People Living With HIV More Likely to Get Sick With, Die From COVID-19 (Medicine)

Over the past year, studies have revealed that certain pre-existing conditions, such as cancer, diabetes and high blood pressure, can increase a person’s risk of dying from COVID-19. New research shows that individuals living with human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) — an estimated 38 million worldwide, according to the World Health Organization — have an increased risk of SARS-CoV-2 infection and fatal outcomes from COVID-19.

In a new studyPenn State College of Medicine researchers found that people living with HIV had a 24% higher risk of SARS-CoV-2 infection and a 78% higher risk of death from COVID-19 than people without HIV. They assessed data from 22 previous studies that included nearly 21 million participants in North America, Africa, Europe and Asia to determine to what extent people living with HIV/AIDS are susceptible to SARS-CoV-2 infection and death from COVID-19.

The majority of the participants (66%) were male and the median age was 56. The most common comorbidities among the HIV-positive population were hypertension, diabetes, chronic obstructive pulmonary disease and chronic kidney disease. The majority of patients living with HIV/AIDS (96%) were on antiretroviral therapy (ART), which helps suppress the amount of HIV detected in the body. 

“Previous studies were inconclusive on whether or not HIV is a risk factor for susceptibility to SARS-CoV-2 infection and poor outcomes in populations with COVID-19,” said Dr. Paddy Ssentongo, lead researcher and assistant professor at the Penn State Center for Neural Engineering. “This is because a vast majority of people living with HIV/AIDS are on ART, some of which have been used experimentally to treat COVID-19.”

According to the researchers, certain pre-existing conditions are common among people living with HIV/AIDS, which may contribute to the severity of their COVID-19 cases. The beneficial effects of antiviral drugs, such astenofovir and protease-inhibitors, in reducing the risk of SARS-CoV-2 infection and death from COVID-19 in people with living with HIV/AIDS remain inconclusive.

“As the pandemic has evolved, we’ve obtained sufficient information to characterize the epidemiology of HIV/SARS-CoV-2 coinfection, which could not be done at the beginning of the pandemic due to scarcity of data,” said Vernon Chinchilli, fellow researcher and chair of the Department of Public Health Sciences. “Our findings support the current Centers for Disease Control and Prevention guidance to prioritize persons living with HIV to receive a COVID-19 vaccine.”

Emily Heilbrunn, Anna Ssentongo and Jonathan Nunez of Penn State College of Medicine; Ping Du of Takeda Pharmaceuticals and Shailesh Advani of Georgetown University also contributed to this research. The researchers declare no conflicts of interest.

This research was supported by the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or FDA.

Featured image: Dr. Zeina Arnouk takes care of a patient in the COVID-19 unit at Penn State Health St. Joseph Medical Center. Image: Penn State Health


Reference: Ssentongo, P., Heilbrunn, E.S., Ssentongo, A.E. et al. Epidemiology and outcomes of COVID-19 in HIV-infected individuals: a systematic review and meta-analysis. Sci Rep 11, 6283 (2021). https://doi.org/10.1038/s41598-021-85359-3


Provided by Penn State

Tumor-promoting Immune Cells Retrained to Fight Most Aggressive Type of Brain Cancer (Medicine)

Regulatory T cells in the brain can be reprogrammed from guarding glioblastoma tumors to attacking them from within

It’s a real-life plot worthy of a classic spy novel: Researchers at Massachusetts General Hospital (MGH), the Dana-Farber Cancer Institute and other Boston-area research centers are turning the tables on glioblastomas, the most devastating and aggressive form of brain cancer, by transforming a type of cell that normally protects tumors and inhibits effective drug therapy into a stone-cold glioblastoma killer.

Glioblastoma, a type of brain tumor, is rapidly fatal: Most patients die within two years of diagnosis despite aggressive therapies such as brain surgery, whole-brain radiation and chemotherapy.

Despite hopes that a class of drugs known as immune checkpoint blockers (ICBs) – drugs that have revolutionized the treatment of patients with malignant melanoma, non-small-cell lung cancer, and other solid tumors – could also benefit patients with glioblastoma, ICBs have not been effective against the disease in clinical trials to date.

