In response to the third wave driven by the delta variant, President Cyril Ramaphosa instituted a two-week Level 4 lockdown during a ‘family meeting’ address to the nation.
He warned that the healthcare system was facing a dire situation. “Our health facilities are stretched to the limit… ICU beds are in short supply,” he said.
In a press briefing on Friday, the head of the World Health Organization said the COVID Delta variant, first seen in India, is “the most transmissible of the variants identified so far,” and warned it is now spreading in at least 85 countries.
“We are in the exponential phase of the pandemic with the numbers just growing very, very, extremely fast and (they) will keep growing in the next weeks,” said Tulio de Oliveira, a leading virologist in the country.
The Delta variant first seen in India now appears to be “dominating infections in South Africa,” de Oliveira of the Network for Genomic Surveillance in South Africa told a virtual briefing.
The Delta variant has emerged as dominant in South Africa. Source: Department of Science & Technology
Koleka Mlisana, the head of a government ministerial advisory committee on COVID, told the same briefing that there is “evidence that the Delta variant may actually be taking over”.
Acting Minister of Health, Mmamoloko Kubayi-Ngubane said that due to the prevalence of the Delta variant, infection numbers “are likely to surpass the second wave peak” in January.
Only about 2.4 million people have been immunised since February. Thousands of EFF activists rallied in Pretoria on Friday to demand a faster coronavirus vaccination rollout, including expedited approvals for the Sinovac vaccine from China and Russia’s Sputnik V.
Colorized scanning electron micrograph of an apoptotic cell (purple) heavily infected with SARS-COV-2 virus particles (yellow), isolated from a patient sample. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Credit: NIAID
A preliminary study has possibly determined why the SARS-CoV-2 Delta variant is more infectious and pathogenic than its ancestor.
Through a series of in vitro experiments, researchers have discovered that variant’s enhanced ability to induce cell-to-cell fusion (syncytia) and reduced susceptibility to vaccine and infection-induced antibodies together help make the Delta variant more infectious than previously circulating variants. The study, which is yet to be peer reviewed, is currently available on the bioRxiv preprint server.
The SARS-CoV-2 virus has undergone more than 12 000 mutations since it was first detected in December 2019, most of which are neutral and do not contribute to viral evolution. However, the acquisition of specific mutations in structural and non-structural proteins has caused the emergence of novel, more virulent SARS-CoV-2 variants.
Spike protein mutations are particularly concerning as they can significantly influence viral infectivity, virulence, and immune evasion ability.
The B.1.617 lineage drove a massive surge in new COVID cases in India. This lineage is further divided into three sub-lineages, namely B.1.617.1, B.1.617.2, and B.1.617.3. Although these emerged first in India, the B.1.617.2 or Delta variant or soon became dominant in many countries, including South Africa where it has driven a new surge of infections, particularly in Gauteng Province. The World Health Organization (WHO) has designated the Delta variant as a ‘Variant of Concern’ (VOC) due to its significantly increased infectivity and pathogenicity.
In the current study, the scientists have evaluated the susceptibility of the Delta variant to neutralisation by vaccine or natural infection-induced antibodies.
Delta variant mutations
The Delta variant’s spike protein contains nine mutations in the S1 subunit and one mutation in the S2 subunit. In the S1 subunit, five mutations are present in the N-terminal domain containing binding sites (epitopes) for neutralising antibodies. In addition, two mutations are present in the receptor-binding domain of the S1 subunit, which is known to influence antibody-mediated neutralisation and infectivity. Among the three remaining mutations, two are known to increase angiotensin-converting enzyme 2 (ACE2) binding, viral replication, and spike protein cleavage at the S1/S2 site.
Delta variant host cell entry
Using African green monkey and human cells, the researchers found that Delta can enter kidney cells of both species with similar efficacy as the wild-type SARS-CoV-2. However, for human colon and lung cells, Delta showed 1.5-fold and 2-fold higher invading ability, respectively, compared to the wild-type virus. Since the Delta variant spike protein did not exhibit increased ACE2 binding, the scientists suggest that increased entry of B.1.617.2 into colon and lung cells is not mediated by enhanced ACE2 binding.
