Tag Archives: #inflammation

How SARS-CoV-2 Promotes Inflammation? (Biology)

Juan Robles and colleagues revealed for the first time that the spike protein of SARS-CoV-2 promotes endothelial inflammation through integrin α5β1 and NF-κB pathway. Their study recently appeared in BioRxiv.

Endothelial cells (ECs) mostly exist in the inner layer of all blood vessels and are normally protected by pericytes. They form a critical interface between blood and tissues that maintains whole-body homeostasis. In COVID-19, disruption of the EC barrier results in edema, vascular inflammation, leukocyte infiltration and coagulation, the hallmarks of the severe disease. However, the mechanisms by which EC are dysregulated in COVID-19 are unclear. Now, Juan Robles and colleagues revealed that the spike activates NF-κB pathway through its interaction with integrin α5β1 in EC to elicit inflammation and leukocyte infiltration.

They also suggested that spike promotes hyperpermeability of EC monolayers and leukocyte adhesion via integrin α5β1 by regulating Rho GTPases and eNOS phosphorylation, and we can prevent or block the leukocyte adhesion and hyperpermeability in response to spike and spike receptor-binding domain by using ‘volociximab’, which is a chimeric anti-integrin α5β1 monoclonal antibody and ‘ATN-161’, which is the integrin α5β1 binding peptide.

“Our findings uncover a new direct action of SARS-CoV-2 on EC dysfunction and introduce integrin ⍺5β1 as a promising target for treating vascular inflammation in COVID-19.”

— they concluded.

Their work was supported by grants A1-S-9620B and 289568 from “Consejo Nacional de Ciencia y Tecnología” (CONACYT) to C.C. Magdalena Zamora is a doctoral student from ‘Programa de Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México (UNAM)’ and received fellowship 768182 from CONACYT.


Reference: Juan Pablo Robles, Magdalena Zamora, Gonzalo Martinez de la Escalera, Carmen Clapp, “The spike protein of SARS-CoV-2 induces endothelial inflammation through integrin α5β1 and NF-κB”, bioRxiv 2021.08.01.454605; doi: https://doi.org/10.1101/2021.08.01.454605


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How Cells Remember Inflammation? (Biology)

When a tissue experiences inflammation, its cells remember. Pinning proteins to its genetic material at the height of inflammation, the cells bookmark where they left off in their last tussle. Next exposure, inflammatory memory kicks in. The cells draw from prior experience to respond more efficiently, even to threats that they have not encountered before. Skin heals a wound faster if it was previously exposed to an irritant, such as a toxin or pathogen; immune cells can attack new viruses after a vaccine has taught them to recognize just one virus. 

Now, a new study in Cell Stem Cell describes the mechanism behind inflammatory memory, also commonly referred to as trained immunity, and suggests that the phenomenon may be universal across diverse cell types.  

“This is happening in natural killer cells, T cells, dendritic cells from human skin, and epidermal stem cells in mice,” says Samantha B. Larsen, a former graduate student in the laboratory of Elaine Fuchs at The Rockefeller University. “The similarities in mechanism are striking, and may explain the remitting and relapsing nature of chronic inflammatory disorders in humans.” 

Uncelebrated immunity 

When thinking about our immune system, we default to specific immunity—that cadre of T cells and B cells trained, by experience or vaccination, to remember the specific contours of the last pathogen that broke into our bodies. But there’s a less specific strategy available to many cells, known as trained immunity. The impact is shorter-lived, but broader in scope. Trained immunity allows cells to respond to entirely new threats by drawing on general memories of inflammation. 

Scientists have long suspected that even cells that are not traditionally involved in the immune response have the rudimentary ability to remember prior insults and learn from experience. The Fuchs lab drove this point home in a 2017 study published in Nature by demonstrating that mouse skin that had recovered from irritation healed 2.5 times faster than normal skin when exposed to irritation at a later date.  

One explanation, the Fuchs team proposed, could be epigenetic changes to the skin cell genome itself. During inflammation, regions of DNA that are usually tightly coiled around histone proteins unravel to transcribe a genetic response to the attack. Even after the dust settles, a handful of these memory domains remain open—and changed. Some of their associated histones have been modified since the assault, and proteins known as transcription factors have latched onto the exposed DNA. A once naïve cell is now raring for its next fight.  

But the molecular mechanism that explained this process, and how the cell could use it to respond to types of inflammation and injury that it had never seen before, remained a mystery. 