ICBs work by removing the brakes on the immune system, allowing previously inactive immune cells to recognize, attack and destroy mutated, cancerous cells while causing minimal damage to the normal tissues.

But as Rakesh K. Jain, PhD, director of the Edwin L. Steele Laboratories in the Department of Radiation Oncology at MGH, and colleagues show in a study published in Nature Communications, glioblastomas wreak havoc with the immune system by altering the landscape surrounding and within the tumor, known as the tumor microenvironment, reorganizing blood vessels, immune cells, and tissue structural proteins into an abnormal glioblastoma-promoting environment, effectively hampering the action of ICBs.

“These abnormalities promote a suppressive environment for the immune system, which blocks tumor-fighting immune cells at the tumor border while allowing infiltration of tumor-promoting immune cells known as regulatory T cells, or Tregs,” explains Jain, who is also Andrew Werk Cook Professor of Radiation Oncology at Harvard Medical School (HMS). “Among elements of the tumor microenvironment, we exploited the preferential accumulation of Tregs in glioblastoma by therapeutically altering their function – a strategy known as reprogramming – to make them kill cancer cells instead of protecting them,” he continues. “Because Tregs already present in these tumors can be reprogrammed, this strategy does not rely on additional recruitment of anti-tumor immune cells – another frequent barrier to successful immunotherapy in brain tumors.”

The investigators accomplished Treg conversions by targeting a receptor (docking site) on glioblastoma Tregs called glucocorticoid-induced TNFR-related receptor (GITR), using an antibody (αGITR) that reprograms the tumor promoter into a tumor-fighting type of T cell. Combining this antibody with an ICB resulted in a strong survival benefit in mouse models of human glioblastoma.

“Importantly, some of these mice not only rejected tumors but developed a long-term immunity against glioblastoma,” comments co-author Dai Fukumura, MD, PhD, deputy director of the Steele Labs.

Although their research thus far has been limited to mouse models of human glioblastoma, “our work offers a possible solution to overcome resistance to immunotherapy, and can be translated to patients,” says lead author Zohreh Amoozgar, PharmD, PhD, a postdoctoral research fellow in the Steele Labs.

“In addition to showing that Tregs can be reprogrammed from tumor promoters to cancer killers, our study also demonstrated that a potent anti-tumor effect can be generated by both alleviating Treg-mediated resistance to immunotherapy and by reinvigorating CD8+ T cells, one of the major players in immune responses against cancer,” explains co-corresponding author Hye-Jung Kim, PhD, an immunologist at the Dana-Farber Cancer Institute.

Their findings support the use of αGITR antibodies in combination with ICBs, with or without the current standard-of-care therapies, in patients with glioblastomas who have high levels of Tregs, Jain says.

The work was supported by grants from the National Institutes of Health as well as the National Foundation for Cancer Research, the Harvard Ludwig Cancer Center, the Advanced Medical Research Foundation and Jane’s Trust Foundation.


Reference: Amoozgar, Z., Kloepper, J., Ren, J. et al. Targeting Treg cells with GITR activation alleviates resistance to immunotherapy in murine glioblastomas. Nat Commun 12, 2582 (2021). https://doi.org/10.1038/s41467-021-22885-8


Provided by Massachusetts General Hospital

UQ Research Finds New Way to Reduce Scarring (Medicine)

Researchers have been able to reduce scarring by blocking part of the healing process in research that could make a significant difference for burns and other trauma patients.

University of Queensland Professor Kiarash Khosrotehrani said scars had been reduced by targeting the gene that instructs stem cells to form them in an animal study.

“The body’s natural response to trauma is to make plenty of blood vessels to take oxygen and nutrients to the wound to repair it,” Professor Khosrotehrani said.

“Once the wound has closed, many of these blood vessels become fibroblast cells which produce the collagens forming the hard materials found in scar tissue.

“We found that vascular stem cells determined whether a blood vessel was retained or gave rise to scar material instead.”

The experimental dermatology team then identified the molecular mechanism to switch off the process by targeting a specific gene involved in scar formation known as SOX9.