Besides inducing fusion between the viral envelope and host cell membrane, the spike protein triggers the fusion of infected cells with nearby cells to form large multinucleated cells, known as syncytia. Given the fact that spike-induced syncytia formation contributes to COVID pathogenesis, the scientists investigated whether Delta variant infection is associated with increased syncytia formation.
By conducting in vitro experiments on human lung cells expressing high levels of ACE2, they found that Delta spike expression leads to 2.5-fold higher and larger syncytia formation than the wild-type spike expression.
Delta variant’s immune evasion ability less than Beta?
The scientists tested the ability of four therapeutic monoclonal antibodies to neutralise the Delta variant, of which only Bamlanivimab failed. The other three antibodies exhibited similar efficacy in neutralising both wild-type virus and Delta variant.
Antibodies derived from COVID recovered patients, and BNT162b2-vaccinated individuals showed only slightly reduced efficacy in neutralising the Delta variant as compared to the wild-type virus. In contrast, the B.1.315 or Beta variant, first detected in South Africa, showed a significantly higher ability to evade infection- and vaccination-induced immunity.
In summary
The study showed that Delta’s increased ability to invade lung cells may enhance infectivity and pathogenicity. Though it has lower susceptibility to antibody-mediated neutralisation, it is possible that Delta may be effectively controlled by immunity developed in response to natural infection or vaccination.
Journal information: Arora P. 2021. Increased lung cell entry of B.1.617.2 and evasion of antibodies induced by infection and BNT162b2 vaccination. bioRxiv. https://www.biorxiv.org/content/10.1101/2021.06.23.449568v1
A new study shows that both anabolic steroid use as well as legal performance-enhancing substances is longitudinally associated with criminal offending.
Although anabolic steroid use was known to be associated with criminal offending, the possibility of a similar link between use of legal performance-enhancing substances, such as creatine, and criminal offending remained unknown.
To address this, researchers analysed a sample of over 9000 US participants from the National Longitudinal Study of Adolescent Health (Add Health). The results show a need for more research on performance-enhancing substances to understand the complex social problems associated with their use.
“This is the first study to identify relationships between legal performance-enhancing substance use and criminal offending,” said lead author Kyle T. Ganson, PhD, MSW, assistant professor at the University of Toronto’s Factor-Inwentash Faculty of Social Work. “This finding is acutely salient because these substances are easily accessible and commonly used, particularly among young people.”
The study highlights the importance of clinical professionals screening for performance-enhancing substance use and assessing patterns of criminal offending among young people.
“We need more research to identify effective prevention and intervention techniques to ensure that we reduce the use of these substances, as well as curtail any connection with criminal offending,” said co-author Jason M. Nagata, MD, MSc, assistant professor at the University of California, San Francisco’s Department of Pediatrics.
“The associations found in this study are likely explained by an intersection of behavioral, psychological, and sociocultural influences,” says Ganson. “We therefore need to target this problem from a multitude of angles, including clinically and via public health and policy interventions.”
Journal information: Ganson, K.T., et al. (2021) Performance-Enhancing Substance Use and Criminal Offending: A 15-Year Prospective Cohort Study. Drug and Alcohol Dependence. doi.org/10.1016/j.drugalcdep.2021.108832.
Muscle sarcomeres (consecutive green lines), the smallest functional unit of muscle, from inside a living human. Credit: Northwestern University
In a new study of stroke patients, researchers have discovered that, in an attempt to adapt for an unusable arm, muscles actually lose sarcomeres — their smallest, most basic building blocks.
Patients that have suffered a stroke are often unable to use the arm on their affected side. Sometimes, they end up holding it close to their body, with the elbow flexed. Northwestern University and Shirley Ryan AbilityLab researchers found out why this happens.
Stacked end to end (in series) and side to side (in parallel), sarcomeres form the length and width of muscle fibres. By imaging biceps muscles with three noninvasive methods, the researchers found that stroke patients had fewer sarcomeres along the length of the muscle fibre, resulting in the muscle structure being shorter overall.
This finding is consistent with the common patient experience of abnormally tight, stiff muscles that resist stretching, and it suggests that changes in the muscle potentially amplify existing issues caused by stroke, which is a brain injury. The team hopes this discovery can help improve rehabilitation techniques to rebuild sarcomeres, ultimately helping to ease muscle tightening and shortening.