Inside a memory domain 

So the Fuchs lab once again exposed mice skin to irritants, and watched as stem cells in the skin changed. “We focused on the regions in the genome that become accessible during inflammation, and remain accessible afterwards,” says Christopher Cowley, a graduate student in the Fuchs lab. “We call these regions memory domains, and our goal was to explore the factors that open them up, keep them open and reactivate them a second time.”  

They observed about 50,000 regions within the DNA of the stem cells that had unraveled to respond to the threat, but a few months later only about 1,000 remained open and accessible, distinguishing themselves as memory domains. Interestingly, many of these memory domains were the same regions that had unraveled most prodigiously in the early days of skin inflammation. 

The scientists dug deeper and discovered a two-step mechanism at the heart of trained immunity. The process revolves around transcription factors, proteins which govern the expression of genes, and hinges on the twin transcription factors known as JUN and FOS. 

The stimulus-specific STAT3 transcription factor responds first, deployed to coordinate a genetic response to a particular genre of inflammation. This protein hands the baton to JUN-FOS, which perches on the unspooled genetic material to join the melee. The specific transcription factor that sounded the original alarm will eventually return home; FOS will float away as the tumult quiets down. But JUN stands sentinel, guarding the open memory domain with a ragtag band of other transcription factors, waiting for its next battle. 

When irritation strikes again, JUN is ready. It rapidly recruits FOS back to the memory domain, and the duo charges into the fray. This time, no specific transcription factor is necessary to respond to a particular type of inflammation and get the ball rolling. The system unilaterally activates in response to virtually any stress—alacrity that may not always benefit the rest of the body. 

Better off forgotten 

Trained immunity may sound like a boon to human health. Veteran immune cells seem to produce broader immune responses; experienced skin cells should heal faster when wounded.  

But the same mechanism that keeps cells on high alert may instill a sort of molecular paranoia in chronic inflammation disorders. When the Fuchs lab examined data collected from patients who suffer from systemic sclerosis, for instance, they found evidence that JUN may be sitting right on the memory domains of affected cells, itching to incite an argument in response to even the slightest disagreement. 

“These arguments need not always be disagreeable, as animals benefit by healing their wounds quickly and plants exposed to one pathogen are often protected against others,” says Fuchs. “That said, chronic inflammatory disorders may owe their painful existence to the ability of their cells to remember, and to FOS and JUN, which respond universally to stress.”  

The scientists hope that shedding light on one possible cause of chronic inflammatory disease may help researchers develop treatments for these conditions. “The factors and pathways that we identify here could be targeted, both in the initial disease stages and, later, during the relapsing stages of disease,” says Cowley. Larsen adds: “Perhaps these transcription factors could be used as a general target to inhibit the recall of the memories that cause chronic inflammation.” 

Featured image: Inflamed mouse stem cells located in the basal layer (red) of the epidermis and FOS (green), a near-universal stress response factor essential to inflammatory memory. Credit: Christopher Cowley.


Provided by Rockefeller University

Novel Autoantibody Adds Fuel to COVID-19 ‘Firestorm’ of Inflammation, Blood Clots (Medicine)

The finding will likely help physicians develop targeted therapies for future COVID patients

Researchers at Michigan Medicine have discovered yet another functional autoantibody in COVID-19 patients that contributes to the disease’s development and the “firestorm” of blood clots and inflammation it induces.

A growing body of studies suggests COVID-19 emulates many aspects of systemic autoimmune disorders, including the release of a flurry of overactive immune cells that produce toxic webs of proteins and DNA called neutrophil extracellular traps, or NETs.

For this study, the team analyzed serum from over 300 hospitalized COVID patients, searching for a novel autoantibody that shields the toxic NETs from being destroyed and produces a lasting noxious effect in a patient’s body.

The results, published in JCI Insight, reveal markedly elevated levels of the anti-NET antibodies in many of the participants. Those with higher levels of the autoantibodies were more likely to develop severe COVID-19 symptoms.

“We see a slew of different antibodies produced in COVID-19 patients, and now we discovered another clinically significant one that is likely contributing to severe COVID,” said Yu (Ray) Zuo, M.D., lead author and a rheumatologist at Michigan Medicine. “They feed into the inflammatory storm that we’re seeing in the most serious cases of viral infection.”

Researchers generated NETs in the lab and incubated them with COVID patient serum. They found the serum from patients with higher levels of anti-NET antibodies struggled to degrade the toxic traps.

The team also spiked healthy serum with anti-NETs purified from the infected patients. While a healthy person’s serum should completely disintegrate the extracellular traps, the purified anti-NET antibodies significantly hindered the process.

