedRxiv4/7/20BiologyComplement pathway suppression may be a promising therapeutic target for COVID-induced pneumonia.Complement hyperactivation has been observed in COVID-19 patients, and may underlie the cytokine storm/ inflammation that contributes to disease severity/ lethality.Basic scienceThe N-proteins of SARS-CoV, MERS-CoV and SARS-COV-2 were found to bind to MASP-2, the key serine protease in the lectin complement activation pathway. Additionally, immunohistochemical staining of lung tissue of patients who died of COVID-19, as well as patient serum 5a levels, suggest that the complement cascade was overactivated in COVID-19 patients, particularly in severe cases. These results suggest that either blocking the N protein:MASP-2 interaction or suppressing complement activation may alleviate complement overactivation, and reduce lung injury.
The dilemma of Coronavirus disease 2019, aging, and cardiovascular disease: insights from cardiovascular aging scienceJAMA4/3/20BiologyCalling for pursuing renin-angiotensin system (RAS) signaling as a treatment avenue and the continuation of treatment of individuals with cardiovascular disease/hypertenstion with ACEI/ARB treatment as it is likely corrective of the aging associated decreases in ACE2 expression. There is a dilemma as to whether ACEI/ARB treatment predisposes individuals to COVID-19. However, the evidence suggests that this treatment benefits the aging population. Should RAS signaling be a treatment target? Ideas, editorials, reviews or opinionsThe severity of disease in older populations (especially in hypertension and diabetes patiens) is likely due to the decreased ACE2 expression and the increase in the proinflammatory profile through angiotensin II. However, in younger individuals, ACE2 expression is higher which increases COVID-19 incidence. However, upon COVID-19 binding to ACE2, the proinflammatory profile (via angiotensin II) is decreased so the disease is less severe. Therefore, ACEI/ARB treatment which leads to increased ACE2 expression may support in suppressing the proinflammatory profile.
A highly conserved cryptic epitope in the receptor-binding domains of SARS-CoV-2 and SARS-CoVScience4/3/20BiologyAn antibody against SARS-CoV failed to neutralize SARS-CoV2 in vitro. Are antibodies to SARS-CoV (2002-2003) reactive against similar antigens on SARS-CoV-2 (2019-)?Basic scienceCR3022 is a neutralizing antibody against the receptor-binding domain of the surface spike (S) protein of SARS-CoV, the major antigen responsible for viral binding and fusion. The SARS-CoV-2 S protein was bound by CR3022, but with less affinity relative to SARS-CoV and the virus was not neutralized. This lack of neutralization in vitro may be due to identified structural differences in the antigens and the authors discuss the possiblity that CR3022 may neutralize SARS-CoV-2 in vivo or in the presence of other antibodies.
Endocrine and metabolic link to coronavirus infectionNature Reviews Endocrinology4/2/20BiologyPeople with type 2 diabetes and/or hypertension may be at increased risk for poor outcomes from COVID-19 infection due to metabolic differences which could, in theory, enhance the virus's ability to infect cells via specific biochemical mechanisms.T2DM is a known risk factor for increased severity of other coronavirus (SARS and MERS-CoV) infections through several postulated pathways of increased inflammation and immune dysregulation.Ideas, editorials, reviews or opinionsT2DM/HTN may increase activation of the AT1 and AT2 receptors, thus producing a systemic pro-inflammatory state which increases risk of ARDS in COVID-19 infection. Pancreatic beta cells express ACE2 and may be susceptible to coronavirus entry; therefore, coronavirus infection may produce transient hyperglycemia. These theoretical links between T2DM/HTN and coronavirus argue for vigilence in glycemic control among diabetics during the pandemic.
Digestive system is a potential route of COVID-19: an analysis of single-cell coexpression pattern of key proteins in viral entry processGut4/2/20BiologyThe upper esophagus, ileum, and colon exihibit high expression of the cell receptor and protease that SARS-CoV-2 uses to enter host cells (ACE2 and TMPRSS2, respectively). Thus, it may be possible for the virus to have fecal-oral transmission.Prevention measures for COVID-19 are centered around transmission through respiratory droplets, however, there may be other routes of transmission. The digestive tract is of particular interest for investigation due to the enteric symptoms seen in some patients.Basic scienceSARS-CoV-2 enters cells through ACE2 and TMPRSS2, which are not only co-expressed in lung AT2 cells, explaining entry through the respiratory tract, but are also co-expressed in upper esophageal epithelial and glandular cells and ileal and colonic absorptive enterocytes, which indicates that the digestive tract could be another site of virus entry into host cells.
