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Blocking immune system pathway may stop COVID-19 infection, prevent severe organ damage

Credit: National Institute of Allergy and Infectious Diseases, National Institutes of Health While the world waits eagerly for a safe…

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Credit: National Institute of Allergy and Infectious Diseases, National Institutes of Health

While the world waits eagerly for a safe and effective vaccine to prevent infections from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus behind the COVID-19 pandemic, researchers also are focusing on better understanding how SARS-CoV-2 attacks the body in the search for other means of stopping its devastating impact. The key to one possibility — blocking a protein that enables the virus to turn the immune system against healthy cells — has been identified in a recent study by a team of Johns Hopkins Medicine researchers.

Based on their findings, the researchers believe that inhibiting the protein, known as factor D, also will curtail the potentially deadly inflammatory reactions that many patients have to the virus.

Making the discovery even more exciting is that there may already be drugs in development and testing for other diseases that can do the required blocking.

The study is published in the Sept. 2, 2020, issue of the journal Blood.

Scientists already know that spike proteins on the surface of the SARS-CoV-2 virus — making the pathogen look like the spiny ball from a medieval mace — are the means by which it attaches to cells targeted for infection. To do this, the spikes first grab hold of heparan sulfate, a large, complex sugar molecule found on the surface of cells in the lungs, blood vessels and smooth muscle making up most organs. Facilitated by its initial binding with heparan sulfate, SARS-CoV-2 then uses another cell-surface component, the protein known as angiotensin-converting enzyme 2 (ACE2), as its doorway into the attacked cell.

The Johns Hopkins Medicine team discovered that when SARS-CoV-2 ties up heparan sulfate, it prevents factor H from using the sugar molecule to bind with cells. Factor H’s normal function is to regulate the chemical signals that trigger inflammation and keep the immune system from harming healthy cells. Without this protection, cells in the lungs, heart, kidneys and other organs can be destroyed by the defense mechanism nature intended to safeguard them.

“Previous research has suggested that along with tying up heparan sulfate, SARS-CoV-2 activates a cascading series of biological reactions — what we call the alternative pathway of complement, or APC — that can lead to inflammation and cell destruction if misdirected by the immune system at healthy organs,” says study senior author Robert Brodsky, M.D., director of the hematology division at the Johns Hopkins University School of Medicine. “The goal of our study was to discover how the virus activates this pathway and to find a way to inhibit it before the damage happens.”

The APC is one of three chain reaction processes involving the splitting and combining of more than 20 different proteins — known as complement proteins — that usually gets activated when bacteria or viruses invade the body. The end product of this complement cascade, a structure called membrane attack complex (MAC), forms on the surface of the invader and causes its destruction, either by creating holes in bacterial membranes or disrupting a virus’ outer envelope. However, MACs also can arise on the membranes of healthy cells. Fortunately, humans have a number of complement proteins, including factor H, that regulate the APC, keep it in check and therefore, protect normal cells from damage by MACs.

In a series of experiments, Brodsky and his colleagues used normal human blood serum and three subunits of the SARS-CoV-2 spike protein to discover exactly how the virus activates the APC, hijacks the immune system and endangers normal cells. They discovered that two of the subunits, called S1 and S2, are the components that bind the virus to heparan sulfate — setting off the APC cascade and blocking factor H from connecting with the sugar — and in turn, disabling the complement regulation by which factor H deters a misdirected immune response.

In turn, the researchers say, the resulting immune system response to chemicals released by the lysing of killed cells could be responsible for the organ damage and failures seen in severe cases of COVID-19.

Most notably, Brodsky says, the research team found by blocking another complement protein, known as factor D, which works immediately upstream in the pathway from factor H, they were able to stop the destructive chain of events triggered by SARS-CoV-2.

“When we added a small molecule that inhibits the function of factor D, the APC wasn’t activated by the virus spike proteins,” Brodsky says. “We believe that when the SARS-CoV-2 spike proteins bind to heparan sulfate, it triggers an increase in the complement-mediated killing of normal cells because factor H, a key regulator of the APC, can’t do its job.”