“We knew that people with severe forms of COVID have higher amounts of these neutrophil extracellular traps, which amplify inflammation and promote blood clot formation,” said Jason Knight, M.D., corresponding author of the paper and an associate professor of rheumatology at Michigan Medicine. “We’ve now found that this process is exacerbated by the anti-NET antibodies, which disrupt our body’s immune homeostasis during COVID-19 infection.”

Similarities to another autoimmune disease

Zuo and the Michigan Medicine team previously reported the presence of anti-NETs in patients with antiphospholipid syndrome, a systemic autoimmune condition characterized by severe blood clots and recurring pregnancy loss.

The anti-NET antibodies, which are likely associated with the development of recurrent blood clots and more severe disease in antiphospholipid syndrome, showed remarkably similar function in this study of COVID-19 patients, said corresponding author Yogen Kanthi, M.D., a cardiologist and vascular medicine specialist at the National Heart, Lung, and Blood Institute and Lasker Investigator at the National Institutes of Health.”

“Studying these [COVID-induced] antibodies will also teach us about the mechanisms of autoimmunity in general, especially in the field of rheumatology.”, said Yu (Ray) Zuo, M.D.

“In both diseases, the anti-NET antibodies coat the surface of the neutrophil extracellular traps, making it much harder for the body to clear out this web that causes inflammation and clotting,” Kanthi said. “Knowing their function is likely to help physicians design more targeted COVID-19 treatments and also for other inflammatory diseases.”

How COVID-19 manages to trigger the production of a variety of autoantibodies, including anti-NETs, remains unknown. Further study of the virus’ autoimmune aspects, Zuo noted, will not only lead to better understanding of the disease, but will also likely shed light onto the origins of autoimmune diseases.

Future research and “long COVID”

The paper’s findings may also unlock other COVID mysteries, including the persistence of symptoms in some people months after clearing the virus, a phenomenon known as long COVID, Zuo said.

The team is currently conducting a follow-up study, calling back patients who were previously hospitalized to repeat testing for the anti-NETs and other autoantibodies that formed during their hospitalizations.

Previously, they found durable anti-NET antibodies that persisted in antiphospholipid syndrome patients for up to four years. The team will investigate if and how the autoantibodies influence long COVID, the post-acute sequalae of the virus marked by symptoms like brain fog, fatigue and shortness of breath.

While vaccination is doing its job to limit severe infections and hospitalizations, millions still feel the effects of long COVID, which is why this research is so important, Zuo said.

“The better we understand these COVID-induced autoantibodies such as anti-NET antibodies, the more equipped we will be to fight COVID-19 at every stage of viral infection,” Zuo said. “Studying these antibodies will also teach us about the mechanisms of autoimmunity in general, especially in the field of rheumatology.”

Featured image credit: Justine Ross, Michigan Medicine


Paper cited: “Autoantibodies stabilize neutrophil extracellular traps in COVID-19,” JCI Insight. DOI: 10.1172/jci.insight.150111


Provided by Michigan Lab

Researchers Discovered Enzymatic Approach For Targeted Treatment Of Intestinal Inflammation (Medicine)

FAU research team investigates blocking inflammatory substance

When the immune system attacks a person’s own intestines, this leads to chronic inflammation and considerable pain and discomfort for patients suffering from the disease. Together with researchers from the US and France, a team of researchers at FAU has discovered a potential new approach to treatment. The results have been published in the journal Gastroenterology.

Ulcerative colitis is a chronic inflammatory bowel disease which leads to diarrhoea, intestinal bleeding and cramps. It is generally triggered by an excessive immune reaction. Within the context of the collaborative research centre (CRC) 1181 Switching points for resolving inflammation, researchers from FAU led by Dr. Markus Neurath, Chair of Internal Medicine I and director of Department of Medicine 1– Gastroenterology, Pneumology and Endocrinology and PD Dr. Dr. Benno Weigmann have now discovered that the production of inflammatory cytokines by T-cells can be prevented and the inflammatory reaction stopped by specifically blocking the enzyme ITK in cases of ulcerative colitis. ‘Our experimental analyses of enzyme ITK demonstrated that blocking this specific enzyme using inhibitors or siRNA was effective in treating murine chronic intestinal inflammation, plausibly making it an attractive treatment option for humans in future,’ explains Kristina Lechner, doctoral candidate in Dr. Weigmann’s working group.

In the Collaborative Research Centre (SFB) 1181 ‘Checkpoints for resolution of inflammation’ at FAU, researchers from various areas of medicine and biology are investigating the basic mechanisms underlying the resolution of inflammatory responses and their clinical relevance.

