Tag Archives: Inflammation

Microbiology

Drug Discovery: Existing Medicines May Treat a Common Kidney Disease

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New research findings reveal that a serious condition that can cause the kidneys to suddenly stop working could be treated with existing medicines.

Scientists found that medicines usually used to treat angina and high blood pressure prevented much of the long-term damage to the kidney and cardiovascular system caused by acute kidney injury (AKI). The study, which was conducted in mice, was published on December 14, in the journal Science Translational Medicine.

Experts hope the findings will pave the way for improved treatment of AKI – a common condition that occurs in approximately 20 percent of emergency hospital admissions in the UK.

The condition is usually caused by other illnesses that reduce blood flow to the kidney (such as low blood pressure, blood loss, heart attack, or organ failure), or due to toxicity arising from some medicines.

AKI must be treated quickly to prevent death. Even if the kidneys recover, AKI can cause long-lasting damage to the kidneys and the cardiovascular system.

Of those who survive an episode of AKI, 30 percent are left with chronic kidney disease (CKD). The remaining 70 percent that recover full kidney function are at an almost 30-fold increased risk of developing CKD. In time, CKD can result in kidneys that stop working altogether. This is known as kidney failure, end-stage renal disease (ESRD), or end-stage kidney disease (ESKD).

A team from the University of Edinburgh found that patients with AKI had increased blood levels of endothelin – a protein that activates inflammation and causes blood vessels to constrict. Endothelin levels remained high long after kidney function had recovered.

After finding the same increase in endothelin in mice with AKI, experts treated the animals with medicines that block the endothelin system. The medicines – normally used to treat angina and high blood pressure – work by stopping the production of endothelin or by shutting off endothelin receptors in cells. 

The mice were monitored over a four-week period after AKI. Those that were treated with the endothelin-blocking medicines had lower blood pressure, less inflammation and reduced scarring in the kidney.

Their blood vessels were more relaxed and kidney function was also improved, compared with untreated mice.

Dr. Bean Dhaun, Senior Clinical Lecturer and Honorary Consultant Nephrologist at the University of Edinburgh’s Centre for Cardiovascular Science, said: “AKI is a harmful condition, particularly in older people and even with recovery it can have a long-term impact on a person’s health. Our study shows that blocking the endothelin system prevents the long-term damage of AKI in mice. As these medicines are already available for use in humans, I hope that we can move quickly to see if the same beneficial effects are seen in our patients.”

Professor James Leiper, Associate Medical Director at the British Heart Foundation, said: “Impaired kidney function that results from acute kidney injury can also increase a person’s chance of developing and dying from heart and circulatory diseases, so it’s vital we find ways to reduce this risk.

“This promising research suggests that widely available medicines could help to tackle the impact of acute kidney injury before it can cause damage and further complications. While further studies will be needed to demonstrate whether this treatment is safe and effective for patients, this early research is an encouraging first step.”

Reference: “Endothelin blockade prevents the long-term cardiovascular and renal sequelae of acute kidney injury in mice” by Alicja Czopek, Rebecca Moorhouse, Peter J. Gallacher, Dan Pugh, Jessica R. Ivy, Tariq E. Farrah, Emily Godden, Robert W. Hunter, David J. Webb, Pierre-Louis Tharaux, David C. Kluth, James W. Dear, Matthew A. Bailey and Neeraj Dhaun, 14 December 2022, Science Translational Medicine.
DOI: 10.1126/scitranslmed.abf5074

The study was published on December 14, 2022, in the journal Science Translational Medicine. It was funded by the Medical Research Council and the British Heart Foundation.

