The scientists, led by Maurizio Pellecchia in the School of Medicine at the University of California, Riverside, report in the journal Molecules that two proteases — enzymes that break down proteins — located on the surface of host cells and responsible for processing viral entry could be inhibited. Such protease inhibition would prevent SARS-CoV2, the coronavirus responsible for COVID-19, from invading the host cell.

The research is featured as the cover story of the journal (Volume 25, Issue 10).

Spike glycoprotein

The outer surface of coronaviruses contains a critical protein called spike glycoprotein, or S-glycoprotein. Responsible for giving the coronavirus its typical crown shape, the S-glycoprotein is essential for the entry of viral particles into host cells. Host cell proteases, however, must first process or cut this viral surface protein to allow the virus to enter the cells.

Pellecchia’s lab and others have recognized that in addition to a previously identified protease called TMPRSS2, the new SARS-CoV2 coronavirus could also be processed by an additional human protease, called furin, for viral entry.

“The use of the host protease furin for processing is a common mechanism of cell entry by both viral fusion proteins and certain bacterial toxins,” said Pellecchia, a professor of biomedical sciences, who led the research team. “SARS-CoV2 uses this mechanism also. The nature of the ‘proteolytic cleavage’ in its S-glycoprotein can determine whether this virus can be transmitted across species, for example from bats or camels to humans.”

A fusion protein combines the attributes of more than one protein. Proteolytic cleavage refers to the process of breaking the peptide bonds between amino acids in a protein, which results in cutting the protein.

The coronavirus S-glycoprotein contains three cleavage sites that human host proteases process. The exact nature and sequence of these cleavage sites, and their respective processing proteases, can determine the level of pathogenicity and whether the virus can cross species.

Spotlight on inhibitors

Pellecchia explained that the anthrax toxin, similar to SARS-CoV2, requires processing by human furin to infect macrophages, a type of white blood cell. Using anthrax toxin as model system, his team found an inhibitor of both TMPRSS2 and furin in cellular and animal models can efficiently suppress cell entry by the toxin.

A clinical trial with COVID-19 patients recently began using the TMPRSS2 inhibitor camostat.

“We found, however, that camostat is a poor furin inhibitor,” Pellecchia said. “Our current study, therefore, calls for the development of additional protease inhibitors or inhibitor-cocktails that can simultaneously target both TMPRSS2 and furin and suppress SARS-CoV2 from entering the host cell.”

Pellecchia added that until now the presence of a furin cleavage site in SARS-CoV2 had been linked to increased pathogenicity. But genetic elimination of furin in cellular laboratory studies failed to stop viral entry, suggesting TMPRSS2 remains the most relevant protease.

Using peptide sequences from SARS-CoV2 S-glycoprotein, however, his team has now demonstrated the new mutations in this coronavirus strain resulted in efficient and increased processing of viral entry by furin and TMPRSS2.

“In other words, SARS-CoV2, unlike other less pathogenic strains, can more efficiently use both proteases, TMPRSS2 and furin, to start the invasion of host cells,” Pellecchia said. “While TMPRSS2 is more abundant in the lungs, furin is expressed in other organs, perhaps explaining why SARS-CoV2 is capable of invading and damaging multiple organs.”

Pellecchia’s lab has already identified potent and effective preclinical inhibitors of furin and demonstrated these inhibitors could be developed as potential COVID-19 therapeutics, perhaps in combination with drugs such as camostat, the TMPRSS2 inhibitor.

Funding sought

“We are seeking additional funding to pursue the design and development of dual inhibitors that can simultaneously target both TMPRSS2 and furin,” Pellecchia said. “The funding would allow us to explore new possible effective therapeutics against COVID-19 and support studies that could have far reaching applications to ward off possible future pandemics resulting from similar activating mutations in other viral strains.”

Pellecchia, who holds the Daniel Hays Chair in Cancer Research at the UCR School of Medicine, was joined in the research by Elisa Barile, Carlo Baggio, and Luca Gambini of UCR; and Sergey A. Shiryaev and Alex Y. Strongin of the Sanford Burnham Prebys Medical Discovery Institute in La Jolla.

