Covid-19: the Spike protein is no longer the only target

Possible mechanism of action of a drug targeting Nsp1 of SARS-CoV-2. In infected cells, Nsp1 blocks the ribosome mRNA canal by acting as a "cap" that prevents the expression of the host's mRNA. Linking a ligand to the proposed cryptic pocket highlighted in purple could prevent blockage mediated by Nsp1 and, ultimately, restore the ability of the ribosome to initiate the translation of the mRNA.
Photo Credit: UNIGE Alberto Borsatto

A research team led by the UNIGE reveals a hidden cavity on a key SARS-CoV-2 protein to which drugs could bind.

With the continuous emergence of new variants and the risk of new strains of the virus, the development of innovative therapies against SARS-CoV-2 remains a major public health challenge. Currently, the proteins that are on the surface of the virus and/or are involved in its replication are the preferred therapeutic targets, like the Spike protein targeted by vaccines. One of them, the non-structural protein Nsp1, had been studied little until now. A team from the University of Geneva (UNIGE), in collaboration with University College London (UCL) and the University of Barcelona, has now revealed the existence of a hidden ''pocket’ on its surface. A potential drug target, this cavity opens the way to the development of new treatments against Covid-19 and other coronaviruses. These results can be found in the journal eLife.

To prevent next pandemic research suggests we need to restore wildlife habit

Researchers found that bats disrupted by a lack of habitat and food move near humans in agricultural and urban areas, where they can spread Hendra virus to horses and then people.
Photo Credit: Vlad Kutepov

Preserving and restoring natural habitats in specific locations could prevent pathogens that originate in wildlife from spilling over into domesticated animals and humans, according to new research led by an international team of researchers, including Penn State.

The research, undertaken in Australia, found that when bats experience a loss of winter habitat and food shortages in their natural settings, their populations splinter and they excrete more virus. Bats disrupted by the lack of food move near humans in agricultural and urban areas. The team studied Hendra virus, a lethal virus that spills over from fruit bats to horses and then infects people.

“One of the biggest challenges we face are threats arising from bat-borne viruses that spillover into humans and have the potential to cause pandemics. Ebola, MERS, SARS, SARS-CoV-2, Nipah and Hendra are all good examples of this,” said Peter Hudson, Willaman Professor of Biology, Penn State. “The response to the pandemic has been to find ways to speed up vaccine development, but since infections invariably spread much faster than vaccine rollout, this reactive response will never stop a pandemic. Instead, the solution lies with preventing viral spillover from bats to humans.”

Call it a CRISPR conundrum

Model grass Brachypodium distachyon plant grown on liquid media.
Photo courtesy of Marta Torres, m-CAFEs postdoctoral researcher, Deutschbauer lab, Environmental Genomics and Systems Biology "
Credit: University of California, Lawrence Berkeley National Laboratory."

Bacteria use CRISPR-Cas systems as adaptive immune systems to withstand attacks from enemies like viruses. These systems have been adapted by scientists to remove or cut and replace specific genetic code sequences in a variety of organisms.

But in a new study, North Carolina State University researchers show that viruses engineered with a CRISPR-Cas system can thwart bacterial defenses and make selective changes to a targeted bacterium – even when other bacteria are in close proximity.

“Viruses are very good at delivering payloads. Here, we use a bacterial virus, a bacteriophage, to deliver CRISPR to bacteria, which is ironic because bacteria normally use CRISPR to kill viruses,” said Rodolphe Barrangou, the Todd R. Klaenhammer Distinguished Professor of Food, Bioprocessing and Nutrition Sciences at NC State and corresponding author of a paper describing the research published today in Proceedings of the National Academy of Sciences. “The virus in this case targets E. coli by delivering DNA to it. It’s like using a virus as a syringe.”

The NC State researchers deployed two different engineered bacteriophages to deliver CRISPR-Cas payloads for targeted editing of E. coli, first in a test tube and then within a synthetic soil environment created to mimic soil – a complex environment that can harbor many types of bacteria.

Limiting antibiotics for cows may create a new dairy market

Photo Credit: David Mark

Consumers would be willing to buy milk from cows only treated with antibiotics when medically necessary – as long as the price isn’t much higher than conventional milk, according to researchers at the College of Veterinary Medicine.

