Хроники Попокалипсиса (COVID-19, science, EN)

[vit_r]

This is a collection of interesting quotas in English as a supplement to the long list of quotation in Russian.

Some referenced articles and preprints explain the information that was already mentioned, some add new information or interesting insights.

Note, the articles mention not only COVID-19 and SARS-CoV-2 but also SARS-CoV and MERS-CoV. This means, a lot of information was already present before current pandemic outbreak.

Bats

Mechanism behind low cancer occurrence in bats signals potential treatment strategies for humans

Researchers from Duke-NUS Medical School have uncovered a potential mechanism behind cancer suppression in bats that may lead to future therapies for human cancers. The research shows that bat cells accumulate less toxic chemicals than human cells, where these chemicals are moved out of the system mediated by a cell surface pump protein, known as ABCB1, that is more abundant and widely distributed in bat tissue than in humans.

Epedimeology

Editor’s Note: This article was published on January 29, 2020, at NEJM.org.

On the basis of this information, there is evidence that human-to-human transmission has occurred among close contacts since the middle of December 2019. Considerable efforts to reduce transmission will be required to control outbreaks if similar dynamics apply elsewhere. Measures to prevent or reduce transmission should be implemented in populations at risk. (Funded by the Ministry of Science and Technology of China and others.)

Temporal dynamics in viral shedding and transmissibility of COVID-19

We observed the highest viral load in throat swabs at the time of symptom onset, and inferred that infectiousness peaked on or before symptom onset. We estimated that 44% (95% confidence interval, 25–69%) of secondary cases were infected during the index cases’ presymptomatic stage, in settings with substantial household clustering, active case finding and quarantine outside the home.

Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study

Between Jan 22, 2020, and Feb 12, 2020, 30 patients were screened for inclusion, of whom 23 were included (median age 62 years [range 37–75]). The median viral load in posterior oropharyngeal saliva or other respiratory specimens at presentation was 5·2 log10 copies per mL (IQR 4·1–7·0). Salivary viral load was highest during the first week after symptom onset and subsequently declined with time (slope −0·15, 95% CI −0·19 to −0·11; R2=0·71). In one patient, viral RNA was detected 25 days after symptom onset. Older age was correlated with higher viral load (Spearman's ρ=0·48, 95% CI 0·074–0·75; p=0·020). For 16 patients with serum samples available 14 days or longer after symptom onset, rates of seropositivity were 94% for anti-NP IgG (n=15), 88% for anti-NP IgM (n=14), 100% for anti-RBD IgG (n=16), and 94% for anti-RBD IgM (n=15). Anti-SARS-CoV-2-NP or anti-SARS-CoV-2-RBD IgG levels correlated with virus neutralisation titre (R2>0·9). No genome mutations were detected on serial samples.

Modes of contact and risk of transmission in COVID-19 among close contacts

Secondary cases were in general clinically milder and were less likely to have common symptoms than those of source cases. Conclusions In conclusion, the proportion of asymptomatic and mild infections account for almost half of the confirmed cases among close contacts. The household contacts were the main transmission mode, and clinically more severe cases were more likely to pass the infection to their close contacts. Generally, the secondary cases were clinically milder than those of source cases.

Impact of changing case definitions for COVID-19 on the epidemic curve and transmission parameters in mainland China

From January through to early March 2020, seven versions of the case definition for COVID-19 were issued by the National Health Commission in China.
...
The case definition was initially narrow, but was gradually broadened to allow detection of more cases as knowledge increased, particularly milder cases and those without epidemiological links to Wuhan or other known cases. This should be taken into account when making inferences on epidemic growth rates and doubling times, and therefore on the reproductive number, to avoid bias.

Flocked swab might be one main reason causing the high false-negative rate in COVID-19 screening----the advantages of a novel silicone swab

RNA testing using RT-PCR can provide direct evidence for diagnoses of COVID-19 which has brought unexpected disasters and changes to our human society. However, the absorption of cotton swab for RNA lysates may lead to a low concentration of detectable RNA, which might be one of the main reasons for the unstable positive detecting rate.

