COVID-19 Susceptibility By Race, Blood Type

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COVID-19 Susceptibility By Race, Blood Type Apr 21, 2020 6:19:54 GMT

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Post by Admin on Apr 21, 2020 6:19:54 GMT

Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations

Yanan Cao, Lin Li, Zhimin Feng, Shengqing Wan, Peide Huang, Xiaohui Sun, Fang Wen, Xuanlin Huang, Guang Ning & Weiqing Wang

Cell Discovery volume 6, Article number: 11 (2020)

The ACE2 gene encodes the angiotensin-converting enzyme-2, which has been proved to be the receptor for both the SARS-coronavirus (SARS-CoV) and the human respiratory coronavirus NL63. Recent studies and analyses indicate that ACE2 could be the host receptor for the novel coronavirus 2019-nCoV/SARS-CoV-21,2. Previous studies demonstrated the positive correlation of ACE2 expression and the infection of SARS-CoV in vitro3,4. A number of ACE2 variants could reduce the association between ACE2 and S-protein in SARS-CoV or NL635. Therefore, the expression level and expression pattern of human ACE2 in different tissues might be critical for the susceptibility, symptoms, and outcome of 2019-nCoV/SARS-CoV-2 infection. A recent single-cell RNA-sequencing (RNA-seq) analysis indicated that Asian males may have higher expression of ACE26. Currently, the clinical reports of 2019-nCoV/SARS-CoV-2 infection from non-Asian populations for comparison are very limited. A study from Munich reported four German cases, all of which showed mild clinical symptoms without severe illness7. However, the genetic basis of ACE2 expression and function in different populations is still largely unknown. Therefore, genetic analysis of expression quantitative trait loci (eQTLs)8 and potential functional coding variants in ACE2 among populations are required for further epidemiological investigations of 2019-nCoV/SARS-CoV-2 spreading in East Asian (EAS) and other populations.

To systematically investigate the candidate functional coding variants in ACE2 and the allele frequency (AF) differences between populations, we analyzed all the 1700 variants (Supplementary Table S1) in ACE2 gene region from the ChinaMAP (China Metabolic Analytics Project, under reviewing) and 1KGP (1000 Genomes Project)9 databases. The AFs of 62 variants located in the coding regions of ACE2 in ChinaMAP, 1KGP, and other large-scale genome databases were summarized (Supplementary Table S2). All of the 32 variants potentially affecting the amino acid sequence of ACE2 in databases were shown (Fig. 1a). Previous study showed that the residues near lysine 31, and tyrosine 41, 82–84, and 353–357 in human ACE2 were important for the binding of S-protein in coronavirus5. The mutations in these residues were not found in different populations in our study. Only a singleton truncating variant of ACE2 (Gln300X) was identified in the ChinaMAP (Fig. 1a). These data suggested that there was a lack of natural resistant mutations for coronavirus S-protein binding in populations. The effects of low-frequency missense variants in populations for S-protein binding could be further investigated. The distributions of seven hotspot variants (Lys26Arg, Ile468Val, Ala627Val, Asn638Ser, Ser692Pro, Asn720Asp, and Leu731Ile/Leu731Phe) in different populations were shown (Fig. 1b). Six low-frequency loci (rs200180615, rs140473595, rs199951323, rs147311723, rs149039346, and rs73635825) were found to be specific in 1KGP database, the AFs of which were also low in the gnomAD and TopMed10 database. Only two of these six variants (rs200180615 and rs140473595) could be found in CHB (Han Chinese in Beijing) population with the AF < 0.01. Interestingly, the SNP rs2285666 with the highest AF in the 62 variants exhibited much higher AF in the ChinaMAP (0.556) and CHS (Han Chinese South, 0.557) populations compared to others (AMR, Ad Mixed American, 0.336; AFR, African, 0.2114; EUR, European, 0.235). In addition, the homozygous mutation rate in males (0.550) was much higher than females (0.310) in the Chinese population (Supplementary Table S2). Taken together, the differences in AFs of ACE2 coding variants among different populations suggested that the diverse genetic basis might affect ACE2 functions among populations.