The findings suggest conventional farmers could tap a potentially large market for this type of milk if they can find the right price point – and that dairy consumers can help slow the rise of antimicrobial resistance.

“Most of the antibiotics produced throughout the world are used for animal agriculture. Therefore, reducing antibiotic use in animals, including dairy cattle, is necessary to tackle antibiotic resistance at a global scale,” said Dr. Renata Ivanek, professor in the Department of Population Medicine and Diagnostic Sciences. She is senior author on the study, which was published Nov. 4 in the Journal of Dairy Science.

In the paper, the researchers propose a new label for milk that indicates responsible antibiotic use (RAU), which would leverage consumer preferences to reduce the use of antibiotics on commercial dairy farms. The study showed that, although a consumer’s willingness to pay for the RAU-labeled milk was comparable to how much they would pay for the unlabeled milk, they strongly preferred the RAU-labeled milk over the unlabeled milk option. Therefore, the researchers hypothesize this new RAU label would entice farmers to minimize antibiotics more than they do for conventional, unlabeled milk.

Therapeutic HIV vaccine with Oxford technology achieves encouraging results

Artist illustration of the HIV virus.
Illustration Credit: Darwin Laganzon

A phase I/IIa clinical trial that the University of Oxford collaborated on has demonstrated that a T-cell therapeutic HIV vaccine was associated with better control of the virus rebound when antiretroviral therapy (ART) was temporarily withdrawn.

Researchers carrying out the AELIX-002 study, whose results have been published in Nature Medicine, reported that two fifths of participants without any genetic background associated with spontaneous HIV control were able to stay off ART for the six-month duration of the supervised ART pause.

The vaccine in the study – developed by AELIX Therapeutics – delivered the HIVACAT T-cell Immunogen (HTI) using a combination of DNA vector, modified vaccinia virus Ankara (MVA) vector and simian adenovirus vector ChAdOx1. The latter two vaccines were constructed at Oxford.

Tomáš Hanke, Professor of Vaccine Immunology at the Jenner Institute, Nuffield Department of Medicine, who leads on HIV vaccine development, said:

‘This result provides further encouragement that active immunization against HIV may be possible, slowing HIV replication, providing a window of treatment holidays for people living with HIV and eventually leading to HIV cure. T cells/T-cell vaccines are likely to play an important part in the final package for HIV cure and, perhaps, other advanced therapies for difficult diseases.’

Infants are less likely to contract COVID, develop severe symptoms than other household caregivers

Image by Pexels

Infants whose mothers test positive for COVID-19 tend to develop less-severe symptoms than their parents, if they become infected with the virus at all.

In one of the first studies to explore how COVID-19 specifically affects older infants, researchers from the University of Washington and at institutions at four other locations in the Western and Southern U.S. found that the number of infected people in a household was the factor most closely linked with the infant’s likelihood of being infected.

“The focus on infants early in the pandemic was about possible transmission risks during pregnancy, birth or through breastfeeding, but there were other questions about the risks in the household to infants and other children when caregivers are sick,” said Melanie Martin, assistant professor of anthropology at the UW and the first author of the study, which in the journal Frontiers in Immunology. “Infants are in the most contact, and very close contact, with their caregiver than with any other family members. And so, we asked, "How much are infants at risk, and how do you protect children when they are sick?”

The study analyzed surveys and antibody results (taken from pin-prick blood samples) of 46 pairs of COVID-positive mothers and their infants for two months following maternal infection. Infants were at least 1 month old, and COVID-positive mothers were enrolled in the study within days, sometimes hours, of receiving their positive PCR test results. The researchers also recruited a comparative group of 11 COVID-negative mothers, who tested negative after exposure or symptoms, and a control group of 26 mothers with no known COVID exposures or symptoms.

Viruses can ‘hitchhike’ on microplastics

Photo Credit: Naja Bertolt Jensen

Microplastics are not just tiny particles that can be ingested, they can also carry viruses, a University of Queensland study has revealed.

The study, led by Associate Prof Jianhua Guo and Dr Ji Lu from UQ’s Australian Centre for Water and Environmental Biotechnology (ACWEB), investigated if microplastics have the ability to harbor viruses, including the one found inside E. coli bacteria.