University of Edinburgh

Microbiology

Study identifies Δ42PD-1 as novel therapeutic target for hepatocellular carcinoma immunotherapy

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Reviewed by Emily Henderson, B.Sc.Dec 15 2022

HKUMed researchers at AIDS Institute, Department of Microbiology and Department of Surgery, School of Clinical Medicine, and School of Biomedical Sciences discover the role of an isoformic programmed cell death protein 1 (PD-1), namely Δ42PD-1, in suppressing the function of killer T cells, which is a type of immune cells essential for killing cancer cells among hepatocellular carcinoma (HCC) patients. The study is a breakthrough because it demonstrates that Δ42PD-1 causes stronger functional loss of killer T cells, revealing a molecular mechanism underlying the failure of PD-1-targeted immune checkpoint blockade (ICB) therapy. Moreover, antibody drug targeting at Δ42PD-1 inhibits HCC progression in animal models, which is independent of the PD-1 pathway. The full research article is now published online in the journal of Gut, a top-tier academic journal.

Background

It is well known that HCC accounts for up to 92.3% of liver cancer cases in China. The 2018 Nobel Prize in Physiology or Medicine was awarded for the discovery of cancer ICB therapy by inhibition of negative immune regulation using PD-1-targeted antibody, such as Nivolumab. The ICB therapy has resulted in prolonged survival and even cure in some cancer patients. The ICB therapy, however, is not effective for about 80% of HCC patients. Understanding the mechanism of unsuccessful ICB, therefore, would be essential for discovering a novel therapeutic target to save more lives of HCC patients.

Research methods and findings

The research team found that human T cells, which express Δ42PD-1 but not PD-1, account for up to 71% of killer T cells in untreated HCC patients. Δ42PD-1 positive T cells are mainly found in tumor tissues, associated significantly with HCC poor prognosis. Moreover, Δ42PD-1 positive T cells have weaker killing function than PD-1 positive T cells. Treatment of HCC patients using Nivolumab, the PD-1-targeted ICB drug, even increases the number of Δ42PD-1 positive T cells, especially in patients with tumor progression. We demonstrated that Δ42PD-1 positive T cells inside tumors promote HCC growth through activating toll-like receptors-4-mediated inflammation. Instead of Nivolumab, anti-Δ42PD-1 antibody inhibits tumor growth in three HCC/humanized murine models through blocking of the Δ42PD-1-TLR4 axis, reducing the number of Δ42PD-1 positive T cells and increasing functional killer T cells inside tumor. These findings not only revealed a mechanism underlying the unsuccessful PD-1-targeted ICB therapy but also identify Δ42PD-1 as a novel therapeutic target for HCC immunotherapy.

Significance of the study

This important discovery has provided scientific evidence that Δ42PD-1 may serve as a novel drug target against HCC or other relevant cancers and may warrant the clinical development of a humanized Δ42PD-1-specific antibody for immunotherapy against HCC and related human cancers/diseases.

‘We were the first research group discovering the Δ42PD-1 protein in the world’, commented by Professor Chen Zhiwei, Director of AIDS Institute and Professor of the Department of Microbiology, School of Clinical Medicine, HKUMed, who led the study. ‘In this study, we not only further discover the dual activities of Δ42PD-1 on human T cells in both suppressing anti-tumor immune response and promoting tumorigenesis but also generate a potential anti-Δ42PD-1 antibody drug for HCC treatment’.

‘Besides immunotherapy against HCC, the anti-Δ42PD-1 antibody can also be used as a drug to prevent HCC recurrence without induction of graft rejection after liver transplantation’, added by Professor Nancy Man Kwan, Department of Surgery, School of Clinical Medicine, HKUMed.

About the research team

The collaborative research team was led by Professor Chen Zhiwei, Director of AIDS Institute and Professor of the Department of Microbiology, School of Clinical Medicine, HKUMed, together with Professor Nancy Man Kwan, Department of Surgery, School of Clinical Medicine, HKUMed and Dr Tan Zhiwu, research assistant professor at AIDS Institute and Department of Microbiology, School of Clinical Medicine, HKUMed. This collaborative team includes Chiu Mei-sum, Dr Zhou Dongyan, Yan Chi-wing, Kwan Ka-yi, Dr Wong Yik-chun, Li Xin, Dr Li Liu from AIDS Institute and Department of Microbiology, School of Clinical Medicine, HKUMed; Dr Yang Xinxiang, Dr Cheung Tan-to, Dr Wang Yuewen, Dr Zhu Jiye, Professor Lo Chung-mau, Department of Surgery, School of Clinical Medicine, HKUMed; Dr Yue Ming and Dr Song Youqiang from School of Biomedical Sciences, HKUMed; and Dr Anthony Chan Wing-hung, Dr Zhou Jingying, Professor To Ka-fai, Professor Alfred Cheng Sze-lok, Professor Stephen Lam Chan from the Chinese University of Hong Kong.