Fig. 1: The coding-region variants and eQTL variants for ACE2 in East Asian and other populations.

a Schematics of 32 coding variants in ACE2 identified in the ChinaMAP and 1KGP databases. Yellow stars indicate the nonsense variants; dots indicate the missense variants. The number of samples with hotspot variants was marked. b The distribution of hotspot missense mutations of ACE2 in different populations. The colors indicate different populations. c The distribution and the allele frequencies of representative eQTL variants for ACE2 in different populations. Pie charts depict the allele frequencies of an intron variant of ACE2 (rs4646127) in the world. Orange color denotes the frequency of alteration allele, and blue color denotes the reference allele. The allele frequencies of 15 eQTLs for ACE2 gene are shown in tables. The color gradient from blue to red indicates the increasing of allele frequencies. The allele frequencies of INDEL variant rs200781818 were annotated by the gnomAD database. EAS, East Asian; EUR, European; AFR, African; SAS, South Asian; AMR, Ad Mixed American.

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To analyze the distribution of eQTLs for ACE2, we used the Genotype Tissue Expression (GTEx) database (https://www.gtexportal.org/home/datasets). We found 15 unique eQTL variants (14 SNPs and 1 INDELs) for ACE2 with q value ≤ 0.05 in 20 tissues from the GTEx database (rs112171234, rs12010448, rs143695310, rs1996225, rs200781818, rs2158082, rs4060, rs4646127, rs4830974, rs4830983, rs5936011, rs5936029, rs6629110, rs6632704, and rs75979613). The AFs of the 15 eQTL variants were compared among different populations. Notably, our results showed most of the 15 eQTL variants had much higher AFs in the ChinaMAP dataset and EAS populations compared to European populations (Fig. 1c and Supplementary Table S3). The AFs of the top 6 common variants (rs4646127, rs2158082, rs5936011, rs6629110, rs4830983, and rs5936029) were higher than 95% in EAS populations, whereas the AFs of these variants in European populations were much lower (52%–65%). All of the 11 common variants (AF > 0.05) and 1 rare variant (rs143695310) in the 15 eQTLs are associated with high expression of ACE2 in tissues (Supplementary Table S3). For instance, the eQTL variant rs4646127 (log allelic fold change = 0.314), which locates in the intron of ACE2 gene, has the highest AFs in both of the ChinaMAP (0.997) and EAS (0.994) populations. Comparatively, the AFs of rs4646127 in EUR (0.651) and AMR (0.754) populations are much lower. These findings suggested the genotypes of ACE2 gene polymorphism may be associated higher expression levels of ACE2 in EAS population.

Recent reports of the ACE2 expression analysis in lung tissues from Asian and Caucasian populations are still controversial. The single-cell RNA-seq analysis reported that the Asian donor had much higher ACE2 expression cell ratio than white and African-American donors6. In contrast, the ACE2 expression analysis using the RNA-seq and microarray datasets from control lung tissues indicated there were no significant differences between Asian and Caucasian, or male and female11. The ACE2-expressing cells are a very small part of cells in lung tissues6. The sample size and the purity of ACE2-positive cells in the selected samples would influence the conclusions. Our analysis showed the differences in distribution and AFs of eQTLs for ACE2 in different populations, indicating the diversity of ACE2 expression pattern in populations (Supplementary Table S3). Large-scale and multiple tissue-level analysis of single-cell RNA-seq would be more accurate for the expression analysis of ACE2 in different populations. In addition, our data showed the moderate difference in AFs of eQTLs between South Asian and EAS, which suggests the potential difference of ACE2 expression in different populations and ethnics in Asia (Fig. 1c).

In summary, we systematically analyzed coding-region variants in ACE2 and the eQTL variants, which may affect the expression of ACE2 using the GTEx database to compare the genomic characteristics of ACE2 among different populations. Our findings indicated that no direct evidence was identified genetically supporting the existence of coronavirus S-protein binding-resistant ACE2 mutants in different populations (Fig. 1a). The data of variant distribution and AFs may contribute to the further investigations of ACE2, including its roles in acute lung injury and lung function12. The East Asian populations have much higher AFs in the eQTL variants associated with higher ACE2 expression in tissues (Fig. 1c), which may suggest different susceptibility or response to 2019-nCoV/SARS-CoV-2 from different populations under the similar conditions.