Professor Khosrotehrani said while more research was required, the potential application of the findings would have obvious benefits for many patients including those who’ve had knee or hip surgeries, melanomas removed, or suffered burns.

“The classic situation where there’s a lot of scarring is burns – where the wound is healed but there is a big scar in that area,” he said.

“Now that we’ve found the molecular drivers, we understand the process better and we are hopeful that a treatment can be developed.

“We used siRNA – or small ribonucleic acid – technology to block the RNA of SOX9 from being expressed and this reduced scarring in animals.

“Whatever we propose has to go through the further trials, but we believe this application won’t be difficult to apply to human patients.”

Part of the research has been funded by the Australian Research Council Discovery Project grant, and Dr Khosrotehrani has been supported by a fellowship of the National Health and Medical Research Council.

The research is published in Nature Communications. (DOI: 10.1038/s41467-021-22717-9).

Featured image: University of Queensland Professor Kiarash Khosrotehrani © University of Queensland


Reference: Zhao, J., Patel, J., Kaur, S. et al. Sox9 and Rbpj differentially regulate endothelial to mesenchymal transition and wound scarring in murine endovascular progenitors. Nat Commun 12, 2564 (2021). https://doi.org/10.1038/s41467-021-22717-9


Provided by University of Queensland

Oregon State Researchers Discover New Class of Cancer Fighting Compounds (Medicine)

A team of Oregon State University scientists has discovered a new class of anti-cancer compounds that effectively kill liver and breast cancer cells.

The findings, recently published in the journal Apoptosis, describe the discovery and characterization of compounds, designated as Select Modulators of AhR-regulated Transcription (SMAhRTs).

Edmond Francis O’Donnell III and a team of OSU researchers conducted the research in the laboratory of Siva Kolluri, a professor of cancer research at Oregon State. They also identified the aryl hydrocarbon receptor (AhR) as a new molecular target for development of cancer therapeutics.

“Our research identified a therapeutic lead that acts through a new molecular target for treatment of certain cancers,” Kolluri said.

O’Donnell added: “This is an exciting development which lays a foundation for a new class of anti-cancer therapeutics acting through the AhR.”

The researchers employed two molecular screening techniques to discover potential SMAhRTs and identified a molecule – known as CGS-15943 – that activates AhR signaling and kills liver and breast cancer cells.

Specifically, they studied cells from human hepatocellular carcinoma, a common type of liver cancer, and cells from triple negative breast cancer, which account for about 15% of breast cancers with the worst prognosis.

“We focused on these two types of cancers because they are difficult to treat and have limited treatment options,” said Kolluri, a professor in the Department of Environmental and Molecular Toxicology in the College of Agricultural Sciences. “We were encouraged by the results because they are unrelated cancers and targeting the AhR was effective in inducing death of both of these distinct cancers.”

The researchers also identified the AhR-mediated pathways that contribute to the anti-cancer actions of CGS-15943. Developing cancer treatments requires a detailed understanding of how they act to induce anti-cancer effects. The researchers determined that CGS-15943 increases the expression of a protein called Fas Ligand through the AhR and causes cancer cell death.

These results provide exciting new leads for drug development, but human therapies based on these results may not be available to patients for 10 years, the researchers said.

An editorial commemorating the 25th anniversary issue of the journal Apoptosis highlighted this discovery and the detailed investigation of cancer cell death promoted by CGS-15943.

In addition to Kolluri and O’Donnell, who recently completed medical school and is an orthopaedic surgery resident at UC Davis Medical Center, other authors of the paper are: Hyo Sang Jang and Nancy Kerkvliet, both from Oregon State; and Daniel Liefwalker, who formerly worked in Kolluri’s lab and is now at Oregon Health and Science University. Kolluri is also part of Oregon State’s Linus Pauling Institute and The Pacific Northwest Center for Translational Environmental Health Research.

Funding for the research came from the American Cancer Society, National Institute of Environmental Health Sciences, the U.S. Army Medical Research and Material Command, the Department of Defense Breast Cancer Research Program, Oregon State University and the National Cancer Institute.