“This is the most direct evidence yet that chronic impairments, which place a muscle in a shortened position, are associated with the loss of serial sarcomeres in humans,” said senior author Wendy Murray. “Understanding how muscles adapt following impairments is critical to designing more effective clinical interventions to mitigate such adaptations and to improve function following motor impairments.”
Murray is a professor of biomedical engineering at Northwestern’s McCormick School of Engineering, a professor of physical medicine and rehabilitation at the Northwestern University Feinberg School of Medicine and research scientist at the Shirley Ryan AbilityLab. The research was completed in collaboration with Julius Dewald, professor of physical therapy and human movement sciences and of physical medicine and rehabilitation at Feinberg, professor of biomedical engineering at McCormick, and research scientist at Shirley Ryan AbilityLab.
Measuring just 1.5 to 4.0 micrometres in length, sarcomeres are made up of two main proteins: actin and myosin. When these proteins work together, they enable a muscle to contract and produce force. Even though previous animal studies have found that serial sarcomeres are lost from muscles after a limb is immobilised in a cast, the phenomenon had never before been demonstrated in humans. The animal studies found that the shorter muscles due to lost serial sarcomeres also became stiffer.
“There is a classic relationship between force and length,” explained first author Amy Adkins, a PhD student in Murray’s laboratory. “Given that the whole muscle is composed of these building blocks, losing some of them affects how much force the muscle can generate.”
To conduct the study in humans, the researchers combined three non-invasive medical imaging techniques: MRI to measure muscle volume, ultrasound to measure bundles of muscle fibers and two-photon microendoscopy to measure the microscopic sarcomeres.
Imaging opens new possibilities Combining these technologies, the researchers imaged biceps from seven stroke patients and four healthy participants. As stroke patients are more affected on one side of their body, the researchers compared imaging from the patients’ affected side to their unaffected side as well as to images from the healthy participants.
In the stroke patients’ affected biceps, researchers found less volume, shorter muscle fibres and comparable sarcomere lengths. After combining data across scales, they found that affected biceps had fewer sarcomeres in series compared to the unaffected biceps. Greater differences between stroke patients’ arms than healthy participants’ arms were seen, indicating that stroke was the cause.
By combining medical imaging to better view muscle structure, the study also establishes that it is possible to study muscle adaptations in sarcomere number in humans. Prior to two-photon microendoscopy, human studies were limited either to examining dissected tissues in anatomy labs, which give imperfect insight into how muscles adapt to injury and impairment, measuring sarcomere lengths during surgery or from a muscle biopsy, which restricts who can participate in the study.
“In almost every facet of our world, there is an important relationship between how something is put together (its structure) and how it works (its function),” the researchers said. “Part of the reason medical imaging is such a valuable resource and clinical tool is that this is also true for the human body, and imaging gives us an opportunity to measure structure.”
Journal information: Adkins, A.N., et al. (2021) Serial sarcomere number is substantially decreased within the paretic biceps brachii in individuals with chronic hemiparetic stroke. PNAS. doi.org/10.1073/pnas.2008597118.
In a new series of studies, University of Alabama at Birmingham researchers have described the reasons behind low levels of natriuretic peptides(NPs) in obese individuals.
First reported six decades ago, NPs are beneficial hormones produced by the heart, and are responsible for blood pressure regulation and the overall cardiovascular and metabolic health of humans. This study also addresses how the disturbance of an individual’s diurnal rhythm of these hormones contributes to poor cardiovascular health in obese individuals.
High blood pressure at nighttime is seen commonly in obese individuals, who already have higher risk of hypertension and poor cardiovascular outcomes. This can contribute to outcomes such as stroke, heart failure, heart attack and cardiac death. But why this impairment of this day-night blood pressure rhythm is not well understood — however, scientists believe that part of the reason lies with NPs.
“All the hormones in the human body have a day-night rhythm,” noted Vibhu Parcha, MD, a clinical research fellow in the Division of Cardiovascular Disease and the first author of both the studies. “It has been hypothesised the NP hormones should also have this rhythm, but this had not yet been demonstrated in humans. Our clinical trial assessed the 24-hour cycle of the NP hormones and compared it to the 24-hour cycle of blood pressure. We also studied how these cycles differ between lean and obese individuals and studied the reasoning behind why obese individuals experience lower levels of NPs.”