Cao, Y., Li, L., Feng, Z. et al. Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations. Cell Discov 6, 11 (2020). doi.org/10.1038/s41421-020-0147-1

Last Edit: Jun 20, 2020 7:57:10 GMT by Admin

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COVID-19 Susceptibility By Race, Blood Type May 14, 2020 0:25:24 GMT

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Post by Admin on May 14, 2020 0:25:24 GMT

Before it can sicken people, the new coronavirus must first sneak into their cells. But not any cell will do. The virus can enter only those with a certain combination of molecules on their surfaces.

Earlier this year, a group of scientists from across the Human Cell Atlas project realized they could look for these molecules on cells throughout the body — using data they had already collected from healthy people.

With information from more than 4 million human cells from people of many different ages, the scientists identified places the virus, called SARS-CoV-2, may invade the body. Their findings suggest that the virus may be able to enter more kinds of cells than previously thought. The work also offers hints about two central SARS-CoV-2 questions: How the virus can harm so many different organs and why some people are more vulnerable to infection. The team posted a preliminary analysis on bioRxiv on April 20, 2020.

A massive collaboration of nearly 200 scientists made this effort possible, says Aviv Regev, one of the collaborators and a Howard Hughes Medical Institute Investigator at the Massachusetts Institute of Technology. “By rallying together and sharing data collected for other purposes, we could draw conclusions we could not have gotten any other way,” she says. “This happened because of SARS-CoV-2. And the Human Cell Atlas network helped us pivot quickly. Science normally doesn’t work like this.”

A comprehensive picture
Regev, like most of the scientists involved in the project, is part of the Human Cell Atlas. Starting in 2016, the Atlas brought together biologists from around the world to thoroughly describe every cell type in the body. Doing so required them to collect and share data.

As COVID-19, the illness caused by the virus, spread, lung-cell researchers decided to see what they could learn from information they had at hand, says Martijn Nawijn, an Atlas member who studies chronic respiratory diseases at the University of Groningen in the Netherlands. “We had already been collaborating, and the infrastructure was already there, so we could respond quickly,” he says. The effort rapidly expanded to include additional parts of the body.

The researchers had previously collected RNA expression levels from individual cells using a technique called single cell RNA-Seq. This data let them identify the expression of genes that encode molecules on the cells’ surfaces – a crucial bit of information for scientists studying SARS-CoV-2. The virus uses two such molecules to enter cells: a receptor called ACE2 and an enzyme known as a protease.

The scientists wanted to survey the body for cells with both molecules; these cells are potentially vulnerable to SARS-CoV-2 infection. Each lab typically had single cell RNA-seq data from only a relatively small number of individuals, so groups of scientists got together to collaborate. The team’s analysis currently incorporates 117 datasets, including 22 for the lung and airways, although an additional 10 datasets are being added, Nawijn says.

So far, the collaboration has yielded four papers. One, published April 23 in Nature Medicine, used more limited data to pinpoint certain nasal cells as likely sites for viral infection and transmission. The bioRxiv paper, which has not yet gone through the scientific vetting process known as peer review, sketches out a more comprehensive picture.

Clues to a complex illness
COVID-19 kills many patients by severely damaging their lungs, but it has become increasingly clear that the disease causes injury elsewhere, too, and that may also lead to death. Even patients with mild cases can experience loss of smell and taste, sometimes diarrhea, and rarely skin lesions. Meanwhile, patients with severe illness can experience heart and kidney failure, spontaneous blood clots, stroke, and even seizures. No one fully understands why, but the team’s findings could help.