The study was supported by grants to Pellecchia from the National Institutes of Health.

The method was created by Nathaniel Barlow, associate professor in RIT’s School of Mathematical Sciences, and Steven Weinstein, head of RIT’s Department of Chemical Engineering. They say that by using this solution to the model, epidemiologists can quickly forecast many different scenarios of how COVID-19 could spread based on a variety of variables. Projections produced by mathematical models help public officials make policy decisions about when to impose and lift restrictions aimed at flattening the curve of infection rates.

The applied mathematicians who developed the method said they were excited to find a way to apply their skills to help combat the pandemic.

“I was at home thinking that I would like to somehow help with everything going on,” said Barlow. “We saw a popular article out there about the SIR model, saw that our method could speed the process up and we quickly wrote the paper. Our goal was to get better tools to the experts who are fighting this disease.”

The method was based on solutions they previously developed to very different problems in thermodynamics, fluid mechanics and predicting the trajectories of light around black holes. They have worked extensively with undergraduate students on those problems over the past six years and found that the solution to the SIR epidemic model had a very similar mathematical structure. Although the authors haven’t previously worked in the field of epidemiology, their previous work translated seamlessly to this new field.

“Many times, that’s what we as applied mathematicians do — work at the boundaries of fields where people are not typically talking,” said Weinstein. “We serve an important function to provide algorithms to support scientific inquiry and prediction. The technique we have developed here is general to many different fields.”

The authors are now working on showing how their method can be applied to more complex models such as the SEIR epidemic model, which is similar to the SIR model but also predicts the population exposed to an epidemic.

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Materials provided by Rochester Institute of Technology. Original written by Luke Auburn. Note: Content may be edited for style and length.

Conducting a genetic analysis, researchers from Duke University, Los Alamos National Laboratory, the University of Texas at El Paso and New York University confirmed that the closest relative of the virus was a coronavirus that infects bats. But that virus’s ability to infect humans was gained through exchanging a critical gene fragment from a coronavirus that infects a scaly mammal called a pangolin, which made it possible for the virus to infect humans.

The researchers report that this jump from species-to-species was the result of the virus’s ability to bind to host cells through alterations in its genetic material. By analogy, it is as if the virus retooled the key that enables it to unlock a host cell’s door — in this case a human cell. In the case of SARS-CoV-2, the “key” is a spike protein found on the surface of the virus. Coronaviruses use this protein to attach to cells and infect them.

“Very much like the original SARS that jumped from bats to civets, or MERS that went from bats to dromedary camels, and then to humans, the progenitor of this pandemic coronavirus underwent evolutionary changes in its genetic material that enabled it to eventually infect humans,” said Feng Gao, M.D., professor of medicine in the Division of Infectious Diseases at Duke University School of Medicine and corresponding author of the study publishing online May 29 in the journal Science Advances.

Gao and colleagues said tracing the virus’s evolutionary pathway will help deter future pandemics arising from the virus and possibly guide vaccine research.

The researchers found that typical pangolin coronaviruses are too different from SARS-CoV-2 for them to have directly caused the human pandemic.

However, they do contain a receptor-binding site — a part of the spike protein necessary to bind to the cell membrane — that is important for human infection. This binding site makes it possible to affix to a cell surface protein that is abundant on human respiratory and intestinal epithelial cells, endothelial cell and kidney cells, among others.

While the viral ancestor in the bat is the most closely related coronavirus to SARS-CoV-2, its binding site is very different, and on its own cannot efficiently infect human cells.

SARS-CoV-2 appears to be a hybrid between bat and pangolin viruses to obtain the “key” necessary receptor-binding site for human infection.

“There are regions of the virus with a very high degree of similarity of amino acid sequences among divergent coronaviruses that infect humans, bats and pangolins, suggesting that these viruses are under similar host selection and may have made the ancestor of SARS-CoV-2 able to readily jump from these animals to humans,” said lead co-author Xiaojun Li from Duke.