Following a rigorous clinical trial of healthy individuals, researchers found that NP hormones have a diurnal rhythm with higher levels in the afternoon and lower levels at nighttime — similar to the 24-hour cycle of blood pressure. In obese individuals however, researchers observed that the relationship between NPs and blood pressure does not function the same way. This leads to higher nighttime blood pressure and increased risk of cardiovascular disease. The low production of NPs combined with a relatively higher elimination of NPs from an obese individual’s system leads to low levels of these beneficial hormones in circulation, which may explain the NP deficiency.
“This is the first time we have seen that NPs, like other hormones, have a 24-hour rhythm,” said senior author Pankaj Arora, MD, a physician-scientist in UAB’s Division of Cardiovascular Disease. “These studies give us a better understanding of NPs and of the reasoning behind the NP deficiency in obese individuals. We now have an FDA-approved medication (LCZ696) that improves circulating NP levels. This medication is considered a first-line treatment for heart failure and may be used to increase NP levels.”
This medication could specifically target NPs and blood pressure if given at the right time of day and could control hypertension with precision, Dr Arora added. These findings point to using a physiologically-driven precision ‘chronopharmacotherapy’ approach to improve the diurnal blood pressure profile in obese individuals.
Journal information: Vibhu Parcha et al, Chronobiology of Natriuretic Peptides and Blood Pressure in Lean and Obese Individuals, Journal of the American College of Cardiology (2021). DOI: 10.1016/j.jacc.2021.03.291
Dopamine can help explain both autistic behaviours and men’s need for motivation or ‘passion’ in order to succeed compared to women’s ‘grit’, according to a new study.
Men – more often than women – need passion to succeed at things. At the same time, boys are diagnosed as being on the autism spectrum four times as often as girls. Both statistics may be related to dopamine, one of our body’s neurotransmitters.
“This is interesting. Research shows a more active dopamine system in most men” than in women, says Hermundur Sigmundsson, a professor at the Norwegian University of Science and Technology’s (NTNU) Department of Psychology.
He is behind a new study addressing gender differences in key motivating factors to excel in something. The study uses men’s and women’s differing activity in the dopamine system as an explanatory model. The study enrolled 917 participants aged 14 to 77, consisting of 502 women and 415 men.
“We looked at gender differences around passion, self-discipline and positive attitude,” said Prof Sigmundsson. The study refers to these qualities as passion, grit and mindset. The researchers also applied theories to possible links with dopamine levels. Dopamine, a neurotransmitter that is released in the brain, is linked to learning, attention and our ability to focus. It can contribute to a feeling of satisfaction.
Men generally secrete more dopamine, but it plays a far more complex role than simply being a ‘happy hormone’. Dopamine is linked to learning, attention and our ability to focus.Previous studies on Icelandic students have shown that men are more dependent on passion in order to succeed at something. This study confirms the earlier findings. In six out of eight test questions, men score higher on passion than women.
However, the association with dopamine levels has not been established previously.
“The fact that we’ve developed a test to measure passion for goal achievement means that we can now relate dopamine levels to passion and goal achievement,” explained Prof Sigmundsson.
Women, on the other hand, may have greater self-discipline – or grit – and be more conscientious, according to other studies. Their level of passion may not be as pronounced in general, but they are also able to use this to excel.
The results for the women, however, are somewhat more ambiguous than men’s need to have a passion for something, and this study found no such gender difference. Nor did the researchers find any difference between the sexes in terms of growth mindset.
Previous studies have associated the dopamine system with many different conditions, such as ADHD, psychoses, manias and Parkinson’s disease. However, it may also be related to a certain form of autistic behaviour.
Some individuals with autism may develop a deep interest in certain topics, something which others may find strange or even off putting. People on the autism spectrum can focus intensely on these topics or pursuits, at least for a while, and dopamine may play a role in this.
“Other research in neuroscience has shown hyperactivity in the dopamine system in individuals with autism, and boys make up four out of five children on the autism spectrum. This, and dopamine’s relationship to passion, might be a mechanism that helps to explain this behaviour,” concluded Prof Sigmundsson.