“The data has good clues to several of COVID-19’s conundrums, including the wide-ranging organ involvement seen in our patients,” says Naftali Kaminski, a physician scientist and Atlas member. Kaminski is the chief of pulmonary, critical care and sleep medicine at Yale University Medical School, and his physician faculty are at the forefront of caring for critically ill patients with COVID-19. In the analysis, for example, the key entry molecules turned up in tissues across the body, from cells lining the lung, to cells in the heart, brain, and kidney. This potentially explains how, if kept unchecked, the virus spreads and damages the body organ by organ.

The new study also offers hints about the immune response’s contribution to the disease. Doctors have noted that COVID-19 can send the immune system into overdrive, prompting harm to the body. In fact, cells with the viral entry molecules also expressed immune genes poised for action, the scientists found. These genes could potentially contribute to the body’s overreaction, says Kaminski.

Other distinct patterns have emerged in the pandemic: the illness more severely affects men, older people, and smokers. The team wanted to see if these differences showed up at the cellular level. Their comparisons revealed that the two molecules are generally present at higher levels in men, and levels tend to increase with age. The effect of smoking needs further study, they say.

The study’s conclusions come with a major caveat, Regev points out. Because the analysis relied on cells from healthy people, those cells identified as potentially vulnerable to SARS-CoV-2 are only predictions, she says. To find out what really happens during infection, Atlas scientists are now examining cells from COVID-19 patients.

Still, Regev adds, this study suggests that across the body’s cells, “there is widespread potential for SARS-CoV-2 infection.”

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Citation

Christoph Muus, et al. “Integrated analyses of single-cell atlases reveal age, gender, and smoking status associations with cell type-specific expression of mediators of SARS-CoV-2 viral entry and highlights inflammatory programs in putative target cells.” Posted on bioRxiv.org on April 20, 2020. www.biorxiv.org/content/10.1101/2020.04.19.049254v1?ct=

Last Edit: Jun 20, 2020 2:21:05 GMT by Admin

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COVID-19 Susceptibility By Race, Blood Type May 14, 2020 4:27:27 GMT

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Post by Admin on May 14, 2020 4:27:27 GMT

COVID-19, the disease caused by coronavirus SARS-Cov-2, has infected over 4 million people in 212 countries, of whom at least 272,000 have died. The ongoing economic and social impact of the pandemic is staggering, but despite a daily flood of news on the disease, few laypeople know that paradoxically, COVID-19 mostly kills through an overreaction of the immune system, whose function is precisely to fight infections.

In a new review article — explicitly targeted to non-specialists as well — in Frontiers in Public Health, a team of experts from Zunyi Medical University review the epidemiology, disease pathway, symptoms, diagnosis, and current treatment of severe COVID-19. They stress the key role of a potentially lethal overreaction of the immune system in the progression of the disease.

They explain step-by-step what is known about how the virus infects the airways, multiplies inside cells, and in severe cases causes the immune defenses to overshoot with a “cytokine storm.” This storm is an over-activation of white blood cells, which release too-great amounts of cytokines — inflammation-stimulating molecules — into the blood.

“Similar to what happens after infection with SARS and MERS, data show that patients with severe COVID-19 may have a cytokine storm syndrome. The rapidly increased cytokines attract an excess of immune cells such as lymphocytes and neutrophils, resulting in an infiltration of these cells into lung tissue and thus cause lung injury,” explains author Professor Daishun Liu from Zunyi Medical University, China.

The cytokine storm ultimately causes high fever, excessive leakiness of blood vessels, blood clotting inside the body, extremely low blood pressure, lack of oxygen and excess acidity of the blood, and build-up of fluids in the lungs (“pleural effusion”).

White blood cells are misdirected to attack and inflame even healthy tissue, leading to failure of the lungs, heart, liver, intestines, kidneys, and genitals (Multiple Organ Dysfunction Syndrome, MODS). This may worsen and shutdown the lungs (Acute Respiratory Distress Syndrome, ARDS) due to the formation of a so-called hyaline membrane, composed of debris of proteins and dead cells, lining the lungs, which makes absorption of oxygen difficult. Most deaths due to COVID-19 are therefore due to respiratory failure.