Coronavirus: Turkey says hydroxychloroquine dramatically reduces pneumonia cases

Turkey has made significant progress in treating coronavirus patients in the early stages of the disease with the controversial malaria drug hydroxychloroquine, Turkish officials have said.

“Turkey had stockpiled one million units of them before the first case appeared in the country,” Turkish Health Minister Fahrettin Koca said on Tuesday evening in a live broadcast, without specifying the name of the drug.

“Many countries prescribe this drug to intubated patients,” Koca said. “However, our science board suggested that the drug is really beneficial in the early stages to prevent the spread of the virus in the body.”
...
“We believe beginning early treatment [with this drug] played a big role in reducing the rate of lung infection among the patients,” he said.

Chest CT Findings in Cases from the Cruise Ship “Diamond Princess” with Coronavirus Disease 2019 (COVID-19)

- Of 104 cases analyzed,
76 (73%) were asymptomatic,
41 (54%) of which had pneumonic changes on CT.
Other 28 (27%) cases were symptomatic,
22 (79%) of which had abnormal CT findings.

- Asymptomatic cases showed more GGO predominance over consolidation (83%),
while symptomatic cases were more likely to show a consolidation predominance over GGO (41%).

- Asymptomatic cases showed milder CT severity score than symptomatic cases.

CT - computed tomography

GGO - Ground-glass opacity

Epidemiological characteristics of COVID-19 cases in Italy and estimates of the reproductive numbers one month into the epidemic

Estimates of R0 varied between 2.5 (95%CI: 2.18-2.83) in Toscana
and 3 (95%CI: 2.68-3.33) in Lazio,
with epidemic doubling time of 3.2 days (95%CI: 2.3-5.2)
and 2.9 days (95%CI: 2.2-4.3), respectively.
The net reproduction number showed a decreasing trend starting around February 20-25, 2020 in northern regions.
Notably, 5,760 cases were reported among health care workers.

Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy

Results Of the 1591 patients included in the study, the median (IQR) age was 63 (56-70) years and 1304 (82%) were male.

Of the 1043 patients with available data,
709 (68%) had at least 1 comorbidity
and 509 (49%) had hypertension.

Among 1300 patients with available respiratory support data,
1287 (99% [95% CI, 98%-99%]) needed respiratory support,
including 1150 (88% [95% CI, 87%-90%]) who received mechanical ventilation
and 137 (11% [95% CI, 9%-12%]) who received noninvasive ventilation.
...
Conclusions and Relevance In this case series of critically ill patients with laboratory-confirmed COVID-19 admitted to ICUs in Lombardy, Italy, the majority were older men, a large proportion required mechanical ventilation and high levels of PEEP, and ICU mortality was 26%.

Reported outcomes among COVID-19 patients of all ages, by hospitalization status, underlying health condition, and risk factor for severe outcome from respiratory infection — United States, February 12–March 28, 2020

Total with completed information (7,162)
Former smoker (165, 2.3%)
Current smoker (96, 1.3%)

Insights into The Codon Usage Bias of 13 Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Isolates from Different Geo-locations

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of Coronavirus disease 2019 (COVID-19) which is an infectious disease that spread throughout the world and was declared as a pandemic by the World Health Organization (WHO). In the present study, we analyzed genome-wide codon usage patterns in 13 SARS-CoV-2 isolates from 13 different geo-locations (countries) by utilizing different CUB measurements.
...
According to their results, natural selection and/or other factors (not investigated in this study) may be the dominant force driving SARS-CoV-2 CUB. It is also worth mentioning that, by using the most expressed genes in human lung tissues, some genes such as Nucleocapsid phosphoprotein, ORF7a protein, and surface glycoprotein had high CAI values which may indicate for selection force acting on their codon usage, as they play important roles in viral assembly and may help viruses avoid the host immune system.

Temperature and Latitude Analysis to Predict Potential Spread and Seasonality for COVID-19

A significant number of infectious diseases display seasonal patterns in their incidence, including human coronaviruses. We hypothesize that SARS-CoV-2 does as well. To date, Coronavirus Disease 2019 (COVID-19), caused by SARS-CoV-2, has established significant community spread in cities and regions only along a narrow east west distribution roughly along the 30-50 N” corridor at consistently similar weather patterns (5-11 degrees Celsius and low specific and absolute humidity).