Journal reference: Sigmundsson, H., et al. (2021) Passion, grit and mindset: Exploring gender differences. New Ideas in Psychology. doi.org/10.1016/j.newideapsych.2021.100878.
Scanning electron micrograph of methicillin-resistant Staphylococcus aureus and a dead human neutrophil. Credit: NIAID
Researchers have uncovered a novel trick employed by the bacterium Staphylococcus aureus — MRSA uses toxins to ‘fight dirty’ and stifle the immune response. This finding is a step towards one day producing a vaccine against MRSA.
Every year, there are some 700 000 deaths due to the emerging global threat of antimicrobial resistance (AMR). Turning the tables against AMR requires immediate action, and the development of novel vaccines to prevent such infections in the first place, are an attractive and potentially very effective option.
Staphylococcus aureus is the causative agent of the infamous MRSA ‘superbug’, one of the chief concerns of AMR. Immunologists from Trinity College Dublin, working with scientists at GSK, discovered the deadly bacteria’s new trick to foil the immune system. They found that the bacterium interferes with the host immune response by causing toxic effects on white blood cells, preventing them from carrying out their infection-fighting jobs.
The study also showed that the toxicity could be lessened following vaccination with a mutated version of a protein specifically engineered to throw a spanner in the MRSA works. This could one day lead to a vaccine for humans.
Rachel McLoughlin, Professor in Immunology in Trinity’s School of Biochemistry and Immunology and the Trinity Biomedical Sciences Institute (TBSI), said: “As a society we are witnessing first-hand the powerful impact that vaccination can have on curbing the spread of infection. However, in the backdrop of the COVID epidemic we must not lose sight of the fact that we are also waging war on a more subtle epidemic of antimicrobial resistant infection, which is potentially equally deadly.
“In this study we have identified a mechanism by which a protein made by the bacterium – known as Staphylococcal Protein A (SpA) – attacks and rapidly kills white blood cells. This protein has been widely studied for its immune evasion capacity and has a well-documented role in rendering antibodies raised against the bacterium non-functional.
“Here we uncover a previously undocumented strategy by which SpA forms immune complexes through its interaction with host antibodies, that in turn exert toxic effects on multiple white blood cell types. This discovery highlights how important it will be for effective vaccines to be capable of disarming the effects of protein A.”
Dr Fabio Bagnoli, Director, Research & Development Project Leader, GSK, said: “Our collaboration with Trinity College Dublin and in particular with Professor Rachel McLoughlin, a worldwide recognised expert on staphylococcal immunology, is critical for increasing our knowledge on protective mechanisms against S. aureus.”
The study documents the latest discovery made by this group at Trinity under an ongoing research agreement with GSK Vaccines (Siena, Italy). Overall, this collaboration aims to increase understanding of the immunology of Staphylococcus aureus infection to advance development of next-generation vaccines to prevent MRSA infections.
Journal information: Fox, P. G., et al. (2021) Staphylococcal Protein A Induces Leukocyte Necrosis by Complexing with Human Immunoglobulins. Scientific Reports. doi.org/10.1128/mBio.00899-21.
Astrocytes (red) from a rat brain. Credit: Jeffrey C. Smith Lab, National Institute of Neurological Disorders and Stroke, NIH
A new study from Duke and UNC scientists has discovered a crucial protein involved in the communication and coordination between astrocytes as they build synapses — essentially a brain building block.
Astrocytes, specialised, star-shaped glial cells that outnumber the neurons they support over fivefold and which make up about half the mass of a human brain, are increasingly being viewed as having a critical role in shaping the development of the brain. Astrocytes tile the entire central nervous system (CNS) and exert many essential complex functions in the healthy CNS, including guiding development of the brain.
The researchers found that a molecule, called hepaCAM, is a key component of this process. Without it, astrocytes aren’t as sticky as they should be, and tend to stick to themselves rather than forming connections with their neighbouring astrocytes.
This finding, in studies on mice with the gene for hepaCAM deleted from their astrocytes, helps in the understanding of several brain disorders, including cognitive decline, epilepsy and autism spectrum disorders.