Liu et al. explain how in the absence of a specific antiviral cure for COVID-19, the goal of treatment must be to the fight the symptoms, lowering the mortality rate through intensive maintenance of organ function, for example an artificial liver blood purification system or renal replacement therapy to filtrate the blood through mechanical means.

Especially important are methods to supplement or replace lung function, for example through non-invasive mechanical ventilation through a mask, ventilation through a tube into the windpipe (if possible with the refinement of Positive End Expiratory Pressure, PEEP, where the ventilator delivers extra pressure at the end of each breath of keep the lung vesicles open throughout), the administration of heated and humidified oxygen via a tube in the nose (“transnasal high-flow oxygen”), or a heart-lung bypass.

The authors conclude by stressing the importance of preventing secondary infections: SARS-Cov-2 also invades the intestines, where it causes inflammation and leakiness of the gut lining, allowing the opportunistic entry of other disease-causing microorganisms. They advocate that this should be prevented with nutritional support, for example with probiotics — beneficial bacteria that protect against the establishment of harmful ones — and nutrients and amino acids to improve the immune defenses and function of the intestine.

“Because treatment for now relies on aggressive treatment of symptoms, preventative protection against secondary infections, such as bacteria and fungi, is particularly important to support organ function, especially in the heart, kidneys, and liver, to try and avoid further deterioration of their condition,” concludes Liu.

Reference: “Severe COVID-19: A Review of Recent Progress with a Look Toward the Future” by Peng Xie, Wanyu Ma, Hongbo Tang and Daishun Liu, 13 May 2020, Frontiers in Public Health.
DOI: 10.3389/fpubh.2020.00189

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COVID-19 Susceptibility By Race, Blood Type May 14, 2020 19:00:16 GMT

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Post by Admin on May 14, 2020 19:00:16 GMT

SARS-CoV-2, the virus that causes COVID-19, can severely damage lungs, but in serious cases it doesn’t stop there—clinicians have observed body-wide damage due to the coronavirus. As researchers begin to better understand the pathology of the disease, new treatments can be deployed to help save lives.

The coronavirus known as SARS-CoV-2 is, to borrow a phrase from Winston Churchill, a riddle wrapped in a mystery inside an enigma. Scientists have mapped its contours and measured its structures to atomic-level precision. They have come to understand its genetic ancestry with a precision that leaves 23andMe in the dust. They have watched it go to work on human cells in a lab.

But after close to six months among us, this coronavirus continues to startle and confound. Why does it kill some and barely graze others? Will it wane through the summer months and surge come fall? Once we understand its behavior, could it just … change?

Governed by a 30,000-base genome coiled up inside its core, the virus will perform that task imperfectly. But it will do it well enough to send millions of copies of itself on to other cells in the lungs, the heart and the gastrointestinal tract.

Eventually, this zombie army will attract the attention of its human host’s immune system. In some people, the response will be swift and effective. Others will fight through weeks of misery and emerge depleted but well.

In an unlucky few, the immune system counterattack will run amok, wreaking havoc on organs not meant to have joined the fight. Death by multi-organ failure can ensue.

In the image above, the spike proteins and the virus’ fatty outer membrane (in gray) have been cut away to reveal its core of nucleocapsid proteins (in green). These contain and protect the single strand of 30,000 RNA nucleotides that govern the virus’ structure and function.

We also know this: that everything required for this fateful encounter with human cells is right here, re-created in three-dimensional detail by the biomedical visualization studio Visual Science.

Each of the millions of units that make up the virus seen here is an atom, and colors are used here to distinguish distinct structures from one another. These deeply researched illustrations join a garden of other viral models executed by the firm, including ones for HIV, Ebola and Zika. With a hint of whimsy, they call this collection the “Viral Park Project.”

The SARS-CoV-2 virus is an average-sized virus, bigger than the enterovirus that causes polio and smaller than the herpes simplex virus that causes cold sores and genital herpes. Its diameter is roughly 1,000 times smaller than that of a human hair, and it is one of just seven coronaviruses known to cause illness in humans.