Rising relapse cases raise alert amid virus infection slowdown

According to the Korea Centers for Disease Control and Prevention (KCDC), 116 people had been confirmed as relapsed COVID-19 cases as of Monday, up three from a day earlier. Health authorities are striving to find the cause of such cases that could possibly lead to a new source of infections.
...
Health authorities have said the virus was highly likely to have been reactivated, instead of the people being reinfected, as they tested positive again in a relatively short time after being released from quarantine.

They also said the COVID-19 virus may remain latent in certain cells in the body and attack the respiratory organs again once reactivated.

Masks

Respiratory virus shedding in exhaled breath and efficacy of face masks

Our results indicate that surgical face masks could prevent transmission of human coronaviruses and influenza viruses from symptomatic individuals.

A cluster randomised trial of cloth masks compared with medical masks in healthcare workers

The aim of this study was to compare the efficacy of cloth masks to medical masks in hospital healthcare workers (HCWs). The null hypothesis is that there is no difference between medical masks and cloth masks.
...
This study is the first RCT of cloth masks, and the results caution against the use of cloth masks. This is an important finding to inform occupational health and safety. Moisture retention, reuse of cloth masks and poor filtration may result in increased risk of infection. Further research is needed to inform the widespread use of cloth masks globally. However, as a precautionary measure, cloth masks should not be recommended for HCWs, particularly in high-risk situations, and guidelines need to be updated.

"Modeling the Effectiveness of Respiratory Protective Devices in Reducing Influenza Outbreak", Jing Yan, Suvajyoti Guha, Prasanna Hariharan, Matthew Myers, 19 September 2018

A risk assessment model previously developed in general form was used to estimate the effectiveness of different types of protective equipment in reducing the rate of infection in an influenza outbreak. It was found that a 50% compliance in donning the device resulted in a significant (at least 50% prevalence and 20% cumulative incidence) reduction in risk for fitted and unfitted N95 respirators, high‐filtration surgical masks, and both low‐filtration and high‐filtration pediatric masks. An 80% compliance rate essentially eliminated the influenza outbreak. The results of the present study, as well as the application of the model to related influenza scenarios, are potentially useful to public health officials in decisions involving resource allocation or education strategies.

Aerosol emission and superemission during human speech increase with voice loudness

Mechanistic hypotheses about airborne infectious disease transmission have traditionally emphasized the role of coughing and sneezing, which are dramatic expiratory events that yield both easily visible droplets and large quantities of particles too small to see by eye. Nonetheless, it has long been known that normal speech also yields large quantities of particles that are too small to see by eye, but are large enough to carry a variety of communicable respiratory pathogens. Here we show that the rate of particle emission during normal human speech is positively correlated with the loudness (amplitude) of vocalization, ranging from approximately 1 to 50 particles per second (0.06 to 3 particles per cm3) for low to high amplitudes, regardless of the language spoken (English, Spanish, Mandarin, or Arabic). Furthermore, a small fraction of individuals behaves as “speech superemitters,” consistently releasing an order of magnitude more particles than their peers. Our data demonstrate that the phenomenon of speech superemission cannot be fully explained either by the phonic structures or the amplitude of the speech. These results suggest that other unknown physiological factors, varying dramatically among individuals, could affect the probability of respiratory infectious disease transmission, and also help explain the existence of superspreaders who are disproportionately responsible for outbreaks of airborne infectious disease.

SARS-CoV-2 infection

Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV-Infected Mice

Highly pathogenic human respiratory coronaviruses cause acute lethal disease characterized by exuberant inflammatory responses and lung damage. However, the factors leading to lung pathology are not well understood. Using mice infected with SARS (severe acute respiratory syndrome)-CoV, we show that robust virus replication accompanied by delayed type I interferon (IFN-I) signaling orchestrates inflammatory responses and lung immunopathology with diminished survival. IFN-I remains detectable until after virus titers peak, but early IFN-I administration ameliorates immunopathology. This delayed IFN-I signaling promotes the accumulation of pathogenic inflammatory monocyte-macrophages (IMMs), resulting in elevated lung cytokine/chemokine levels, vascular leakage, and impaired virus-specific T cell responses. Genetic ablation of the IFN-αβ receptor (IFNAR) or IMM depletion protects mice from lethal infection, without affecting viral load. These results demonstrate that IFN-I and IMM promote lethal SARS-CoV infection and identify IFN-I and IMMs as potential therapeutic targets in patients infected with pathogenic coronavirus and perhaps other respiratory viruses.

IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes

Type 1 IFNs (IFN-I) generally protect mammalian hosts from virus infections, but in some cases, IFN-I is pathogenic. Because IFN-I is protective, it is commonly used to treat virus infections for which no specific approved drug or vaccine is available. The Middle East respiratory syndrome–coronavirus (MERS-CoV) is such an infection, yet little is known about the role of IFN-I in this setting. Here, we show that IFN-I signaling is protective during MERS-CoV infection. Blocking IFN-I signaling resulted in delayed virus clearance, enhanced neutrophil infiltration, and impaired MERS-CoV–specific T cell responses. Notably, IFN-I administration within 1 day after infection (before virus titers peak) protected mice from lethal infection, despite a decrease in IFN-stimulated gene (ISG) and inflammatory cytokine gene expression. In contrast, delayed IFN-β treatment failed to effectively inhibit virus replication; increased infiltration and activation of monocytes, macrophages, and neutrophils in the lungs; and enhanced proinflammatory cytokine expression, resulting in fatal pneumonia in an otherwise sublethal infection. Together, these results suggest that the relative timing of the IFN-I response and maximal virus replication is key in determining outcomes, at least in infected mice. By extension, IFN-αβ or combination therapy may need to be used cautiously to treat viral infections in clinical settings.

On the interactions of the receptor-binding domain of SARS-CoV-1 and SARS-CoV-2 spike proteins with monoclonal antibodies and the receptor ACE2

Analyzing the interactions between these RBD proteins and the SARS-CoV-1 S RBD specific neutralizing mAbs (80R, F26G19, m396, CR3022) allowed us to reproduce the experimental results. The only mAb with measured affinities for the SARS-CoV-2 S RBD protein by BLI assay was CR30208 which was also the one with higher affinity quantified in the present theoretical study. Moreover, we could map their electrostatic epitopes and identify that all mAbs tend to share the same titratable residues, and they are like the residues involved in the interaction with ACE2. However, the RBD protein responsible for COVID-19 clearly has more titratable residues interacting with ACE2 than its precursor suggesting that its binding to ACE2 might be less specific. This can explain the general difficulty that mAbs can experience to completely block the SARS-CoV-2 S RBD-ACE2 interaction.

SARS-CoV-2 invades host cells via a novel route: CD147-spike protein

Currently, COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been widely spread around the world; nevertheless, so far there exist no specific antiviral drugs for treatment of the disease, which poses great challenge to control and contain the virus. Here, we reported a research finding that SARS-CoV-2 invaded host cells via a novel route of CD147-spike protein (SP). SP bound to CD147, a receptor on the host cells, thereby mediating the viral invasion. Our further research confirmed this finding. First, in vitro antiviral tests indicated Meplazumab, an anti-CD147 humanized antibody, significantly inhibited the viruses from invading host cells, with an EC50 of 24.86 μg/mL and IC50 of 15.16 μg/mL. Second, we validated the interaction between CD147 and SP, with an affinity constant of 1.85×10−7M. Co-Immunoprecipitation and ELISA also confirmed the binding of the two proteins. Finally, the localization of CD147 and SP was observed in SARS-CoV-2 infected Vero E6 cells by immuno-electron microscope. Therefore, the discovery of the new route CD147-SP for SARS-CoV-2 invading host cells provides a critical target for development of specific antiviral drugs.