Virological assessment of hospitalized patients with COVID-2019Nature4/1/20BiologyCOVID-19 can present as a mild URI and there is evidence that it actively replicates in the upper respiratory tract. Viral shedding in sputum outlasts the end of symptoms.Given reports of COVID-19 cases with only mild URI symptoms - can COVID-19 replicate in and cause illness in the upper respiratory tract?Basic scienceVirological analysis of 9 cases in GermanyHigh pharyngeal virus shedding during the first symptomatic week (peaks at day 4). Active replication and infectivity confirmed in throat samples. This replication is independent from replication in the lung. Seroconversion occurs after 7 days in 50% of patients, but is not followed by a significant reduction in viral load.
Detection of Air and Surface Contamination by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in Hospital Rooms of Infected PatientsmedRxiv4/1/20BiologySurface contamination seems to peak during the first week of illness and declines afterwards. The floor is the most likely surface to be contaminated at 65% of rooms tested, followed by the bed rail (59%), and bedside locker (42%).Do COVID-19 patients contaminate hospital rooms they stay in? If so, at what stage of disease progression and in what form are these particles?Cross-sectional studyEnvironmental swabs and particle measurements from airborne infection isolation rooms at the National Centre for Infectious Disease in Singapore after COVID-19 patients have stayed there.SARS-CoV-2 was detected by PCR in 56.7% of 30 rooms tested. High touch surface contamination was greater during the first week of illness when compared to beyond the first week (66.7% vs. 20%). On the 5th day of symptoms, PCR-positivity for SARS-CoV-2 was found in particles >4μm and between 1-4μm.
SARS-CoV-2 in wastewater: potential health risk, but also data sourceThe Lancet Gastroenerology and Hepatology4/1/20BiologyWastewater does contain SARS-CoV-2 RNA within a week of initial reports of disease. This could be a method of disease surveillance.Reports suggest that SARS-CoV-2 can be shed in feces leaving the potential for fecal-oral transmission. This prompts the question of whether virus persists in wastewater?Basic scienceTesting from 2 wastewater samples in the NetherlandsWastewater was PCR-positive for SARS-CoV-2 within 1 week of initial detection of an infected patient in proximity to the wastewater sites.
An Uncomplicated Delivery in a Patient with Covid-19 in the United StatesNEJM4/1/20BiologyNo evidence for maternal-infant transmission in COVID-19 positive mother with symptom onset 6 days prior to uncomplicated spontaneous vaginal delivery. Most reports on lack of maternal-infant transmission of SARS-CoV-2 have been in the context of cesarean section deliveriesCase reports/series34 year old G7P5 with COVID-19 at 39 weeks of gestation with symptom onset 6 days prior to deliverySpontaneous labor with oxytocin augmentation and uncomplicated vaginal delivery. No delayed cord clamping or skin-to-skin contact. No symptomatic evidence of intraamniotic or neonatal infection up to 7 days post-delivery.
Cigarette smoke triggers the expansion of a subpopulation of respiratory epithelial cells that express the SARS-CoV-2 receptor ACE2bioRxiv3/31/20BiologyQuitting smoking could lessen coronavirus susceptibility via decreased lung ACE2 levels.Factors mediating fatal SARS-CoV-2 infections are poorly understood.Basic scienceCigarette smoke causes a dose-dependent upregulation of ACE2, the SARS-CoV-2 receptor, in rodent and human lungs via expansion of mucus-secreting goblet cells that secrete ACE2. Quitting smoking does the opposite.
Susceptibility of ferrets, cats, dogs, and different domestic animals to SARS-coronavirus-2bioRxiv3/31/20BiologyReplication of SARS-CoV-2 is possible in cats and ferrets but not in dogs, pigs, chickens or ducks. Droplet transmission was identified between cats.Does SARS-CoV-2 have tropism for other mammalian species besides humans? Could these species have served as intermediate hosts for zoonotic spread or as viral reservoirs?Basic scienceViral RNA is able to be recovered from the pharynx of ferrets and cats up to 8 days after intranasal inoculation. Cats exposed through droplets to inoculated cats have detectable pharyngeal virus. Dogs, pigs, chickens, and ducks do not have detectable oropharyngeal SARS-CoV-2 virus 2 days after inoculation.
The Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Directly Decimates Human Spleens and Lymph NodesmedRxiv3/31/20BiologySARS-CoV-2 directly neutralizes human spleens and lymph nodes through infecting tissue-resident macrophagesWhat's the mechanism behind lymphocytopenia in COVID-19 patientsBasic sciencePostmortem examination from 6 patients show ACE2 expression and positive viral NP antigen in resident macrophages in spleen and lymph nodes, suggesting direct virus infection of these cells. Widely distributed necrosis and apoptosis of lymphocytes could be mediated by general Fas upregulation in spleen and lymph nodes and IL-6 upregulation from the infected macrophages.