Provided by Oregon State University

Study: Researchers Use Eel-like Protein to Control Brain (Neuroscience)

Bruchas Lab uses protein called parapinopsin found in lamprey to turn brain neurons on and off; the discovery could lead to turning off mood disorders, addiction.

Researchers looking to help people suffering from addiction, depression, and pain are studying how certain brain neurons operate to see if they can be controlled.

In a paper published May 11 in Neuron, researchers at the University of Washington School of Medicine and Washington University in St. Louis, along with several other universities, successfully used a protein called parapinopsin to turn off brain circuits. This protein is found in lamprey – an ancient lineage of jawless fish similar to eel.

“We found a particular protein that comes from lamprey that has been around for hundreds of millions of years. We took the gene from that protein and found we can control the way neurons talk to each other, which is how chemicals are transmitted into the brain,” said lead corresponding author Michael Bruchas, professor of anesthesiology and pain medicine at the University of Washington School of Medicine and co-director of the Imaging and Neural Circuits core of the Center for Neurobiology of Addiction, Pain, and Emotion.

For decades, neuroscientists have been using different types of light-sensitive proteins that are expressed in plants and bacteria to experiment with brain circuitry, said Bruchas. But this is the first time a protein was taken from lamprey to control brain circuits.

Parapinopsin is a type of protein called a “g protein coupled receptor” or GPCR. These GPCRs emerged early on in evolution and can be found in organisms ranging from bacteria to humans. Bruchas said there at least 850 of these kinds of proteins in mammals. These proteins control everything from heart rate to fat storage, to reward and stress responses. GPCRs also respond well to chemicals, such as dopamine and serotonin, which make people feel good.

“Some of these GPCR pathways are highly conserved across millions of years of evolution, and that allowed us to hack into them using parapinopsin,” said Bryan Copits, lead author and co-corresponding author, assistant professor of anesthesiology in the Pain Center at Washington University School of Medicine, where Dr. Bruchas was formerly located. Researchers from University of California (UC), Los Angeles, UC Davis, UC San Diego, and University of Zurich were also involved.

The Bruchas Lab focuses on GPCRs. But finding a way to inhibit neurons had been hard to come by until the parapinopsin discovery, Bruchas said. He said the ability to inhibit neurons could eventually lead to turning off mood disorders and unwanted behaviors like depression and addiction.

The researchers found that the protein in lamprey respond to light not chemicals – another approach for targeted delivery. For example, if a part of the brain was having seizures from Parkinson’s, it might be possible to isolate the effect with an electrode, dampen it with adjustments to neurotransmission, or to inhibit specific pathways to improve mood.

Bruchas said the original discovery of parapinopsin was made by researchers in Japan in the Terakita lab, who have been discovering different light-sensitive GPCRs across species.

“This is a perfect rationale for why basic science is so incredibly important,” said Bruchas. “Because of someone’s hard work of basic biological discovery, we have a new tool for medical research. “

Bruchas said his team is planning to use the discovery for research into expanding their knowledge of the inner workings of the brain and to identify treatments for stress, depression, addiction, and pain.  

This work was funded by the National Institutes of Health Brain Initiative, National Institute of Mental Health, and National Institute of Drug Abuse. Grant numbers: R01 MH111520; NIH R21 DA049569, K01 DA042219, K01 DK115634, T32DA007278, P30DA048736, and R35 GM122577.

Study in brief:
Optical approaches to  inhibit neuronal projections rapidly and reversibly have lagged behind those for activation. Copits and others identify a photoswitchable GPCR-based opsin that couples to inhibitory effectors. This opsin leverages the natural ability of presynaptic GPCRs to inhibit transmitter release to provide an alternative strategy to manipulate distinct synaptic projections.