More information on SFB 1181: http://www.sfb1181.forschung.fau.de

Original publication: https://pubmed.ncbi.nlm.nih.gov/34224738/

‘Targeting of the Tec kinase ITK drives resolution of T cell-mediated colitis and emerges as potential therapeutic option in ulcerative colitis’

Featured image credit: colourbox


Provided by FAU

Researchers Find Signs of Inflammation in Brains of People Who Died of COVID-19 (Neuroscience)

The most comprehensive molecular study to date of the brains of people who died of COVID-19 turned up unmistakable signs of inflammation and impaired brain circuits.

Investigators at the Stanford School of Medicine and Saarland University in Germany report that what they saw looks a lot like what’s observed in the brains of people who died of neurodegenerative conditions such as Alzheimer’s disease and Parkinson’s disease.

The findings may help explain why many COVID-19 patients report neurological problems. These complaints increase with the severity of infection with SARS-CoV-2, the virus that causes COVID-19. And they can persist as an aspect of “long COVID,” a long-lasting disorder that sometimes arises following infection. About one-third of individuals hospitalized for COVID-19 report symptoms of fuzzy thinking, forgetfulness, difficulty concentrating and depression, said Tony Wyss-Coray, PhD, professor of neurology and neurological sciences at Stanford.

Yet the researchers couldn’t find any signs of SARS-CoV-2 in brain tissue they obtained from eight individuals who died of the disease. Brain samples from 14 people who died of other causes were used as controls for the study.

“The brains of patients who died from severe COVID-19 showed profound molecular markers of inflammation, even though those patients didn’t have any reported clinical signs of neurological impairment,” said Wyss-Coray, who is the D. H. Chen Professor II.

Scientists disagree about whether SARS-CoV-2 is present in COVID-19 patients’ brains. “We used the same tools they’ve used — as well as other, more definitive ones — and really looked hard for the virus’s presence,” he said. “And we couldn’t find it.”

A paper describing the study will be published June 21 in Nature. Wyss-Coray shares senior authorship with Andreas Keller, PhD, chair of clinical bioinformatics at Saarland University. The lead authors are Andrew Yang, PhD, a postdoctoral scholar in Wyss-Coray’s group, and Fabian Kern, a graduate student in Keller’s group.

Blood-brain barrier

The blood-brain barrier, which consists in part of blood-vessel cells that are tightly stitched together and blob-like abutments created by brain cells’ projections squishing up against the vessels, has until recently been thought to be exquisitely selective in granting access to cells and molecules produced outside the brain.

But previous work by Wyss-Coray’s group and by others has shown that bloodborne factors outside the brain can signal through the blood-brain barrier to ignite inflammatory responses inside the brain. This could explain why, as Wyss-Coray and his colleagues have discovered, factors in young mice’s blood can rejuvenate older mice’s cognitive performance, whereas blood from old mice can detrimentally affect their younger peers’ mental ability.

On hearing reports of enduring neurological symptoms among some COVID-19 patients, Wyss-Coray became interested in how SARS-CoV-2 infection might cause such problems, which resemble those that occur due to aging as well as to various neurodegenerative diseases. Having also seen conflicting reports of the virus’s presence in brain tissue in other studies, he wanted to know whether the virus does indeed penetrate the brain.

Brain tissue from COVID-19 patients is hard to find, Wyss-Coray said. Neuropathologists are reluctant to take the steps required to excise it because of potential exposure to SARS-CoV-2 and because regulations often prohibit such procedures to prevent viral transmission. But Keller, who has worked in the Wyss-Coray lab as a visiting professor at Stanford, was able to access COVID-19 brain-tissue samples from autopsies conducted at the hospital that’s associated with Saarland University.

Using an approach called single-cell RNA sequencing, the scientists logged the activation levels of thousands of genes in each of 65,309 individual cells taken from brain-tissue samples from the COVID-19 patients and the controls.

In neurons of the cerebral cortex, signs of distress

Activation levels of hundreds of genes in all major cell types in the brain differed in the COVID-19 patients’ brains versus the control group’s brains. Many of these genes are associated with inflammatory processes.

There also were signs of distress in neurons in the cerebral cortex, the brain region that plays a key role in decision-making, memory and mathematical reasoning. These neurons, which are mostly of two types — excitatory and inhibitory — form complex logic circuits that perform those higher brain functions.

The outermost layers of the cerebral cortex of patients who died of COVID-19 showed molecular changes suggesting suppressed signaling by excitatory neurons, along with heightened signaling by inhibitory neurons, which act like brakes on excitatory neurons. This kind of signaling imbalance has been associated with cognitive deficits and neurodegenerative conditions such as Alzheimer’s disease.