“We often hear about the human and environmental harm caused by microplastics in water, but there is little known about whether the tiny microplastic particles can carry viruses,” Dr Guo said.

“What we found is that viruses can hitchhike on microplastics and prolong their infectivity, which means there could be an increased risk of virus transmission throughout waterways and the environment.”

Dr Lu said they used the E. coli bacteriophage in the study, which is a virus that infects and replicates within the bacteria itself and is not harmful to humans.

Study Identifies Key T Cells for Immunity Against Fungal Pneumonia

 GM-CSF+ and IL-17A+ lineages of T cells are instrumental in controlling many fungal and bacterial infections and implicated in autoimmune pathology. This study shows that GM-CSF expressing Tc17 cells are necessary for mediating fungal vaccine immunity without augmenting pathology.
Credit: Som Nanjappa

Researchers at the University of Illinois College of Veterinary Medicine have demonstrated in a mouse model that a specific type of T cell, one of the body’s potent immune defenses, produces cytokines that are necessary for the body to acquire immunity against fungal pathogens. This finding could be instrumental in developing novel, effective fungal vaccines.

Despite vaccines being hailed as one of the greatest achievements of medicine, responsible for controlling or eradicating numerous life-threatening infectious diseases, no vaccines have been licensed to prevent or control human fungal infections.

This lack proved especially deadly during the COVID-19 pandemic. In countries where steroids were widely used to suppress inflammation of the lungs, COVID-19 patients with preexisting conditions such as uncontrolled diabetes showed a greater likelihood of developing lethal fungal infections.

Covid-19 is linked to increased degradation of connections between nerve cells in a new brain model

Postdoctoral fellow Samudyata and doctoral student Susmita Malwade.
Source: Karolinska Institutet

Researchers at Karolinska Institutet have used cellular reprogramming in a new study to create human three-dimensional brain models and infected them with SARS-CoV-2. In infected models, the brain's immune cells showed an excessive elimination of connections between the nerve cells. The gene expression of these cells also mimicked changes observed in neurodegenerative diseases. The results hope to identify new treatments for cognitive symptoms after Covid-19 infection.

Several studies have reported persistent cognitive symptoms following a covid-19 infection, but the underlying mechanisms for this are still unknown. The researchers behind the study, published in the journal Molecular Psychiatry, have created from human induced pluripotent stem cells (iPS) three-dimensional models of the brain in test tubes, so-called brain organoids. The model differs from previous organoid models in that they also contain microglia - the brain's immune cells. In the infected models, microglia regulated genes involved in phagocytosis, "cell-eating," the researchers could also see how microglia contained an increased amount of proteins from brain cell connections, so-called synapses. The developed model and results of the study can help guide future efforts to address cognitive symptoms in the aftermath of COVID-19 and other neuroinvasive viral infections.

Attack on 2 fronts leads ocean bacteria to require carbon boost

The study is the first to observe these complex interactions under the ocean surface: photosynthetic bacteria simultaneously infected with viruses and floating in the presence of organisms, called protists, that eat them. Photo Credit: Matt Hardy

The types of ocean bacteria known to absorb carbon dioxide from the air require more energy – in the form of carbon – and other resources when they’re simultaneously infected by viruses and face attack from nearby predators.

Viruses are abundant in the ocean, and research now suggests that marine viruses have beneficial functions, including helping to drive carbon absorbed from the atmosphere to permanent storage on the ocean floor. When viruses infect other microbes in that environment (and anywhere, in fact), the interaction results in creation of entirely new organisms called “virocells.”

In this new study, researchers worked with cyanovirocells – cyanobacteria that absorb carbon and release oxygen through photosynthesis that have been infected with viruses. The analysis of changes in the infected bacteria’s gene activation and metabolism under lab conditions designed to mimic nature hints at an intriguing possibility: The dual threat of viral infection and drifting among hungry predator microbes might lead cyanovirocells to take in more carbon.