“People had already looked at the coronavirus sequences sampled from pangolins that we discuss in our paper, however, the scientific community was still divided on whether they played a role in the evolution of SARS-CoV-2,” said study co-lead author Elena Giorgi, staff scientist at Los Alamos National Laboratory.

“In our study, we demonstrated that indeed SARS-CoV-2 has a rich evolutionary history that included a reshuffling of genetic material between bat and pangolin coronavirus before it acquired its ability to jump to humans,” Giorgi said.

In addition to Gao, Li and Giorgi, study authors include, Manukumar Honnayakanahalli Marichannegowda, Brian Foley, Chuan Xiao, Xiang-Peng Kong, Yue Chen, S. Gnanakaran and Bette Korber.

A recent study from the University of Washington explores the ways parasitism will respond to climate change, providing researchers new insights into disease transmission. The paper was published May 18 in Trends in Ecology and Evolution.

The review builds upon previous research by adding nearly two decades of new evidence to build a framework showing the parasite-host relationship under climate oscillations. Traditionally, climate-related research is done over long timescales, however this unique approach examines how increasingly frequent “pulse warming” events alter parasite transmission.

“Much of what is known about how organisms and ecosystems can respond to climate change has focused on gradual warming,” said lead author Danielle Claar, a postdoctoral researcher at the UW School of Aquatic and Fishery Sciences. “Climate change causes not only gradual warming over time, but also increases the frequency and magnitude of extreme events, like heat waves.”

Claar explained that both gradual warming and pulse warming can and have influenced ecosystems, but do so in different ways. Organisms may be able to adapt and keep pace with the gradual warming, but an acute pulse event can have sudden and profound impacts.

The 2013-2015 “blob” is one such extreme heat pulse event which has been linked to a massive die-off of sea stars along the Pacific coast of the U.S. and Canada. Many species of sea stars, including the large sunflower sea star, were decimated by a sudden epidemic of wasting disease. Five years later, populations in the region are still struggling to recover. The abnormally warm waters associated with the blob are thought to have favored the spread of the sea star-associated densovirus, the suggested cause of the disease.

The authors compare the prevalence of these marine diseases to a rising tide, an ebbing tide, or a tsunami. Disease transmission can rise or ebb in concert with gradual warming or a series of pulse warming events. However, a severe pulse warming event could result in a tsunami, “initiating either a deluge or drought of disease,” as was observed with sea stars along the Pacific Northwest.

However, not all pulse heat events will cause the same response. What may benefit a particular parasite or host in one system can be detrimental in another. Warming can alter a parasite’s life cycle, limit the range of suitable host species, or even impair the host’s immune response. Some flatworms which target wildlife and humans cannot survive as long in warmer waters, decreasing their window for infecting a host. Another recent UW study found that parasites commonly found in sushi are on the rise with their numbers increasing 283-fold in the past 40 years, though the relationship between heat pulse events and their abundance is not yet clear.

“The relationships between hosts, parasites, and their corresponding communities are complex and depend on many factors, making outcomes difficult to predict,” said Claar, who recommends researchers make predictions on a case-by-case basis for their individual systems.

The authors conclude that rather than a straightforward tidal prediction, they would expect pulse warming to cause “choppy seas with the occasional rogue wave.”

“It is important that we are able to understand and predict how parasitism and disease might respond to climate change, so we can prepare for, and mitigate, potential impacts to human and wildlife health,” said Claar.

Story Source:

Materials provided by University of Washington. Original written by Dan DiNicola. Note: Content may be edited for style and length.

Since 2007, several state and local governments have enacted laws requiring employers to provide their workers with paid sick leave. Michael Pesko, an associate professor in Georgia State’s Andrew Young School of Policy Studies, and co-author Kevin Callison studied the effects of these staggered mandate adoptions using multiple government-collected survey data sources from 2005 to 2018.