An additional finding was that peripheral immune cells called T cells, immune cells that prowl for pathogens, were significantly more abundant in brain tissue from dead COVID-19 patients. In healthy brains, these immune cells are few and far between.

“Viral infection appears to trigger inflammatory responses throughout the body that may cause inflammatory signaling across the blood-brain barrier, which in turn could trip off neuroinflammation in the brain,” Wyss-Coray said.

“It’s likely that many COVID-19 patients, especially those reporting or exhibiting neurological problems or those who are hospitalized, have these neuroinflammatory markers we saw in the people we looked at who had died from the disease,” he added. It may be possible to find out by analyzing these patients’ cerebrospinal fluid, whose contents to some extent mirror those of the living brain.

“Our findings may help explain the brain fog, fatigue, and other neurological and psychiatric symptoms of long COVID,” he said.

Wyss-Coray is co-director of the Paul F. Glenn Center for Biology of Aging Research at Stanford, a member of Stanford Bio-X, Stanford’s Maternal and Child Health Research Institute, and Wu Tsai Neurosciences Institute at Stanford, and a faculty fellow of ChEM-H.

Other Stanford co-authors of the study are postdoctoral scholars Patricia Losada, PhD, Nicholas Schaum, PhD, Ryan Vest, PhD, Nannan Lu, PhD, and Oliver Hahn, PhD; basic life research scientist Daniela Berdnik, PhD; life science research professionals Maayan Agam and Kruti Calcuttawala; former life science research associate Davis Lee; former visiting student researcher Christina Maat; life science research professional Divya Channappa; David Gate, PhD, instructor of neurology and neurological sciences; M. Windy McNerney, PhD, clinical assistant professor of psychiatry and behavioral sciences; and Imma Cobos, MD, PhD, assistant professor of pathology.

In addition to Keller and Kern, other researchers at Saarland University also contributed to the study.

The work was funded by the Nomis Foundation, the National Institutes of Health (grants T32-AG0047126, 1RF1AG059694 and P30AG066515), Nan Fung Life Sciences, the Wu Tsai Neurosciences Institute and the Stanford Alzheimer’s Disease Research Center.


Reference: Yang, A.C., Kern, F., Losada, P.M. et al. Dysregulation of brain and choroid plexus cell types in severe COVID-19. Nature (2021). https://doi.org/10.1038/s41586-021-03710-0


Provided by Stanford Medicine

Study Uncovers Major Breakthrough in Understanding and Treating Respiratory Inflammation (Medicine)

Common OTC drugs for sore throat causing more harm than good

Applied Biological Laboratories (Applied Bio), a biopharmaceutical company focused on the respiratory disease market, announced that its study published online in Immunology, Inflammation and Disease was able to determine the mechanism behind respiratory inflammation and treat it effectively with Biovanta(TM), a 100% naturally derived, over-the-counter (OTC) drug for cold, cough and sore throat.

The study results also showed that almost all of the leading OTC products on the market can damage the upper respiratory cells and may prolong illness. This research study and its findings represent one of the first major breakthroughs in decades for the cold and flu market.

The study, titled “A Novel Anti-inflammatory Treatment for Bradykinin-induced Sore Throat or Pharyngitis,” explored the efficacy of common OTC medications. Sore throat, or pharyngitis, is one of the most common symptoms of upper respiratory infection and a leading cause of physician visits and antibiotic prescriptions, but few, if any, OTC medications are proven to address sore throat inflammation. The randomized, blinded, placebo-controlled study utilized state-of-the-art, fully developed human respiratory tissues (organoids) grown from nasal stem cells, stimulated with a molecule called bradykinin (one of the body’s first inflammatory signals following an upper respiratory infection). Bradykinin uses Cox enzymes to stimulate more inflammatory molecules, such as prostoglandin. Once the mechanisms behind pharyngitis were understood, the cells were treated with a variety of OTC sore throat medications. Aspirin and a formula containing it as an active ingredient were also investigated as treatments and were found to be much more effective than any OTC treatment. Despite being a well-known Cox inhibitor, aspirin is not widely used for upper respiratory inflammation.

“Furthering our understanding of the mechanism behind respiratory inflammation is a key step in studying the effectiveness of common medications, and this study is profound because it also shows that ingredients commonly used in leading cough, cold and sore throat products like dextromethorphan, acetaminophen, guaifenesin and benzocaine are ineffectual and can even be toxic,” said Alan Greene, MD, practicing physician and founder of DrGreene.com. “Alternatively, this study shows that the ingredients in Biovanta offer a safe and effective treatment for inflammation vs. a reduction of the symptoms.”