Obesity and biological sex may make individuals more vulnerable to COVID-19

A new West Virginia University study suggests obesity may impair the ability to fight off SARS-CoV-2, the virus that causes COVID-19, in a sex-dependent manner.
Credit: WVU Illustration/Graham Curry

A new animal study from Katherine Lee, a researcher with the West Virginia University School of Medicine, investigates why individuals with obesity may have a particularly difficult time fending off SARS-CoV-2, the virus that causes COVID-19. Specifically, female obese mice experienced worse disease symptoms, showing the importance of both obesity and biological sex in COVID-19 outcomes.

Lee’s findings appear in the journal iScience.

Obesity dramatically increases someone’s risk of being hospitalized, placed on a ventilator or dying due to COVID-19. Considering that about two out of every five Americans are obese, that risk is far from negligible.

“No human is 100% healthy in every respect,” said Lee, a doctoral student in the Department of Microbiology, Immunology and Cell Biology. “There are always going to be little differences in the way our bodies function and those changes can ultimately affect the ways we respond to everything. So, I think as soon as we start incorporating those differences and changes — metabolic diseases and preexisting conditions — into our work, we can learn more about how vaccines and therapeutics might be more or less effective in these people.”

Virologists close gap on unknown viruses affecting amphibians and reptiles

It took three years to identify the virus that all but wiped out the Bellinger River turtle in 2015. It is hoped that amassing new viral data affecting herptiles will allow quicker conservation responses.
Credit: Pelagic, CC BY-SA 4.0

New knowledge about amphibian and reptile viruses will help us act faster to conserve threatened species.

A study of viruses that affect amphibians and reptiles has closed the gap on the knowledge of viruses affecting animals which until now has largely focused on humans and other mammals.

Third year PhD student Emma Harding, who led the study published today in ISME Communications, used the UNSW supercomputer Katana to comb through petabytes (millions of gigabytes) of publicly available amphibian and reptile RNA data in search of new viruses affecting these classes of animals.

“We know a lot about viruses that infect us and livestock, however not many people have investigated viruses that infect amphibians and reptiles, even though there are over 18,000 species globally,” Ms. Harding, lead author on the paper, says.

“We looked through more than 200 RNA datasets from amphibians and reptiles for evidence of new viruses that could lead to disease. We found 26 new viruses from a range of different families and now have a better understanding of what viruses can infect these animals.”

The cell sentinel that neutralizes hepatitis B

Confocal microscopy images showing in the cell nucleus (blue), the recruitment of Smc5/6 (green) by SLF2 (red) into PML bodies.
Credit: UNIGE - Laboratory of Professor Michel Strubin - Regulation of hepatitis B virus gene expression - Department of Microbiology and Molecular Medicine.

The hepatitis B virus (HBV) is responsible for one of the most serious and common infectious diseases. Transmitted through biological fluids, it attacks the liver cells. The chronic form of the disease can lead to serious complications, including cirrhosis and liver cancer. There is no effective treatment for the chronic form of the disease, which can only be prevented by vaccination. After identifying a key protein complex that is active when our body is infected by the virus, a team from the University of Geneva (UNIGE) has deciphered the precise functioning of this protective mechanism, opening the way to new therapeutic targets. These results can be read in the journal Nature Structural and Molecular Biology.

Hepatitis B is the most common form of hepatitis. It is a viral disease caused by the hepatitis B virus. It is mainly blood or sexually transmitted. It is up to 100 times more contagious than HIV. By infecting the liver cells, this virus causes a transitory inflammation of this organ that can also evolve towards a chronic infection. This can then lead to serious pathologies, such as cirrhosis or liver cancer. It is estimated that nearly one million people die each year from this disease worldwide. There is no definitive treatment for chronic hepatitis B. The only way to prevent it is to be vaccinated before the disease appears.

In 2016, a UNIGE team led by Michel Strubin, an associate professor in the Department of Microbiology and Molecular Medicine and in the Geneva Centre for Inflammation Research at the UNIGE Faculty of Medicine, revealed a mechanism that is crucial for understanding this disease: when our immune system defends itself against it, a complex - i.e. an interdependent set - of six proteins called SMC5/6, present in our cells, detects the viral DNA and blocks it. The virus then strikes back and produces a specific protein, the X protein. This protein enters the cell and degrades SMC5/6, which is no longer able to play its sentinel role.