To better understand what happens, Brodsky says think of the APC like a car in motion.

“If the brakes are disabled, the gas pedal can be floored without restraint, very likely leading to a crash and destruction,” he explains. “The viral spike proteins disable the biological brakes, factor H, enabling the gas pedal, factor D, to accelerate the immune system and cause cell, tissue and organ devastation. Inhibit factor D, and the brakes can be reapplied and the immune system reset.”

Brodsky adds that cell death and organ damage from a misdirected APC associated with factor H suppression is already known to occur in several complement-related human diseases, including age-related macular degeneration, a leading cause of vision loss for people age 50 and older; and atypical hemolytic uremic syndrome (aHUS), a rare disease that causes clots to block blood flow to the kidneys.

Brodsky and his colleagues hope that their work will encourage more study into the potential use against COVID-19 of complement-inhibiting drugs already in the pipeline for other diseases.

“There are a number of these drugs that will be FDA-approved and in clinical practice within the next two years,” Brodsky says. “Perhaps one or more of these could be teamed with vaccines to help control the spread of COVID-19 and avoid future viral pandemics.”

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Along with Brodsky, the other members of the Johns Hopkins Medicine research team are lead author Jia Yu; Xuan Yuan; Hang Chen; Shruti Chaturvedi, M.B.B.S.; and Evan Braunstein, M.D., Ph.D.

The study was supported by National Heart, Lung and Blood Institute grant R01 HL133113.

https://www.hopkinsmedicine.org/news/newsroom/news-releases/blocking-immune-system-pathway-may-stop-covid-19-infection-prevent-severe-organ-damage

Source: https://bioengineer.org/blocking-immune-system-pathway-may-stop-covid-19-infection-prevent-severe-organ-damage/

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$1 million grant to address cold storage logistics in vaccine delivery

Credit: Penn State College of Engineering COVID-19 vaccines have been tested, validated and administered to millions of people around the

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COVID-19 vaccines have been tested, validated and administered to millions of people around the world. But in some countries, the vaccines have yet to arrive in great enough numbers.

One significant hurdle is that the vaccines must be stored between 36 and 46 degrees Fahrenheit to retain their full efficacy, according to the Centers for Disease Control. To ensure the proper temperature, the vaccines need a refrigerated supply chain, also known as a cold chain, as they are distributed across the globe.

“If they are in warm temperatures, COVID vaccines and other medications are susceptible to degradation, which means they lose potency,” said Medina, who heads the Medina Group Precision Therapeutics and Bioresponsive Materials Lab at Penn State. “And the cold storage supply chain is expensive to maintain, with several transport steps necessary from the manufacturer to the distributer to the provider facility.”

To address that challenge, Medina and his team plan to develop fluorochemical dispersants, known as “FTags,” which coat the proteins within the vaccine liquids to stabilize them thermally.

“The FTags dissolve the proteins in a fluorine-based liquid, which yields proteins that we believe may be stable at elevated temperatures, without compromising their structure or function,” Medina said. “When dissolved in the fluorine-based liquid, the proteins also are immune to contamination by microorganisms and enzymes.”

Fluorochemicals are used in a range of applications, such as in making surfaces resistant to scratches and chemical degradation, as in the case of non-stick cookware.

Eventually, Medina plans to study the use of fluorochemical coatings in other biological products, with the goal of eliminating the need to move any pharmaceutical via a cold chain.

“This will allow access to medications in places where currently there is not,” Medina said. “For example, a soldier at war could be exposed to a harmful chemical agent. A fluorochemical-coated protein, which can be carried without refrigeration, could neutralize that agent immediately. This is part of DARPA’s interest in supplying this grant.”

The grant is part of DARPA’s Young Faculty Award program, which provides funding, mentoring and networking opportunities to faculty early in their careers who plan to focus their research on Department of Defense and national security interests.

In 2020, Medina published a study in ACS Nano on delivering therapeutic medications directly to a precise area of the body through an acoustically sensitive carrier, guided by ultrasound. The proposed DARPA-funded study is a spin-off of that study’s findings.