Specific study results include:

  • Of the 20 OTC products tested, all but one showed inflammatory and damaging effects on at least one of the measures tested, which were: level of prostaglandin E2 (PGE2) or interleukin 8 (IL-8) – key measures of inflammation, damage to the membrane barrier as measured by the electrical resistance across it and microscopy (through a microscope), and the release of lactate dehydrogenase (LDH), a chemical that is released by cells when they die.
  • Biovanta, an OTC product with low-dose aspirin and other anti-inflammatory ingredients, reduced inflammation when applied to affected cells and tissues, making it the first scientifically proven 100% naturally derived, OTC medicine for treating cough, cold and sore throat.
  • Aspirin can lower prostaglandin levels, but there is a small therapeutic window in which aspirin is anti-inflammatory when sprayed onto cells: 6 mg per dose. Below this the drug would not have a significant affect and above it, it becomes inflammatory. For comparison, a baby aspirin contains 81 mg.

“This study is a major breakthrough in understanding the underlying mechanism of inflammation in upper respiratory illnesses, which wasn’t possible until recent scientific advancements that enabled the creation of organoids for use in testing human tissue reactions,” said Nazlie Latefi, PhD, co-founder and chief science officer, Applied Bio. “These scientifically proven results show that our groundbreaking formulas strengthen the respiratory barrier, unlike common OTC products, and we look forward to further demonstrating their effectiveness through a post-market real-world study.”

Featured image: Researchers at Applied Biological Laboratories used human respiratory organoids from adult stem cells to measure the effect of OTC drugs on the respiratory system. © Applied Biological Laboratories


Reference: Leyva-Grado, V, Pugach, P, Sadeghi-Latefi, N. A novel anti-inflammatory treatment for bradykinin-induced sore throat or pharyngitis. Immun Inflamm Dis. 2021; 1- 15. https://doi.org/10.1002/iid3.479


Provided by Merryman Communications

COVID-19 Can Cause Severe Inflammation in the Brain (Neuroscience)

Various immune cells in the brainstem cause formation of inflammatory nodules

Both during and after infection with the Coronavirus SARS-CoV-2, patients may suffer from severe neurological symptoms, including “anosmia”, the loss of taste and smell typically associated with COVID-19. Along with direct damage caused by the virus, researchers suspect a role for excessive  inflammatory responses in the disease. A team of researchers from the Freiburg University Medical Center and the Cluster of Excellence CIBSS has now shown that a severe inflammatory response can develop in the central nervous system of COVID-19 patients involving different immune cells around the vascular system and in the brain tissue. The team led by Professor Dr. Marco Prinz, Medical Director at the Institute of Neuropathology, and Professor Dr. Dr. Bertram Bengsch, Section Head of Translational Systems Immunology in Hepatogastroenterology at the Internal Medicine II just published their results in the current issue of Immunity.

“Even though there was already evidence of central nervous system involvement in COVID-19, the extent of inflammation in the brain surprised us,” says lead author Henrike Salié. “In particular the many microglial nodules we detected cannot usually be found in the healthy brain,” comments lead author Dr. Marius Schwabenland. Using a novel measurement method, imaging mass cytometry, they were able to determine different cell types as well as virus-infected cells and their spatial interaction in previously unseen detail. 

Disruption of the brain’s immune response

“Until now, the inflammatory pattern in COVID-19 was poorly understood. Even compared to other inflammatory brain diseases, the inflammatory responses triggered by COVID-19 are unique and indicate a severe disturbance of the brain’s immune response. In particular, the essential defense cells of the brain, known as microglial cells, are particularly strongly activated, and we also observed migration of T-killer cells and development of a pronounced neuroinflammation in the brain stem,” says Prinz, who received the Leibniz Prize in 2020 for his research.

“The immune changes are particularly detectable near small brain vessels. In these areas, the viral receptor ACE2 is expressed, onto which the coronavirus can dock, and the virus was also directly detectable there,” Bengsch adds, “It seems plausible that the immune cells recognize infected cells there and that inflammation then spreads to the nerve tissue, causing symptoms It is possible that early immunomodulatory or immunosuppressive treatment could reduce inflammation.”

Immunological, virological, and neuropathological research

Professor Dr. Robert Thimme, Medical Director of Internal Medicine II at the Freiburg Medical Center and Vice Dean for Academic Affairs of the University of Freiburg Medical Faculty, emphasizes how  high levels of scientific expertise and excellent cooperation between different research teams is a basic prerequisite for rapid knowledge gain in the pandemic. “Patient-oriented immunological, virological, and neuropathological research using state-of-the-art methods is a core strength at the Freiburg Medical Center. This study shows how we can contribute to understanding the disease processes in the Coronavirus pandemic through excellent research in Freiburg. While we already knew that a strong immune response is needed for recovery from Coronavirus infection, apparently a misdirected immune response can cause severe damage.”