One rare brain disorder, called megalencephalic leukoencephalopathy (MLC) is also known to be caused by a mutation in the hepaCAM gene, and this work might provide answers about what exactly has gone wrong. MLC is a developmental disorder that grows progressively worse, causing macrocephaly (a large head), swelling of the brain’s white matter, intellectual disability and epilepsy.
By deleting hepaCAM from astrocytes to see what it does, “we sort of made the cells into introverts,” explained senior author Cagla Eroglu, an associate professor of cell biology at the Duke University School of Medicine. “They’re normally wanting to reach out, but without hepaCAM, they started to hug themselves instead.”
“If the astrocyte makes junctions to its neighbours, then you start to have a network,” Prof Eroglu said. “To make a functional brain, you need a functional astrocytic network.”
The researchers zeroed in on hepaCAM by searching for highly active genes in astrocytes, and which have been implicated in brain dysfunction. They partnered with another group working on hepaCAM at the University of Barcelona, but that group has been looking at the molecule for its role in regulating chloride signaling channels in astrocytes.
The Duke group found that deleting hepaCAM from astrocytes led to a synaptic network that was too easily excited and not as well dampened. “The effect on the inhibitory synapses was the strongest,” said first author Katie Baldwin, who recently became an assistant professor of cell biology and physiology at the University of North Carolina at Chapel Hill. “You’re putting the inhibition down and the excitation up, so that really could point to a mechanism for epilepsy.”
Prof Baldwin plans to test whether hepaCAM-deficient mice have behavioural differences or changes in learning and memory, or whether they exhibit the stress and social anxiety that are markers of autism spectrum disorders. She said they might also reintroduce the disease-mutation versions of the protein to mice that were born without it to see what effects it has.
“We know hepaCAM is interacting with itself between two astrocytes, but we don’t know what it’s interacting with at the synapse,” Prof Baldwin said. “We don’t know if it could be interacting with hepaCAM which is also found in the neurons, or if it could be some other protein that we don’t know about yet.
Scientists have found that common artificial sweeteners can turn previously healthy gut bacteria pathogenic, invading the gut wall and potentially leading to serious health issues.
This study is the first to show the pathogenic effects of some of the most widely used artificial sweeteners (saccharin, sucralose, and aspartame) on two types of gut bacteria, Escherichia coli and Enterococcus faecalis. E. faecalis is capable of crossing the intestinal wall to enter the bloodstream and congregate in the lymph nodes, liver, and spleen, causing a number of infections including septicaemia. To top it off, this commensal bacteria has emerged as a multi-drug resistant pathogen.
Previous studies have shown that artificial sweeteners can affect the composition of gut bacteria, but this new molecular research, led by academics from Anglia Ruskin University (ARU), has shown that sweeteners can also induce pathogenic features in certain bacteria. It found that these pathogenic bacteria can latch onto, invade and kill epithelial Caco-2 cells lining the intestinal wall.
This new study discovered that at a concentration equivalent to two cans of diet soft drink, all three artificial sweeteners significantly increased the adhesion of both E. coli and E. faecalis to intestinal Caco-2 cells, and differentially increased biofilm formation. Bacteria growing in biofilms are less sensitive to antimicrobial resistance treatment and are more likely to secrete toxins and express disease-causing virulence factors.
Additionally, all three sweeteners caused the pathogenic gut bacteria to invade Caco-2 cells found in the wall of the intestine, save for saccharin, which had no significant effect on E. coli invasion.
Senior author Dr Havovi Chichger, Senior Lecturer in Biomedical Science at ARU, said: “There is a lot of concern about the consumption of artificial sweeteners, with some studies showing that sweeteners can affect the layer of bacteria which support the gut, known as the gut microbiota.
“Our study is the first to show that some of the sweeteners most commonly found in food and drink—saccharin, sucralose and aspartame—can make normal and ‘healthy’ gut bacteria become pathogenic. These pathogenic changes include greater formation of biofilms and increased adhesion and invasion of bacteria into human gut cells.
“These changes could lead to our own gut bacteria invading and causing damage to our intestine, which can be linked to infection, sepsis and multiple-organ failure.
“We know that overconsumption of sugar is a major factor in the development of conditions such as obesity and diabetes. Therefore, it is important that we increase our knowledge of sweeteners versus sugars in the diet to better understand the impact on our health.” Source: EurekAlert!