“Janna Sloand, my former grad student who recently defended her doctoral research, came up with the coating technology in our last study,” Medina said. “It dovetails nicely with our new study, which will use those same coatings to take on the limitations of the cold chain.”

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Source: https://bioengineer.org/1-million-grant-to-address-cold-storage-logistics-in-vaccine-delivery/

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Reduced microbial stability linked to soil carbon loss in active layer under alpine permafrost degra

Credit: NIEER Chinese researchers have recently discovered links between reduction in microbial stability and soil carbon loss in the active

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Chinese researchers have recently discovered links between reduction in microbial stability and soil carbon loss in the active layer of degraded alpine permafrost on the Qinghai-Tibet Plateau (QTP).

The researchers, headed by Prof. CHEN Shengyun from the Northwest Institute of Eco-Environment and Resources (NIEER) of the Chinese Academy of Sciences (CAS), and XUE Kai from University of Chinese Academy of Sciences, conducted a combined in-depth analysis of soil microbial communities and their co-occurrence networks in the active permafrost layer along an extensive gradient of permafrost degradation.

The QTP encompasses the largest extent of high-altitude mountain permafrost in the world. This permafrost is different than high-latitude permafrost and stores massive soil carbon. An often ignored characteristic of permafrost is that the carbon pool in the active layer soil is more active and directly affected by climate change, compared to deeper layers.

Triggered by climate warming, permafrost degradation may decrease soil carbon stability and induce massive carbon loss, thus leading to positive carbon-climate feedback. However, microbial-mediated mechanisms for carbon loss from the active layer soil in degraded permafrost still remain unclear.

In this study, the researchers found that alpine permafrost degradation reduced the stability of active layer microbial communities as evidenced by increased sensitivity of microbial composition to environmental change, promoted destabilizing network properties and reduced resistance to node or edge attacking of the microbial network.

They discovered that soil organic carbon loss in severely degraded permafrost is associated with increased microbial dissimilarity, thereby potentially contributing to a positive carbon feedback in alpine permafrost on the QTP.

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The results were published in PNAS in an article entitled “Reduced microbial stability in the active layer is associated with carbon loss under alpine permafrost degradation”.

This research was financially supported by the National Natural Science Foundation of China, the Strategic Priority Research Program (A) of CAS and the Second Tibetan Plateau Scientific Expedition and Research Program.

Triggered by climate warming, permafrost degradation may decrease soil carbon stability and induce massive carbon loss, thus leading to positive carbon-climate feedback. However, microbial-mediated mechanisms for carbon loss from the active layer soil in degraded permafrost still remain unclear.

Source: https://bioengineer.org/reduced-microbial-stability-linked-to-soil-carbon-loss-in-active-layer-under-alpine-permafrost-degra/

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SNMMI Image of the Year: PET imaging measures cognitive impairment in COVID-19 patients

Credit: G Blazhenets et al., Department of Nuclear Medicine, Medical Center – University of Freiburg, Faculty of Medicine, University of

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Credit: G Blazhenets et al., Department of Nuclear Medicine, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg.

Reston, VA–The effects of COVID-19 on the brain can be accurately measured with positron emission tomography (PET), according to research presented at the Society of Nuclear Medicine and Molecular Imaging (SNMMI) 2021 Annual Meeting. In the study, newly diagnosed COVID-19 patients, who required inpatient treatment and underwent PET brain scans, were found to have deficits in neuronal function and accompanying cognitive impairment, and in some, this impairment continued six months after their diagnosis. The detailed depiction of areas of cognitive impairment, neurological symptoms and comparison of impairment over a six-month time frame has been selected as SNMMI’s 2021 Image of the Year.

Each year, SNMMI chooses an image that best exemplifies the most promising advances in the field of nuclear medicine and molecular imaging. The state-of-the-art technologies captured in these images demonstrate the capacity to improve patient care by detecting disease, aiding diagnosis, improving clinical confidence, and providing a means of selecting appropriate treatments. This year, the SNMMI Henry N. Wagner, Jr., Image of the Year was chosen from more than 1,280 abstracts submitted to the meeting and voted on by reviewers and the society leadership.