SARS-CoV-2 infects T lymphocytes through its spike protein-mediated membrane fusion

Based on the results of pseudovirus and live virus infection, here we proved that
(1) SARS-CoV-2 could infect T cells,
(2) SARS-CoV-2 infected T cells through receptor-dependent, S protein-mediated membrane fusion,
and (3) infection could be inhibited by EK1 peptide.
However, we observed a very low expression level of hACE2 in T cells; therefore, we further proposed that a novel receptor might mediate SARS-CoV-2 entry into T cells.
...
This result could be attributed to nonproductive replication of SARS-CoV-2 in T lymphocytes, with little viral genome in PBMCs possibly degrading in the sample collection and RNA extraction process. Thus, the questions of SARS-CoV-2 infection and replication in primary T cells and whether the infection induces apoptosis in T cells still need further research, potentially evoking new ideas about pathogenic mechanisms and therapeutic interventions.

The Curious Case of the Nidovirus Exoribonuclease: Its Role in RNA Synthesis and Replication Fidelity

Among RNA viruses, the order Nidovirales stands out for including viruses with the largest RNA genomes currently known. Nidoviruses employ a complex RNA-synthesizing machinery comprising a variety of non-structural proteins (nsps). One of the postulated drivers of the expansion of nidovirus genomes is the presence of a proofreading 3′-to-5′ exoribonuclease (ExoN) belonging to the DEDDh family. ExoN may enhance the fidelity of RNA synthesis by correcting nucleotide incorporation errors made by the RNA-dependent RNA polymerase. Here, we review our current understanding of ExoN evolution, structure, and function. Most experimental data are derived from studies of the ExoN domain of coronaviruses (CoVs), which were triggered by the bioinformatics-based identification of ExoN in the genome of severe acute respiratory syndrome coronavirus (SARS-CoV) and its relatives in 2003. Although convincing data supporting the proofreading hypothesis have been obtained, from biochemical assays and studies with CoV mutants lacking ExoN functionality, the features of ExoN from most other nidovirus families remain to be characterized. Remarkably, viable ExoN knockout mutants were obtained only for two CoVs, mouse hepatitis virus (MHV) and SARS-CoV, whose RNA synthesis and replication kinetics were mildly affected by the lack of ExoN function. In several other CoV species, ExoN inactivation was not tolerated, and knockout mutants could not be rescued when launched using a reverse genetics system. This suggests that ExoN is also critical for primary viral RNA synthesis, a property that poorly matches the profile of an enzyme that would merely boost long-term replication fidelity. In CoVs, ExoN resides in a bifunctional replicase subunit (nsp14) whose C-terminal part has (N7-guanine)-methyltransferase activity. The crystal structure of SARS-CoV nsp14 has shed light on the interplay between these two domains, and on nsp14’s interactions with nsp10, a co-factor that strongly enhances ExoN activity in vitro assays. Further elucidation of the structure-function relationships of ExoN and its interactions with other (viral and/or host) members of the CoV replication machinery will be key to understanding the enzyme’s role in viral RNA synthesis and pathogenesis, and may contribute to the design of new approaches to combat emerging nidoviruses.

Angiotensin-converting enzyme 2 (ACE2)

Note, ACE inhibitors are heart medications that widen, or dilate, blood vessels. This are commonly prescribed medications and they increase the numbers of ACE2 receptors.

Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis, Copyright © 2004

Severe acute respiratory syndrome (SARS) is an acute infectious disease that spreads mainly via the respiratory route. A distinct coronavirus (SARS‐CoV) has been identified as the aetiological agent of SARS. Recently, a metallopeptidase named angiotensin‐converting enzyme 2 (ACE2) has been identified as the functional receptor for SARS‐CoV. Although ACE2 mRNA is known to be present in virtually all organs, its protein expression is largely unknown. Since identifying the possible route of infection has major implications for understanding the pathogenesis and future treatment strategies for SARS, the present study investigated the localization of ACE2 protein in various human organs (oral and nasal mucosa, nasopharynx, lung, stomach, small intestine, colon, skin, lymph nodes, thymus, bone marrow, spleen, liver, kidney, and brain). The most remarkable finding was the surface expression of ACE2 protein on lung alveolar epithelial cells and enterocytes of the small intestine. Furthermore, ACE2 was present in arterial and venous endothelial cells and arterial smooth muscle cells in all organs studied. In conclusion, ACE2 is abundantly present in humans in the epithelia of the lung and small intestine, which might provide possible routes of entry for the SARS‐CoV. This epithelial expression, together with the presence of ACE2 in vascular endothelium, also provides a first step in understanding the pathogenesis of the main SARS disease manifestations.