Featured image: An ancient lineage of jawless fish similar to eel called lamprey was the key to successful experiment published in Neuron. © Getty Images


Reference: Bryan A. Copits, Raaj Gowrishankar et al., “A photoswitchable GPCR-based opsin for presynaptic inhibition”, Neuron, 2021. DOI: https://doi.org/10.1016/j.neuron.2021.04.026


Provided by University of Washington School of Medicine

COVID-19 Alters Gray Matter Volume in the Brain, New Study Shows (Neuroscience)

Covid-19 patients who receive oxygen therapy or experience fever show reduced gray matter volume in the frontal-temporal network of the brain, according to a new study led by researchers at Georgia State University and the Georgia Institute of Technology.

The study found lower gray matter volume in this brain region was associated with a higher level of disability among Covid-19 patients, even six months after hospital discharge.

Gray matter is vital for processing information in the brain and gray matter abnormality may affect how well neurons function and communicate. The study, published in the May 2021 issue of Neurobiology of Stress, indicates gray matter in the frontal network could represent a core region for brain involvement in Covid-19, even beyond damage related to clinical manifestations of the disease, such as stroke.

The researchers, who are affiliated with the Center for Translational Research in Neuroimaging and Data Science (TReNDS), analyzed computed tomography scans in 120 neurological patients, including 58 with acute Covid-19 and 62 without Covid-19, matched for age, gender and disease. They used source-based morphometry analysis, which boosts the statistical power for studies with a moderate sample size.

“Science has shown that the brain’s structure affects its function, and abnormal brain imaging has emerged as a major feature of Covid?19,” said Kuaikuai Duan, the study’s first author, a graduate research assistant at TReNDS and Ph.D. student in Georgia Tech’s School of Electrical and Computer Engineering. “Previous studies have examined how the brain is affected by Covid-19 using a univariate approach, but ours is the first to use a multivariate, data-driven approach to link these changes to specific Covid-19 characteristics (for example fever and lack of oxygen) and outcome (disability level).”

The analysis showed patients with higher levels of disability had lower gray matter volume in the superior, medial and middle frontal gyri at discharge and six months later, even when controlling for cerebrovascular diseases. Gray matter volume in this region was also significantly reduced in patients receiving oxygen therapy compared to patients not receiving oxygen therapy. Patients with fever had a significant reduction in gray matter volume in the inferior and middle temporal gyri and the fusiform gyrus compared to patients without fever. The results suggest Covid-19 may affect the frontal-temporal network through fever or lack of oxygen.

Reduced gray matter in the superior, medial and middle frontal gyri was also present in patients with agitation compared to patients without agitation. This implies that gray matter changes in the frontal region of the brain may underlie the mood disturbances commonly exhibited by Covid-19 patients.

“Neurological complications are increasingly documented for patients with Covid-19,” said Vince Calhoun, senior author of the study and director of TReNDS. Calhoun is Distinguished University Professor of Psychology at Georgia State and holds appointments in the School of Electrical and Computer Engineering at Georgia Tech and in neurology and psychiatry at Emory University. “A reduction of gray matter has also been shown to be present in other mood disorders such as schizophrenia and is likely related to the way that gray matter influences neuron function.”

The study’s findings demonstrate changes to the frontal-temporal network could be used as a biomarker to determine the likely prognosis of Covid-19 or evaluate treatment options for the disease. Next, the researchers hope to replicate the study on a larger sample size that includes many types of brain scans and different populations of Covid-19 patients.

TReNDS is a partnership among Georgia State, Georgia Tech and Emory University and is focused on improving our understanding of the human brain using advanced analytic approaches. The center uses large-scale data sharing and multi-modal data fusion techniques, including deep learning, genomics, brain mapping and artificial intelligence.

Featured image: Researchers Kuaikuai Duan and Vince Calhoun have found that neurological complications of Covid-19 patients may be linked to lower gray matter volume in the front region of the brain even six months after hospital discharge. © Vince Calhoun, Georgia Tech


Reference: K. Duan, et. al., “Alterations of frontal-temporal gray matter volume associate with clinical measures of older adults with COVID-19.” (Neurobiology of Stress, May 2021) https://doi.org/10.1016/j.ynstr.2021.100326


Provided by Georgia Institute of Technology

How Coronal Loops Form? (Planetary Science)

Astronomers found first direct observational evidence for the formation of coronal loops through magnetic reconnection