Coronavirus formation is successfully modeled

Roya Zandi (left) and Siyu Li. (UCR/Zandi lab)
Source: University of California, Riverside

A physicist at the University of California, Riverside, and her former graduate student have successfully modeled the formation of SARS-CoV-2, the virus that spreads COVID-19, for the first time.

In a paper published in Viruses, a journal, Roya Zandi, a professor of physics and astronomy at UCR, and Siyu Li, a postdoctoral researcher at Songshan Lake Materials Laboratory in China, offer an overall understanding of the assembly and formation of SARS-CoV-2 from its constituent components.

“Understanding viral assembly has always been a key step leading to therapeutic strategies,” Zandi said. “Numerous experiments and simulations of viruses such as HIV and hepatitis B virus have had a remarkable impact on elucidating their assembly and providing means to combat them. Even the simplest questions regarding the formation of SARS-CoV-2 remain unanswered.”

Zandi explained that a critical step in the life cycle of any virus is the packaging of its genome into new virions or virus particles. This is an especially challenging task for coronaviruses, like SARS-CoV-2, with their very large RNA genomes. Indeed, coronaviruses have the largest genome known for a virus that uses RNA as its genetic material.

Chipping away at the many unknowns of obscure animal viruses

Patas monkeys are among the wild African monkeys believed to be natural reservoirs for the simian hemorrhagic fever virus. 
Photo Credit: Andrew S

Researchers have identified enough biological details about a virus endemic in African primates to suggest that this virus, which causes a hemorrhagic fever disease in monkeys, has decent potential to spill over to humans.

The findings suggest a surveillance program is warranted for citizens in Africa who may be at risk for exposure to the virus. But the study teaches a much larger lesson as well, researchers say: It’s never too early to start preparing for the next animal virus to come along and unexpectedly cause disease in people.

“There are a lot of unknown animal viruses out there that may pose risk to humans,” said Cody Warren, first author of the study and assistant professor of veterinary biosciences at The Ohio State University.

“We need to be prospectively looking at animal viruses that have been ignored to see if they have the capacity to replicate in human cells. If they do, will we continue to ignore them? I don’t think we should,” he said.

Warren completed this work at the University of Colorado Boulder as a postdoctoral researcher in the lab of senior author Sara Sawyer, professor of molecular, cellular & developmental biology.

Study reveals how COVID-19 damages the heart

Image Credit: Sanjay k j

University of Queensland researchers have discovered how COVID-19 damages the heart, opening the door to future treatments.

This initial study – featuring a small cohort – found COVID-19 damaged the DNA in cardiac tissue, which wasn’t detected in influenza samples.

UQ Diamantina Institute researcher Dr Arutha Kulasinghe said the team found while COVID-19 and influenza are both severe respiratory viruses, they appeared to affect cardiac tissue very differently.

“In comparison to the 2009 flu pandemic, COVID has led to more severe and long-term cardiovascular disease but what was causing that at a molecular level wasn’t known,” Dr Kulasinghe said.

“During our study, we couldn’t detect viral particles in the cardiac tissues of COVID-19 patients, but what we found was tissue changes associated with DNA damage and repair.

“DNA damage and repair mechanisms foster genomic instability and are related to chronic diseases such as diabetes, cancer, atherosclerosis and neurodegenerative disorders, so understanding why this is happening in COVID-19 patients is important.”

To Stop Viruses, SDSU Researchers are Figuring Out How They're Built

Multiple protein subunits (green, purple and red) of a plant-infecting virus have separate nucleation and growth phases similar to the MS2 bacteria-infecting virus (right).
Source: Protein Data Bank.

An SDSU team, along with Harvard and UCLA collaborators, are researching how distantly related viruses self-organize to improve disease-fighting tactics.

Without a multi-page instruction manual or a commanding Captain America, how do viruses assemble hundreds of individual pieces into elaborate structures capable of spreading disease?

Solving the secret of self-assembly can pave the way for engineering advancements like molecules and robots that put themselves together. It could also contribute to more efficient packaging, automated delivery and targeted design of medicine in the fight against viruses that cause colds, diarrhea, liver cancer and polio.