Unlike the snake-like Ebola virus or the egg-shaped H1N1 influenza virus, the form of the coronavirus varies. It is shown here as spherical. Its surface is studded with an average of about 90 spike proteins (in red) that give it its name. “Corona” is Latin for crown.

At the virus’ core, the genetic code is tightly intertwined with protective proteins that instruct the host cell in viral production and assembly. Among viruses whose genetic material is made of RNA, coronaviruses have the largest genomes. But compared with DNA viruses, coronaviruses are generally smaller, less complex and less accurate in replicating themselves. Each time SARS-CoV-2 replicates, about 30 mutations can be expected to occur.

Last Edit: May 14, 2020 19:01:49 GMT by Admin

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COVID-19 Susceptibility By Race, Blood Type May 20, 2020 6:34:23 GMT

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Post by Admin on May 20, 2020 6:34:23 GMT

Researchers have used a single-cell analysis method to identify multiple antibodies from COVID-19 patients that could neutralise the novel coronavirus, an advance which may lead to better therapeutics against the deadly disease. According to the scientists, including Sunney Xie, director of the Beijing Advanced Innovation Center for Genomics at Peking University, antibodies could be successfully used to treat viruses like Ebola, AIDS, and MERS.

In the current study, published in the journal Cell, the scientists used a method called high-throughput single-cell genome sequencing to identify the antibodies from convalescent plasma, a component of patients' blood. Citing earlier studies, the researchers said antibodies can lead to significant recovery of COVID-19 patients.

Convalescent patients' plasma, which contains neutralising antibodies produced by the immune response, has led to a clear clinical improvement of both mild and severe COVID-19 patients, they noted in the study. However, the scientists said screening for potent neutralising molecules called monoclonal antibodies (mAbs) from the immune system's B cells is often a slow and laborious process.

They said the existing methods are particularly not ideal when responding to a global health emergency. Since only some B cells produce antibodies specific to neutralising the virus, the researchers said, a process to rapidly screen for those cells producing the desired immune molecules was needed.

In this study, the researchers demonstrated a rapid and efficient single-cell genome sequencing method to narrow down on specific B cells, and identify SARS-CoV-2 neutralising antibodies from convalescent COVID-19 patients.

"We showed that high-throughput single-cell sequencing could lead to the identification of highly potent neutralizing mAbs that have strong therapeutic and prophylactic efficacy," the scientists noted in the study.

The method could greatly assist in the intervention of prevailing and emerging infectious diseases, such as COVID-19, they said. Following the discovery of the antibodies, they tested them in genetically engineered mice expressing the human form of the receptor ACE2, which is the gateway protein used by the novel coronavirus to enter cells.

Potent neutralizing antibodies against SARS-CoV-2 identified by
high-throughput single-cell sequencing of convalescent patients’ B cells

Summary
The COVID-19 pandemic urgently needs therapeutic and prophylactic interventions. Here we report the rapid identification of SARS-CoV-2 neutralizing antibodies by high-throughput single-cell RNA and VDJ sequencing of antigen-enriched B cells from 60 convalescent patients. From 8,558 antigen-binding IgG1+ clonotypes, 14 potent neutralizing antibodies were identified with the most potent one, BD-368-2, exhibiting an IC50 of 1.2 ng/mL and 15 ng/mL against pseudotyped and authentic SARS-CoV-2, respectively. BD-368-2 also displayed strong therapeutic and prophylactic efficacy in SARS-CoV-2-infected hACE2-transgenic mice. Additionally, the 3.8Å Cryo-EM structure of a neutralizing antibody in complex with the spike-ectodomain trimer revealed the antibody’s epitope overlaps with the ACE2 binding site. Moreover, we demonstrated that SARS-CoV-2 neutralizing antibodies could be directly selected based on similarities of their predicted CDR3H structures to those of SARS-CoV neutralizing antibodies. Altogether, we showed that human neutralizing antibodies could be efficiently discovered by high-throughput single B-cell sequencing in response to pandemic infectious diseases.

doi.org/10.1016/j.cell.2020.05.025