The study was made possible by Germany-wide collaborations with groups, including Professor Dr. Markus Glatzel from the Institute of Neuropathology at the University Medical Center Hamburg-Eppendorf (UKE), as well as researchers from the University Medical Center Göttingen and the University of Heidelberg.

Sponsors of this research included the state of Baden-Württemberg, three Collaborative Research Centers (SFB992, SFB1160, TRR179), and the German Research Foundation’s Heisenberg Program, as well as the Cluster of Excellence CIBSS Centre for Integrative Biological Signalling Studies at the University of Freiburg.


Publication:
Schwabenland, M., Salié, H. et al., Thimme, R., Glatzel, M., Prinz, M., Bengsch, B. (2021): Deep spatial profiling of human COVID-19 brains reveals neuroinflammation with distinct microanatomical microglia-T cell interactions. In: Immunity. DOI: 10.1016/j.immuni.2021.06.002


Provided by University of Freiburg

VUMC Team Develops Potential Treatment For Life-threatening Microbial Inflammation (Medicine)

A cell-penetrating peptide developed by researchers at Vanderbilt University Medical Center can prevent, in an animal model, the often-fatal septic shock that can result from bacterial and viral infections.

Their findings, published this week in Scientific Reports, could lead to a way to protect patients at highest risk for severe complications and death from out-of-control inflammatory responses to microbial infections, including COVID-19.

“Life-threatening microbial inflammation hits harder (in) patients with metabolic syndrome, a condition afflicting millions of people in the United States and worldwide,” said the paper’s corresponding author, Jacek Hawiger, MD, PhD, the Louise B. McGavock Chair in Medicine and Distinguished Professor of Medicine at VUMC.

An international authority on inflammation as the mechanism of multiple diseases, Hawiger also is professor of Molecular Physiology and Biophysics at Vanderbilt and a Health Research Scientist at the Nashville Veterans Affairs (VA) Medical Center.

“We explore the pathways to the cell’s nucleus, the command center of inflammation,” he said.

In response to bacterial infection, transcription factors are ferried to the nucleus of immune and vascular cells, where they reprogram gene expression to ramp up production of infection-fighting inflammatory molecules. Like a wildfire, however, the inflammatory response, if unchecked, can damage small blood vessels, leading to multiple organ failure and death.

Patients with pre-existing health conditions, including obesity and high blood levels of glucose (diabetes), triglycerides and cholesterol (hyperlipidemia) — hallmarks of metabolic syndrome — are at increased risk of developing a damaging inflammatory response to infection.

They also are more likely to die of complications of COVID-19, which include acute respiratory distress syndrome, septic cardiomyopathy (damage to heart muscle), microvascular thrombosis (tiny blood clots) and acute kidney injury. These complications result from infection-induced septic shock due to the collapse of small blood vessels.

Pre-existing conditions, notably hyperlipidemia, already can cause inflammation in these small vessels. Infection, the researchers reasoned, may only make it worse.

In 2014 Hawiger and colleagues developed a cell-penetrating peptide, or protein fragment, that blocked signaling pathways leading to lethal shock in animals exposed to the endotoxin lipopolysaccharide (LPS), which is released during infection by Gram-negative bacteria.

This “parent” peptide, called cSN50.1, selectively suppressed the transport into the nucleus of transcription factors responsible for the out-of-control inflammatory response, and dramatically increased survival in mice exposed to high doses of LPS.

In a 2017 the Hawiger team used a polymicrobial sepsis model to show that the same treatment combined with an antibiotic increased survival in mice from 30% (using antibiotic alone) to 55%.

In 2019 the U.S. Food and Drug Administration designated the peptide as an “Investigational New Drug” and allowed a clinical trial in an inflammatory skin disease sponsored by Amytrx, a start-up company co-founded by Hawiger.

In the current study, the researchers tested whether, in a mouse model of hyperlipidemia, two novel, pathway-selective forms of this peptide could, as they put it, “stop pro-inflammatory and metabolic transcription factors in their tracks” at the nuclear transport checkpoint.

One peptide, which selectively targets the nuclear shuttle for proinflammatory transcription factors, protected against the acute stage of lethal microbial inflammation, while extended treatment with the other peptide, which targets the nuclear transport checkpoint for metabolic transcription factors, reduced production of cholesterol, triglycerides and fatty acids.