“If we understand the physical rules of how viruses assemble, then we can try to make them form incorrect structures to hinder their spread,” said Rees Garmann, a chemist at San Diego State University and lead author of a new paper published in the journal PNAS that fills in a piece of the puzzle.

Mysterious soil virus gene seen for first time

Crystals of the soil virus AMG product (chitosanase) at 400x magnification. Individual crystals were cryo-cooled in liquid nitrogen before being exposed to the powerful SSRL X-rays beams for structure analysis.
Credit: Clyde Smith/SLAC National Accelerator Laboratory

In every handful of soil, there are billions of bacteria, fungi, and viruses, all working to sustain the cycle of life. Understanding how these microorganisms interact with one another helps scientists analyze soil health, soil carbon and nutrient cycling, and even the ways in which dead insects decompose.

Soil viruses contain genes that appear to have some metabolic function, but they are clearly not required for normal viral replication. These genes are called auxiliary metabolic genes (AMGs) and they produce proteins, some of which are enzymes that have a variety of functions. Until now, scientists have wondered whether some AMG proteins play a role in critical soil processes, like carbon cycling. To find out more about soil AMGs, researchers determined the atomic structure of a protein that is expressed by a particular AMG.

Specifically, researchers irradiated fragile crystallized protein samples with high-brightness X-rays generated by the Stanford Synchrotron Radiation Lightsource’s (SSRL) Beam Line 12-2 at the Department of Energy’s (DOE) SLAC National Accelerator Laboratory. The X-rays struck the proteins within the crystal samples, revealing their molecular structures and a bit of the mystery behind their makeup.

AMGs do not, like many viral genes, help a virus replicate. Instead, they encode a variety of proteins, each with their own predicted function. The AMG that was expressed was a putative enzyme that plays a key role in how soils process and cycle carbon in the biosphere.

The first look at how rabies affects vampire bat social behavior

Researchers said no previous studies had tried to quantify changes in grooming habits in vampire bats infected with rabies – despite the possibility that they might infect each other through the licking and chewing that constitute the grooming behavior they engage in for up to 5% of their active time in the roost.
Photo credit: Rachel Moon

Vampire bats infected with the rabies virus aren’t likely to act stereotypically “rabid,” according to a new study – instead, infected male bats tended to withdraw socially, scaling back on the common habit of grooming each other before they died of the disease.

The study was the first to observe how rabies affects vampire bat social behavior, and one of only a few research efforts to understand how rabies infection impacts behavior in one of the species most responsible for causing rabies outbreaks in humans and livestock in Latin America. The virus is typically transmitted to other species by direct contact between vampire bats’ infected saliva and the broken skin of the livestock or other animals (and, rarely, humans) they bite to feed on blood.

In the roost, vampire bats might infect each other through the licking and chewing that constitute the grooming behavior they engage in for up to 5% of their active time, said Gerald Carter, senior author of the study and assistant professor of evolution, ecology and organismal biology at The Ohio State University.

Higher risk of serious COVID-19 complications in children with immunodeficiency

Qiang Pan Hammarström, professor at Karolinska Institutet.
Photo credit: Erik Flyg.

Children with certain immunodeficiency diseases carry mutations in genes that regulate the body’s immune system against viral infections and they have a higher mortality rate due to COVID-19. This is according to a study by researchers from Karolinska Institutet, published in the Journal of Allergy and Clinical Immunology (PDF).

Most children infected with the SARS-CoV-2 coronavirus develop a mild illness or show no symptoms at all. But for a small percentage, serious complications may develop.

“Mortality is much higher among children with primary immunodeficiency diseases infected with SARS-CoV-2. Our results indicate that basic immunological examination and genetic analysis should be conducted in children with severe COVID-19 or multi-inflammatory syndrome (MIS-C). The clinicians will then be able to help these children with more precise therapies based on their genetic changes,” says Qiang Pan-Hammarström, professor at the Department of Biosciences and Nutrition, Karolinska Institutet, who led the study.

How the infection affects patients with primary immunodeficiency diseases, i.e. hereditary and congenital diseases of the immune system, is controversial. Even among these patients, some suffer from severe COVID-19 while others experience mild or no symptoms.