The scRNA-seq expression profiling of the receptor ACE2 and the cellular protease TMPRSS2 reveals human organs susceptible to COVID-19 infection

Findings:
For the first time, we found the brain, gall bladder, and fallopian tube are vulnerable to COVID-19 infection. Besides, the nose, heart, small intestine, large intestine, esophagus, testis and kidney are also identified to be high-risk organs with high expression levels of ACE2 and TMPRSS2. Moreover, the susceptible organs are grouped into three risk levels based on the TMPRSS2 expression. As a result, the respiratory system, digestive system and reproductive system are at the top-risk level to COVID-19 infection.

Interpretation:
This study provides evidence for COVID-19 infection in the human nervous system, digestive system, reproductive system, respiratory system, circulatory system and urinary system using scRNA-seq data, which helps for the clinical diagnosis and treatment of patients.

Human Kidney is a Target for Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection

27.06% (23/85) patients exhibited acute renal failure (ARF). The eldery patients and cases with comorbidities such as hypertension and heart failure more easily developed ARF (65.22% vs 24.19%, p< 0.001; 69.57% vs 11.29%, p< 0.001, respectively). H&E staining demonstrated kidney tissues from postmortems have severe acute tubular necrosis and lymphocyte infiltration. Immunohistochemistry showed that SARS-CoV-2 NP antigen was accumulated in kidney tubules. EM observation also demonstrated that viruses- like particles are visible in the kidneys. Viral infection not only induces CD68+ macrophages infiltrated into tubulointerstitium, but also enhances complement C5b-9 deposition on tubules.

CONCLUSIONS

SARS-CoV-2 induces ARF in COVID-19 patients. Viruses directly infect human kidney tubules to induce acute tubular damage. The viruses not only have direct cytotoxicity, but also initiate CD68+ macrophage together with complement C5b-9 deposition to mediate tubular pathogenesis.

Treatment

The Antiviral Compound Remdesivir Potently Inhibits RNA-dependent RNA Polymerase From Middle East Respiratory Syndrome Coronavirus

Antiviral drugs for managing infections with human coronaviruses are not yet approved, posing a serious challenge to current global efforts aimed at containing the outbreak of severe acute respiratory syndrome-coronavirus 2 (CoV-2). Remdesivir (RDV) is an investigational compound with a broad spectrum of antiviral activities against RNA viruses, including severe acute respiratory syndrome-CoV and Middle East respiratory syndrome (MERS-CoV). RDV is a nucleotide analog inhibitor of RNA-dependent RNA polymerases (RdRps). Here, we co-expressed the MERS-CoV nonstructural proteins nsp5, nsp7, nsp8, and nsp12 (RdRp) in insect cells as a part a polyprotein to study the mechanism of inhibition of MERS-CoV RdRp by RDV. We initially demonstrated that nsp8 and nsp12 form an active complex. The triphosphate form of the inhibitor (RDV-TP) competes with its natural counterpart ATP. Of note, the selectivity value for RDV-TP obtained here with a steady-state approach suggests that it is more efficiently incorporated than ATP and two other nucleotide analogs. Once incorporated at position i, the inhibitor caused RNA synthesis arrest at position i + 3. Hence, the likely mechanism of action is delayed RNA chain termination. The additional three nucleotides may protect the inhibitor from excision by the viral 3'-5' exonuclease activity. Together, these results help to explain the high potency of RDV against RNA viruses in cell-based assays.

https://www.jbc.org/content/295/15/4773.full.pdf

In vitro screening of a FDA approved chemical library reveals potential inhibitors of SARS-CoV-2 replication

As no approved therapeutics exists to treat Covid-19, the disease associated to SARS-Cov-2, there is an urgent need to propose molecules that could quickly enter into clinics. Repurposing of approved drugs is a strategy that can bypass the time consuming stages of drug development.
...
By providing new information on molecules inhibiting SARS-CoV-2 replication in vitro, this study could contribute to the short-term repurposing of drugs against Covid-19.