Journal reference: Shil, A & Chichger, H (2021) Artificial Sweeteners Negatively Regulate Pathogenic Characteristics of Two Model Gut Bacteria, E. coli and E. faecalis. International Journal of Molecular Sciences. doi.org/10.3390/ijms22105228.
SARS-CoV-2 viruses emerging from a human cell. Credit: NIAID
Australian researchers studying SARS-CoV-2 have discovered that the virus is most ideally adapted to infect human cells — instead of bat or pangolin cells, prompting renewed questions about its origin.
The scientists, from Flinders University and La Trobe University, described how they used high-performance computer modelling of SARS-CoV-2’s structure at the beginning of the pandemic to predict its ability to infect humans and a range of 12 domestic and exotic animals.
They were hoping to identify an intermediate animal vector that may have played a role in transmitting a bat virus to humans, and to understand any risk posed by the susceptibilities of pets and livestock.
Using genomic data from 12 animal species, the researchers painstakingly built computer models of the key ACE2 protein receptors for each species. These models were then used to calculate how strongly the SARS-CoV-2 spike protein bound to each species’ ACE2 receptor.
Surprisingly, the results showed that SARS-CoV-2 bound to ACE2 on human cells more tightly than any of the tested animal species, including bats and pangolins. If one of the animal species tested was the origin, it would normally be expected to show the highest binding to the virus.
“Humans showed the strongest spike binding, consistent with the high susceptibility to the virus, but very surprising if an animal was the initial source of the infection in humans,” said Professor David Winkler at La Trobe University.
The findings, originally released on the ArXiv preprint server, have now been peer reviewed and published in Scientific Reports.
“The computer modelling found the virus’s ability to bind to the bat ACE2 protein was poor relative to its ability to bind human cells. This argues against the virus being transmitted directly from bats to humans. Hence, if the virus has a natural source, it could only have come to humans via an intermediary species which has yet to be found,” says Flinders affiliated Professor Nikolai Petrovsky.
The team’s computer modelling also showed fairly strong binding of SARS-CoV-2 to ACE2 from pangolins, which are occasionally used as food or in traditional medicines. Professor Winkler noted that pangolins displayed the highest spike binding energy of all the animals in the study – significantly higher than bats, monkeys and snakes.
“While it was incorrectly suggested early in the pandemic by some scientists that they had found SARS-CoV-2 in pangolins, this was due to a misunderstanding and this claim was rapidly retracted as the pangolin coronavirus they described had less than 90% genetic similarity to SARS-CoV-2 and hence could not be its ancestor,” Prof Petrovsky said.
Similarity in spike proteins
As shown in this and other studies, the specific part of the pangolin coronavirus spike protein that binds to ACE2 was almost identical to its SARS-CoV-2 counterpart.
“This sharing of the almost identical spike protein almost certainly explains why SARS-CoV-2 binds so well to pangolin ACE2. Pangolin and SARS-CoV-2 spike proteins may have evolved similarities through a process of convergent evolution, genetic recombination between viruses, or through genetic engineering, with no current way to distinguish between these possibilities,” Prof Petrovsky said.
“Overall, putting aside the intriguing pangolin ACE2 results, our study showed that the COVID-19 virus was very well adapted to infect humans.”
“We also deduced that some domesticated animals like cats, dogs and cows are likely to be susceptible to SARS-CoV-2 infection too,” Prof Winkler added.
The question of how the virus came to infect humans currently has two main explanations. The virus may have jumped to humans from bats through an intermediary animal which remains to be identified. The other explanation making headlines in the media is an accidental release from a virology lab, where it perhaps was created in ‘gain of function‘ tests, which are carried out around the world to better understand pathogens. A number of organisations and governments, including the World Health Organization and the United States have urged further investigation to find out which of these is correct — though a definitive answer may take years. How and where the SARS-CoV-2 virus adapted to become such an effective human pathogen remains a mystery, the researchers concluded, adding that finding the origins of the disease will help efforts to protect humanity against future coronavirus pandemics.
Journal information: Sakshi Piplani et al, In silico comparison of SARS-CoV-2 spike protein-ACE2 binding affinities across species and implications for virus origin, Scientific Reports (2021). DOI: 10.1038/s41598-021-92388-5