You may have seen several pictures of coronal loops on google. They are bright, curving structures that appear as arcs above the Sun’s surface. Hot plasma causes these loops to glow. Based on their temperature, they are actually classified into 3 groups: cool, warm and hot loops. Cool loops have temperature of about 0.1–1 MK and could be observed in ultraviolet (UV) spectral lines or narrow-band images. Warm loops consist of plasma at a temperature of around 1–2 MK, and they are well observed by extreme ultraviolet (EUV) imagers and spectrographs. While, hot loops have temperature more than 2 MK, which are typically observed in some spectral lines with a high formation temperature and filters with a high temperature response, often at the wavelengths of soft X-ray, EUV and UV. Both hot and warm loops may be called coronal loops.

Since coronal loops are building blocks of solar active regions (ARs), it is important to understand how they are formed. However, despite intensive investigations on the plasma properties of quiescent coronal loops, their formation process has rarely been studied and thus the formation mechanism is not well understood.

But now, a team of international astronomers for the first time, reported on the direct observational evidence for the formation of coronal loops through magnetic reconnection as new magnetic fluxes rise into the upper atmosphere. Their study recently appeared in Arxiv.

(article continues below image)

Figure 1. Images of the HMI LOS magnetic field (a), NVST Hα line core (b), AIA 171 Å (c) and AIA 211 Å (d) taken at 06:53 UT. The white dotted line marks the approximate location of the newly formed overlying loops. The red dotted line and blue arrows in (b) indicate some dark threads that are located close to the top part of these loops. The red arrows indicate a pair of bright ribbons that correspond to the footpoints of the newly formed small loops underneath the plasma sheet. The red and blue contours in (c) represent positive and negative magnetic fluxes with the levels of ± 300 G, respectively. The black lines in (c) outline the geometry of the reconnection region. The cyan box in (c) marks the field-of-view of the 171 Å image sequence in (e1)–(e4), which shows the formation process of quiescent coronal loops during the second episode. The arrows in (e2) – (e4) mark several newly formed coronal loops. An animation of this figure is available, showing the formation process of coronal loops. It includes the images of the HMI LOS magnetic field, NVST Hα line core, AIA 171 Å and AIA 211 Å, and covers 82 minutes starting at 05:49 UT with a cadence of 12 s. © Hou et al.

They identified this evidence, with the help of EUV observations of Solar Dynamics Observatory/Atmospheric Imaging Assembly (SDO/AIA) and Hα line core observations of NVST.

Astronomers observed that, the magnetic reconnection occurs within plasma sheet at the interface of two-approaching loop like structures. They also clearly observed, converging motions of opposite-polarity magnetic fluxes and the subsequent flux cancellation, from photospheric magnetograms.

“The reconnection results in the formation of overlying loops with typical coronal temperatures and low-lying small loops/fibrils above and below the plasma sheet, respectively. In the meantime, the transverse magnetic field in the photosphere is enhanced. After reconnection, the transverse field becomes weaker and the fibrils disappear, indicating the submergence of the low-lying loops.”

In addition, they have also revealed the presence of numerous bright plasma blobs in the plasma sheet with the help of EUV observations. These blobs have an average width of 1.37 Mm, and they appear intermittently in the plasma sheet and move upward with projected velocities of ∼114 km s¯1. Through a DEM analysis, they found the temperature, emission measure and density of the blobs to be about 3 MK, 2.0×1028 cm¯5 and 1.2×1010 cm¯3, respectively.

(article continues below image)

Figure 2. Velocities and sizes of plasma blobs in the plasma sheet. (a) An AIA 171 Å image taken at 06:53:45 UT. (b) AIA 171 Å intensity along slice I–J shown in (a). The black and green curves indicate the original intensity profile and the Gaussian fit. (c) and (d) Distributions of the projected velocity and size for the identified plasma blobs. © Hou et al.

Finally, they have performed a power spectral analysis for these blobs, and found a spectral index that is distinctly different from the expected one in a turbulent reconnection scenario. It has also been found that, plasma flows with speeds of 20 to 50 km s¯1 towards the footpoints of the newly formed coronal loops.