Amantadine disrupts lysosomal gene expression; potential therapy for COVID19

SARS-coronavirus 2 is the causal agent of the COVID-19 outbreak. SARS-Cov-2 entry into a cell is dependent upon binding of the viral spike (S) protein to cellular receptor and on cleavage of the spike protein by the host cell proteases such as Cathepsin L and Cathepsin B. CTSL/B are crucial elements of lysosomal pathway and both enzymes are almost exclusively located in the lysosomes.CTSL disruption offers potential for CoVID-19 therapies. The mechanisms of disruption include: decreasing expression of CTSL, direct inhibition of CTSL activity and affecting the conditions of CTSL environment (increase pH in lysosomes). We have conducted a high throughput drug screen gene expression analysis to identify compounds that would downregulate the expression of CTSL/CTSB. One of the top significant results shown to downregulate the expression of the CTSL gene is Amantadine.

LY6E impairs coronavirus fusion and confers immune control of viral disease

doi: https://doi.org/10.1101/2020.03.05.979260

Our results demonstrate that LY6E is a critical antiviral immune effector that controls CoV infection and pathogenesis. 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 CoV.

Tocilizumab treatment in severe COVID-19 patients attenuates the inflammatory storm incited by monocyte centric immune interactions revealed by single-cell analysis

Approximately 14% of patients with COVID-19 experienced severe disease and 5% were critically ill. Studies have shown that dysregulation of the COVID-19 patients' immune system may lead to inflammatory storm and cause severe illness and even death. Tocilizumab treatment targeting interleukin 6 receptor has shown inspiring clinical results of severe COVID-19 patients.

COVID-19 and treatment with NSAIDs and corticosteroids: should we be limiting their use in the clinical setting?

Given the current SARS-CoV-2 (COVID-19) pandemic, the availability of reliable information for clinicians and patients is paramount. There have been a number of reports stating that non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids may exacerbate symptoms in COVID-19 patients. Therefore, this review aimed to collate information available in published articles to identify any evidence behind these claims with the aim of advising clinicians on how best to treat patients. This review found no published evidence for or against the use of NSAIDs in COVID-19 patients. Meanwhile, there appeared to be some evidence that corticosteroids may be beneficial if utilised in the early acute phase of infection, however, conflicting evidence from the World Health Organisation surrounding corticosteroid use in certain viral infections means this evidence is not conclusive. Given the current availability of literature, caution should be exercised until further evidence emerges surrounding the use of NSAIDs and corticosteroids in COVID-19 patients.

A SARS-CoV-2 Vaccination Strategy Focused on Population-Scale Immunity

Here we propose a vaccination strategy for SARS-CoV-2 based on identification of both highly conserved regions of the virus and newly acquired adaptations that are presented by MHC class I and II across the vast majority of the population, are highly dissimilar from the human proteome, and are predicted B cell epitopes. We present 65 peptide sequences that we expect to result in a safe and effective vaccine which can be rapidly tested in DNA, mRNA, or synthetic peptide constructs. These include epitopes that are contained within evolutionarily divergent regions of the spike protein reported to increase infectivity through increased binding to the ACE2 receptor, and within a novel furin cleavage site thought to increase membrane fusion. This vaccination strategy specifically targets unique vulnerabilities of SARS-CoV-2 and should engage a robust adaptive immune response in the vast majority of the human population.

The SARS-CoV-2 receptor-binding domain elicits a potent neutralizing response without antibody-dependent enhancement

These data suggest that an RBD-based vaccine for SARS-CoV-2 could be safe and effective.

Links

How to Obtain a Nasopharyngeal Swab Specimen (Video)

Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma.

COVID-19 and Coagulopathy: Frequently Asked Questions

Genomic epidemiology of novel coronavirus

Intensivregister, Aktuelle Belegungssituation intensivmedizinischer Bereiche der Kliniken Deutschlands (German intensive care stations)

CORONAVIRUS ANTIVIRAL RESEARCH DATABASE, Targeted antivirals, investigational agents, monoclonal antibodies, interferons, repurposed drugs, and promising leads.

Comments

[juan_gandhi]

Спасибо.