A Dynamic Immune Response Shapes COVID-19 ProgressionCell Host & Microbe3/30/20BiologyTranscriptional profiling of three COVID-19 patients over the course of several days showed that only expression of genes in the IL1 pathway peaked before respiratory function nadir, indicating a potential role in the inflammatary response to SARS-CoV-2.Whether a dynamic immune response to SARS-CoV-2 contributes to pathogenesis remains unknown. This study sought to understand the temporal changes in pro-inflammatory genes throughout infection in order to aid future studies addressing pathogenesis and therapeutic targets.Basic scienceWhile previous findings suggested cytokine storm to be responsible for inflammation, this study demonstrated that genes in the IL1 pathway were the only genes to hit peak expression before respiratory function nadir. This finding suggests that it is the IL1 pathway, and not other pro-inflammatory pathways, that leads to the inflammatory response contributing to SARS-CoV-2 pathogenesis.
Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2Science3/27/20BiologyACE2, the cellular receptor of SARS-CoV-2, and its chaperone B0AT forms a dimer of heterodimers. ACE2 recognizes receptor binding domain (RBD) of the surface spike glycoprotein (S protein) by the extracellular peptidase domain through polar residues.How does viral S protein interact with human ACE2 receptorBasic scienceCryo–electron microscopy structure of full length ACE2 and its chaperone B0AT1 are presented with or without the receptor binding domain (RBD) of the surface spike glycoprotein (S protein) of SARS-CoV-2.
Immune cell profiling of COVID-19 patients in the recovery stage by single-cell sequencingmedRxiv3/27/20BiologySingle cell transcriptional profiling revealed a unique immune cell signature in the early recovery stage in COVID-19 patients, with decreased T cells and increased monocytes. Immune dysregulation sustains for >7 days after discharge, highlighting potential need for close observation.Lymphopenia and inflammatory cytokine elevation have been observed in COVID-19 patients.Basic sciencePeripheral blood mononuclear cells from 10 patients recovered from COVID-19Compared to healthy controls, blood samples from COVID-19 patients in early recovery are notable for a decrease in T and NK cells, and an increase in monocytes with predominantly inflammatory signatures. Adaptive immune dysregulation is sustained for more than 7 days after discharge, suggesting potential need for longer observation.
Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoVNature Communications3/27/20BiologyThe primary receptor for SARS-CoV-2 is confirmed to be ACE2; SARS-CoV-2 cell entry into hACE2-expressing HEK293 cells is through endocytosis and is dependent upon PIKfyve and its downstream effector TPC2 as well as the protease Cathepsin L; Previous infection with SARS-CoV may only provide moderate protection against SARS-CoV-2While past evidence has implicated the SARS-CoV-2 spike (S) protein as critical for viral entry, many questions remain in regards to virus entry, such as the entry pathway and protease priming.Basic scienceA SARS-CoV-2 S pseudovirions efficiently transduced hACE2-expressing 293 cells mainly through endocytosis. This may be dependent upon the PI(3,5)P2 pathway with inhibition of PIKfyve, its downstream effector TPC2, or the protease Cathepsin L significantly blocking viral entry, presenting potential novel drug targets. The anti-SARS S1 antibody T62 and sera from recovered SARS-CoV patients demonstrated only moderate cross-neutralization of SARS-CoV-2, implying only moderate protection being granted from prior SARS-CoV infection.
Identifying SARS-CoV-2 related coronaviruses in Malayan pangolinsNature3/26/20BiologySARS-CoV-2 related viruses identified in pangolins--possible intermediate hosts that facilitated emergence and transfer to humanBats identified as likely resovoir hosts, but intermediate host unknownBasic scienceComplete coronavirus genome sequences identified from frozen pangolin tissue samples have high sequence similarity to SARS-CoV-2. Evidence of recombination between pangolin, bat, and human coronaviruses.
A genomic perspective on the origin and emergence of SARS-CoV-2Cell3/26/20BiologyWhen looking at genomic data of SARS-CoV-2, many questions still remain regarding its emergence, such as the role and identity of intermediate host species, the possibility of viral recombination, as well as a possible cryptic spread period among humans before it was initially detected.While genomic data we have at our disposal for SARS-CoV-2 has proven invaluable for the development of diagnostic tests, vaccines, and antivirals, it has also shed light on major gaps in our understanding its emergence.Ideas, editorials, reviews or opinionsFor the future, the authors recommend overall wider sampling, including looking at other species besides simply bats when monitoring animal coronaviruses, as well as limiting exposure to animal-borne pathogens whenever possible through strong action against illegal wildlife trade and removing mammalian and avian wildlife from wet markets.
scRNA-seq reveals ACE2 and TMPRSS2 expression in TROP2+ Liver Progenitor Cells: Implications in COVID-19 associated Liver DysfunctionbioRxiv3/25/20BiologyACE2 expression detected in liver progenitor cells by scRNA-seq analysisAST and ALT elevation seen in some COVID-19 patients. Unclear whether SARS-CoV-2 can directly infect liver cells.Basic scienceACE2 expression detected in a rare population of liver progenitors with high TROP2 expression, which is a marker for cholangiocyte fate.