Reference: Zhenyong Hou, Hui Tian, Hechao Chen, Xiaoshuai Zhu, Zhenghua Huang, Xianyong Bai, Jiansen He, Yongliang Song, Lidong Xia, “Formation of solar quiescent coronal loops through magnetic reconnection in an emerging active region”, Arxiv, pp. 1-15, 2021. https://arxiv.org/abs/2105.03199


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How A Much-needed Oral Antiviral Drug Confuses the Replication Machinery of SARS-CoV-2 (Medicine)

Molnupiravir under consideration for emergency use in India to slow explosive spread of COVID-19 infections.

A University of Alberta virology lab has uncovered how an oral antiviral drug works to attack the SARS-CoV-2 virus, in findings published May 10 in the Journal of Biological Chemistry.

The researchers demonstrated the underlying mechanism of action by which the antiviral drug molnupiravir changes the viral genome, a process known as excessive mutagenesis or “error catastrophe.”

“The polymerase, or replication engine of the virus, mistakes molnupiravir molecules for the natural building blocks required for viral genome replication and mixes them in,” explained Matthias Götte, professor and chair of the Department of Medical Microbiology & Immunology in the Faculty of Medicine & Dentistry and member of the Li Ka Shing Institute of Virology. “It causes the polymerase to make sloppy copies—nonsense genomes that are useless and not viable.”

Molnupiravir is currently in Phase 3 human clinical trials, which are expected to report preliminary data by the end of June. Phase 2 trial results recently revealed that the drug eliminated SARS-CoV-2 infectivity in newly diagnosed patients after five days of treatment.

The drug is taken as a pill, making it much easier to administer than other approved treatments such as remdesivir or monoclonal antibodies, which must be given intravenously. It has not yet been shown to be effective in treating hospitalized COVID-19 patients with advanced disease, so current trials are focused on determining how well it works for newly diagnosed patients. It is hoped the drug could also be used as a preventive measure to protect household members against infection.

“Molnupiravir is one of the few compounds under investigation that is orally available,” Götte said. “Data reported so far demonstrate that this drug is well tolerated with no signs of severe side-effects, and it shows an antiviral effect after five days. Whether it can also reduce hospitalizations remains to be seen.”

“Our work to demonstrate that the effect of the drug is indeed mediated by the viral polymerase is reassuring, because if the drug somehow generates mistakes in the virus and you don’t know how it happens, there could be other mechanisms at work that could also harm the cell,” he said. “Still, the safety of the drug for COVID-19 patients remains to be evaluated and monitored.”

Another step in the hunt for a weapon against future pandemics

Molnupiravir was first identified as a broad spectrum antiviral at Emory University in Atlanta, Georgia. In 2003 it was developed as a treatment for chronic hepatitis C, but it was dropped due to possible side-effects associated with long-term use. The drug was then tested in humans with influenza, because the course of treatment for flu is much shorter. The focus of testing switched to SARS-CoV-2 after the COVID-19 pandemic emerged. The drug is now being developed in partnership by Merck and Ridgeback Biotherapeutics.

Merck has made deals with five generic drugmakers in India to make molnupiravir, and at least one of them has applied for approval to use it on an emergency basis, as at least 350,000 new infections are diagnosed in that country every day and vaccination levels are low.

Götte and his team previously uncovered the mechanisms of action for remdesivir, a now-approved treatment that inhibits replication of the SARS-CoV-2 virus, and baloxavir, an influenza drug. 

Next, they will test molnupiravir’s mechanism of action against the polymerases of some of the other viruses the World Health Organization has identified as having high epidemic potential.

“All are recognized as emerging pathogens where we need to develop countermeasures,” Götte said. “We need to be prepared with broad-spectrum antivirals that can serve as a first line of defence.”

“Even once vaccines are developed, we can’t get them into all the arms at once,” he said. “To really fight outbreaks and epidemics, one tool is unlikely to be sufficient.”