“Experimentally, by targeting the nuclear transport checkpoint, we suppressed the burst of inflammatory mediators while lowering elevated levels of blood glucose, triglycerides, and cholesterol and protecting small blood vessels from injury in the liver, lungs, heart and kidneys,” Hawiger said.

“Our findings are of significant relevance to individuals displaying signs of metabolic syndrome that predisposes them to life-threatening microbial diseases, including recent outbreaks of COVID-19 as well as autoimmune and allergic disorders,” the researchers concluded.

Yan Liu, MD, research assistant professor of Medicine, and Jozef Zienkiewicz, PhD, research associate professor of Medicine, are co-first authors of the paper. Other contributors were Kelli Boyd, DVM, PhD, currently at Gilead Sciences, Taylor Smith, MS, now attending Indiana University School of Medicine, and Zhi-Qi Xu.

The research was supported by grants from the U.S. Department of Veterans Affairs and the endowed McGavock Chair at Vanderbilt.

Featured image: From left, Taylor Smith, MS, Jacek Hawiger, MD, PhD, Jozef Zienkiewicz, PhD, and Yan Liu, MD, and colleagues developed a peptide that may protect against life-threatening microbial inflammation with underlying metabolic syndrome. Photo courtesy Hawiger lab


Reference: Liu, Y., Zienkiewicz, J., Boyd, K.L. et al. Hyperlipidemic hypersensitivity to lethal microbial inflammation and its reversal by selective targeting of nuclear transport shuttles. Sci Rep 11, 11907 (2021). https://doi.org/10.1038/s41598-021-91395-w


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Diets That Promote Inflammation Could Increase Breast Cancer Risk (Food)

Analysis of dietary patterns for over 350,000 women suggests eating more anti-inflammatory foods helps lower risk

A new study of more than 350,000 women found that women with diets incorporating more foods that increase inflammation in the body had a 12% increase in their risk of breast cancer compared to women who consume more anti-inflammatory diets. The new findings are being presented at NUTRITION 2021 LIVE ONLINE.

The study authors found that moving from a more anti-inflammatory diet toward one that increases inflammation upped breast cancer risk in an almost linear manner. Foods that increase inflammation include red and processed meat; high-fat foods such as butter, margarines and frying fats; and sweets including sugar, honey and foods high in sugar. Fruits, vegetables, legumes, tea and coffee all have potentially anti-inflammatory properties.

“Most studies examining diet and breast cancer risk have focused on single nutrients or foods rather than the whole diet,” said the study’s first author Carlota Castro-Espin, a predoctoral fellow at the Catalan Institute of Oncology and Bellvitge Biomedical Research Institute in Barcelona, Spain. “People consume food not nutrients, thus examining overall dietary patterns, rather than single components of diets can lead to more accurate conclusions when analysing associations with a health outcome such as breast cancer.”

The new results are based on data from the European Investigation into Cancer and Nutrition (EPIC) study, a prospective study that recruited more than 500,000 participants across 10 European countries starting in the mid-1990s. The study included more than 13,000 breast cancer diagnoses during approximately 15 years of follow-up.

The typical diet for EPIC participants was measured for a year using food frequency or diet history questionnaires. The researchers used this information to calculate an inflammatory score for each study participant based on their intake of 27 foods.

The researchers examined dietary patterns linked with inflammation because long-term, low grade inflammation has been linked with the development of breast cancer. The large number of women in the study allowed the researchers to take a more nuanced look at the relationship between dietary patterns and breast cancer risk.

Their analysis showed that the increase in breast cancer risk due to pro-inflammatory diets appears to be more pronounced among premenopausal women. They also found that the association did not vary by breast cancer hormone receptor subtypes.

“Our results add more evidence of the role that dietary patterns play in the prevention of breast cancer,” said Castro-Espin. “With further confirmation, these findings could help inform dietary recommendations aimed at lowering cancer risk.”

As a next step, the researchers plan to evaluate the association of the inflammatory potential of diet and other dietary patterns with breast cancer survival using participants in the EPIC study.

Castro-Espin will present this research on-demand during NUTRITION 2021 LIVE ONLINE from noon on Monday, June 7 through 5:30 p.m. on Friday, June 10 (abstractpresentation details).

Featured image: A new study of more 350,000 women found that women with diets incorporating more foods that increase inflammation in the body had a 12% increase in their risk of breast cancer compared to women consuming more anti-inflammatory diets. © Carlota Castro-Espin, Catalan Institute of Oncology and Bellvitge Biomedical Research Institute.


Provided by American Society for Nutrition