SARS-CoV-2 launches a unique transcriptional signature from in vitro, ex vivo, and in vivo systemsbioRxiv3/24/20BiologySARS-CoV-2 elicits a muted response that lacks robust induction of a subset of cytokines including the Type I and Type III interferons as well as a numerous chemokinesWhat's the host transcriptional response to SARS-CoV-2?Basic scienceHost transcriptional response to SARS-CoV-2, seasonal influenza A virus (IAV), and human orthopneumovirus (RSV) were tested in both primary human lung epithelium, transformed lung alveolar cells and in vivo in ferrets. The host response of SARS-CoV-2 presents an intermediate transcriptional footprint with upregulation of ISGs yet a general muted induction of antiviral genes. Comparing to responses to IAV and RSV, the response to SARS-CoV-2 lack induction members of IFN-I and IFN-III.
Emergence of SARS-CoV-2 through Recombination and Strong Purifying SelectionbioRxiv3/22/20BiologyWhile the exact entryway for SARS-CoV-2 into humans has yet to be identified, it is most similar to a CoV in bats with human receptor binding motifs similar to CoV in pangolins.Determination of the origins of CoVid-19 could assist in preventing future transmission of zoonotic respiratory disease. Basic science43 complete genome sequences three clades of human, bat and pangolin CoVPangolin CoVs are too distant from CoVid-19 to be progenitors, but they share an ACE2 receptor binding motif allowing entry into humans. CoVid-19 is most similar to CoVs in bats, suggesting entry from bats of a virus with pangolin CoV components.
Protein Structure and Sequence Reanalysis of 2019-nCoV GenomeRefutes Snakes as Its Intermediate Host and the Unique Similaritybetween Its Spike Protein Insertions and HIV‑1ACS3/22/20BiologyContrary to previously reported results, the 4 insertions found in the nCoV-2019 spike protein are not unique to HIV-1 and pangolins are the most likely intermediate hosts for nCoV-2019 versus snakes.Understanding the infection mechanisms as well as the identity of the intermediate host is important for controlling and treating the spread of the novel coronavirus.Basic scienceFour insertions in nCoV-2019 previously reported are not unique to HIV-1 and are present in other viruses. Metagenomic assembly of pangolin-derived CoV covers 73% of the nCoV-2019 genome with 91% sequence identity, implicating the pangolin as the most likely intermediate host, contradicting results pointing to snakes through relative synonymous codon usage (RSCU), demonstrated by the authors as an ineffective means to identify intermediate hosts.
Aerodynamic Characteristics and RNA Concentration of SARS-CoV-2 Aerosol in Wuhan Hospitals during COVID-19 OutbreakbioRxiv3/10/20BiologyThe virus aerosol deposition on protective apparel or floor surface and their subsequent resuspension is a potential transmission pathwayaerosol transmission of SARS-CoV-2 has been
little studied
Basic science1) RNA concentration of SARS-CoV-2 in aerosol: 19 copies m^-3 in patient mobile toilet room, 18-42 copies m^-3 in the Protective Apparel Removal Rooms (both in Fangcang hospital; viral copies in PARRs dropped with reduced staff and more stringent sanitization); over 3 copies m^-3 in crowd gathering sites (Renmin hospital). 2) Size of particles carrying viral RNA peak at 0.25-1µm in PPARs, and above 2.5µm in staff office. 3) Area normalized deposition rate inside ICU is between 31 - 113 copies m^-2 hour^-1.
Age-Associated B CellsAnn Rev of Immunology1/27/20BiologyVaccine aimed toward efficacy in elderly should consider the more dominant ABCs in their B cell pools Ideas, editorials, reviews or opinionsB cell subset ABC increase with age. ABCs contribute to damped B cell genesis, altered immune responses to both primary and recall antigen challenges, and an increasing overall inflammatory climate. ABCs are elevated in autoimmune and autoinflammatory diseases, and their diminution has been associated with clinical response.
An infectious cDNA clone of SARS-CoV-2Cell Host MicrobeBiologyA U.S. patient derived full genome cDNA plasmid for SARS-CoV-2 was developed and has a similar replication profile to the original viral samples. From this, a fluorescent reporter virus was also derived.Infectious viral constructs allow for basic biology and drug and vaccine development.Basic scienceViral samples from the first U.S. COVID-19 patients were passaged in vitro, viral RNA was extracted and reverse transcribed, and complete viral genomic cDNA was ligated and cloned into a plasmid. In vitro transcription of the plasmid produced infectious RNA with similar replication kinetics to the original sample. A mNeonGreen reporter was inserted into an viral open-reading frame. The reporter gene was stable over 5 passages.