The researchers were supported by grants from the Canadian Institutes of Health Research, the Alberta Ministry of Jobs, Economy and Innovation, and the U.S. National Institutes of Health Centers for AIDS Research. The other authors were graduate student Calvin Gordon and research associate Egor Tchesnokov of the U of A, and Raymond Schinazi of the Emory School of Medicine.

Featured image: Virologist Matthias Götte and his team have discovered how the oral antiviral drug called molnupiravir works against the SARS-CoV-2 virus. The drug is under consideration for emergency use in India to stem the rapid spread of COVID-19. (Photo: Faculty of Medicine & Dentistry)


Reference: Calvin J. Gordon, Egor P. Tchesnokov, Raymond F. Schinazi and Matthias Götte, “Molnupiravir promotes SARS-CoV-2 mutagenesis via the RNA template”, JBC, 2021. DOI: https://doi.org/10.1016/j.jbc.2021.100770


Provided by University of Alberta

Researchers Find Target to Fight Antibiotic Resistance (Biology)

Significance of molecule in bacteria was previously unknown

Gram-negative bacteria are the bane of health care workers’ existence.

They’re one of the most dangerous organisms to become infected with—and one of the hardest to treat. But new research from the University of Georgia suggests a component of bacteria’s cell walls may hold the key to crushing the antibiotic-resistant microbes.

The reason Gram-negative bacteria are difficult to kill is their double cell membranes, which create an almost impenetrable shield of protection. This shield blocks antibiotics from entering, preventing medications from doing their job of destroying the bacteria. Meanwhile, toxic molecules, known as lipopolysaccharides, on the surface of the bacteria’s outer membrane provoke a potentially deadly immune response.

In the study published by PNAS, researchers at the College of Veterinary Medicine identified the molecule cardiolipin’s key role in getting those toxic molecules onto the membrane surface, something that could serve as a new target for future therapeutics.

“If you ask where we’re having the most trouble in the world of antibiotic resistance, it is with Gram-negative bacteria,” said Stephen Trent, corresponding author of the study and a UGA Foundation Distinguished Professor of Infectious Diseases. “The implication of this finding is that without cardiolipin, bacteria can’t make the outer membrane. Without that membrane, they’re sensitive to antibiotics and the bacteria is toast.”

Blocking transport to the cell membrane could not only make bacteria vulnerable to antibiotics, but the accumulation of their own toxic molecules within the cell also cause the bacteria’s death.

Molecule illustration
Cardiolipin (shown in red) assist the lipopolysaccharide (shown in blue) transport machine, MsbA (shown in green). (Illustration by Ali Ennis)

Potential applications

Prior to the study, no one really understood cardiolipin’s role in bacteria. In animals, however, it plays an integral part in making up the membrane of mitochondria, the organelles from which cells generate energy.

To determine the molecule’s role in bacteria, the researchers created mutant forms of E. coli, which has multiple ways of making cardiolipin, to try to determine what purpose the lipid served in the cell. The team manipulated the enzymes responsible for building cardiolipin to see whether their disruption had any effect on the bacterium.

Those experiments showed that altering the cardiolipin production in a bacteria’s cell had deadly ramifications for the bacteria. Without cardiolipin, the cell will continue to produce its toxic lipopolysaccharides but is unable to transport them to the cell surface.

“Eventually the cell will pop open. They just bust,” Trent said. And without the large molecules on the cell surface, the bacteria’s armor that typically would make it invulnerable to most antibiotics becomes penetrable.

“This paper is one of the first to link cardiolipin to maintaining the outer membrane of E. coli,” said Martin Douglass, lead author of the paper and a doctoral student in UGA’s Department of Infectious Diseases. “Future therapeutics could target aspects of this process and make Gram-negative bacteria vulnerable to antibiotics.”

Featured image: Graduate students (from left) Martin Douglass and Alexandria Purcell work in the laboratory with professor Stephen Trent in 2019. (Photo by Andrew Davis Tucker/UGA)


Reference: Martin V. Douglass, François Cléon, et al., “Cardiolipin aids in lipopolysaccharide transport to the gram-negative outer membrane”, PNAS April 13, 2021 118 (15) e2018329118; https://doi.org/10.1073/pnas.2018329118


Provided by UGA Today