The mandates were effective in increasing the number of workers holding Paid Sick Leave coverage, particularly those in low-wage industries who were unlikely to have previously received PSL benefits from their employers, they found. Women and racial/ethnic minorities benefitted disproportionately from the PSL mandates.

“These mandates reduced the number of people attending work while sick, which is similar to an earlier study showing influenza-like disease rates decreased after employees gained access to paid sick leave,” said Pesko. “If paid sick leave helps stop people from attending work while sick and prevents the spread of disease as a result, this has important policy implications in today’s fight to contain COVID-19.”

Paid Sick Leave reduces the rate of those working while sick by 4.5 percentage points on average for workers in industries with historically low rates of PSL, such as the accommodation and food service industries. PSL mandates are particularly likely to increase work absences among women and households with children, where workers may be using their benefits to care for a sick child or other family obligations.

“What are the policy implications? The Families First Coronavirus Response Act, which went into effect April 1, is the first congressionally passed bill that provides Paid Sick Leave for employees in medium- and small-sized businesses with coronavirus issues,” Pesko said. “We believe that the bill will reduce people attending work with COVID-19 because it pays for them to stay home and recover. This bill is, therefore, an important component in COVID-19 containment efforts.”

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Materials provided by Georgia State University. Note: Content may be edited for style and length.

This might sound like science fiction but it could soon become reality. A team of researchers led by Martin Fussenegger, ETH Professor of Biotechnology and Bioengineering at the Department of Biosystems Science and Engineering in Basel, have presented their prototype for such an implant in a new paper in the journal Science. Their study is the first to examine how gene expression can be directly activated and regulated using electrical signals. When testing their approach in mice, the researchers established that it worked perfectly.

The Basel-based scientists have a wealth of experience in developing genetic networks and implants that respond to specific physiological states of the body, such as blood lipid levels that are too high or blood sugar levels that are too low. Although such networks respond to biochemical stimuli, they can also be controlled by alternative, external influences like light. “We’ve wanted to directly control gene expression using electricity for a long time; now we’ve finally succeeded,” Fussenegger says.

A circuit board and cell container hold the key

The implant the researchers have designed is made up of several parts. On one side, it has a printed circuit board (PCB) that accommodates the receiver and control electronics; on the other is a capsule containing human cells. Connecting the PCB to the cell container is a tiny cable.

A radio signal from outside the body activates the electronics in the implant, which then transmits electrical signals directly to the cells. The electrical signals stimulate a special combination of calcium and potassium channels; in turn, this triggers a signalling cascade in the cell that controls the insulin gene. Subsequently, the cellular machinery loads the insulin into vesicles that the electrical signals cause to fuse with the cell membrane, releasing the insulin within a matter of minutes.

Coming soon: the Internet of the Body

Fussenegger sees several advantages in this latest development. “Our implant could be connected to the cyber universe,” he explains. Doctors or patients could use an app to intervene directly and trigger insulin production, something they could also do remotely over the internet as soon as the implant has transmitted the requisite physiological data. “A device of this kind would enable people to be fully integrated into the digital world and become part of the Internet of Things — or even the Internet of the Body,” Fussenegger says.

When it comes to the potential risk of attacks by hackers, he takes a level-headed view: “People already wear pacemakers that are theoretically vulnerable to cyberattacks, but these devices have sufficient protection. That’s something we would have to incorporate in our implants, too,” he says.

As things stand, the greatest challenge he sees is on the genetic side of things. To ensure that no damage is caused to the cells and genes, he and his group need to conduct further research into the maximum current that can be used. The researchers must also optimise the connection between the electronics and the cells.

And a final hurdle to overcome is finding a new, easier and more convenient way to replace the cells used in the implant, something that must be done approximately every three weeks. For their experiments, Fussenegger and his team of researchers attached two filler necks to their prototype in order to replace the cells; they want to find a more practical solution.

Before their system can be used in humans, however, it must still pass a whole series of clinical tests.

Story Source:

Materials provided by ETH Zurich. Original written by Peter Rüegg. Note: Content may be edited for style and length.