“As the SARS-CoV-2 pandemic proceeds, it has become increasingly clear that neurocognitive long-term consequences occur not only in severe COVID-19 cases, but in mild and moderate cases as well. Neurocognitive deficits like impaired memory, disturbed concentration and cognitive problems may persist well beyond the acute phase of the disease,” said Ganna Blazhenets, PhD, a post-doctoral researcher in Medical Imaging at the University Medical Center Freiburg, in Freiburg, Germany.

To study cognitive impairment associated with COVID-19, researchers carried out a prospective study on recently diagnosed COVID-19 patients who required inpatient treatment for non-neurological complaints. A cognitive assessment was performed, followed by imaging with 18F-FDG PET if at least two new neurological symptoms were present. By comparing COVID-19 patients to controls, the Freiburg group established a COVID-19-related covariance pattern of brain metabolism with most prominent decreases in cortical regions. Across patients, the expression of this pattern showed a very high correlation with the patients’ cognitive performance.

Follow-up PET imaging was performed six months after the initial COVID-19 diagnosis. Imaging results showed a significant improvement in the neurocognitive deficits in most patients, accompanied by an almost complete normalization of the brain metabolism.

“We can clearly state that a significant recovery of regional neuronal function and cognition occurs for most COVID-19 patients based on the results of this study. However, it is important to recognize the evidence of longer-lasting deficits in neuronal function and accompanying cognitive deficits is still measurable in some patients six months after manifestation of disease,” noted Blazhenets. “As a result, post-COVID-19 patients with persistent cognitive complaints should be presented to a neurologist and possibly allocated to cognitive rehabilitation programs.”

“18F-FDG PET is an established biomarker of neuronal function and neuronal injury,” stated SNMMI’s Scientific Program Committee chair, Umar Mahmood, MD, PhD. “As shown the Image of the Year, it can be applied to unravel neuronal correlates of the cognitive decline in patients after COVID-19. Since 18F-FDG PET is widely available, it may therefore aid in the diagnostic work-up and follow-up in patients with persistent cognitive impairment after COVID-19.”

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Abstract 41. “Altered regional cerebral function and its association with cognitive impairment in COVID 19: A prospective FDG PET study.” Ganna Blazhenets, Johannes Thurow, Lars Frings and Philipp Meyer, Department of Nuclear Medicine, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Nils Schroeter, Tobias Bormann, Cornelius Weiller, Andrea Dressing and Jonas Hosp; Department of Neurology and Clinical Neuroscience, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; and Dirk Wagner, Department of Internal Medicine, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

All 2021 SNMMI Annual Meeting abstracts can be found online at https://jnm.snmjournals.org/content/62/supplement_1.

About the Society of Nuclear Medicine and Molecular Imaging

The Society of Nuclear Medicine and Molecular Imaging (SNMMI) is an international scientific and medical organization dedicated to advancing nuclear medicine and molecular imaging, vital elements of precision medicine that allow diagnosis and treatment to be tailored to individual patients in order to achieve the best possible outcomes.

SNMMI’s members set the standard for molecular imaging and nuclear medicine practice by creating guidelines, sharing information through journals and meetings and leading advocacy on key issues that affect molecular imaging and therapy research and practice. For more information, visit http://www.snmmi.org.

“As the SARS-CoV-2 pandemic proceeds, it has become increasingly clear that neurocognitive long-term consequences occur not only in severe COVID-19 cases, but in mild and moderate cases as well. Neurocognitive deficits like impaired memory, disturbed concentration and cognitive problems may persist well beyond the acute phase of the disease,” said Ganna Blazhenets, PhD, a post-doctoral researcher in Medical Imaging at the University Medical Center Freiburg, in Freiburg, Germany.

Source: https://bioengineer.org/snmmi-image-of-the-year-pet-imaging-measures-cognitive-impairment-in-covid-19-patients/

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