Source:

The University of Hong Kong

Journal reference:

Tan, Z., et al. (2022) Isoformic PD-1-mediated immunosuppression underlies resistance to PD-1 blockade in hepatocellular carcinoma patients. Gut. doi.org/10.1136/gutjnl-2022-327133.

Microbiology

New Compound Reverses Gut Inflammation – Acts Like a Master Reset Switch in the Intestines

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New therapeutic has the potential to treat inflammatory bowel disease by targeting a molecule that keeps order in the intestines.

Salk Institute scientists have developed a new drug that acts like a master reset switch in the gut. Called FexD, the compound has previously been found to burn fat, lower cholesterol,  and ward off colorectal cancer in mice. Now, the team reports that FexD can also prevent and reverse intestinal inflammation in mouse models of inflammatory bowel disease. The study was published on December 12, 2022, in the journal Proceedings of the National Academy of Sciences.

“The Salk-developed drug FexD provides a new way to restore balance to the digestive system and treat inflammatory diseases that are currently very difficult to manage,” says Salk Professor Ronald Evans, senior author of the study. Evans is also director of Salk’s Gene Expression Laboratory and March of Dimes Chair in Molecular and Developmental Biology.

Inflammatory bowel disease (IBD), which includes both Crohn’s disease and ulcerative colitis, is estimated by the CDC to affect approximately 1.3% of American adults (about 3 million people). It is a condition that is characterized by chronic inflammation of the gastrointestinal tract with an excess of immune cells and inflammatory signaling molecules known as cytokines in the gut. Existing treatments mostly work by either suppressing the entire immune system or by targeting individual cytokines. They are only effective for some patients and carry a large number of significant side effects.

Evans’ lab has studied Farnesoid X receptor (FXR) for more than two decades. FXR is a master regulator protein that senses the bile acids delivered to the digestive system to help digest food and absorb nutrients. When FXR detects a shift in bile acids at the beginning of a meal, it prepares the body for an influx of food by flipping on and off dozens of cellular programs related to digestion, blood sugar, and fat metabolism.

Evans and his colleagues developed a pill called fexaramine in 2015 that activates FXR in the gut. They initially showed the pill can stop weight gain and control blood sugar in mice. In 2019, they showed that an updated version of fexaramine—FexDan—also prevented cancer-associated changes to stem cells in the gut. Their work suggested that FXR also played a role in regulating inflammation.

“Every time you eat, you’re causing small amounts of inflammation in your gut as your intestinal cells encounter new molecules. FXR makes sure inflammation stays under control during normal feeding,” says Senior Staff Scientist Michael Downes, co-corresponding author of the new paper.

In the new work, Evans’ group discovered that activating FXR can be used to ease symptoms in inflammation-driven diseases. When the researchers gave mice with IBD a daily dose of oral FexD, either before or after the onset of intestinal inflammation, the drug prevented or treated the inflammation. By activating FXR, FexD reduced the infiltration of a class of highly inflammatory immune cells called innate lymphoid cells. In turn, levels of cytokines already implicated in IBD decreased to levels normally seen in healthy mice.

“When we activate FXR, we restore appropriate signaling pathways in the gut, bringing things back to a homeostatic level,” says Senior Research Scientist Annette Atkins, co-author of the study.

Cytokines are not completely blocked by FexD because FXR acts more like a reset button than an off switch for the immune system. This means that after a dose of FexD, the immune system continues functioning in a normal way. The compound still must be optimized for use in humans and tested in clinical trials, but the researchers say their findings provide important information about the complex links between gut health and inflammation and could eventually lead to an IBD therapeutic.

“In people with IBD, our strategy could potentially be very effective at preventing flare-ups and as a long-term maintenance drug,” says first author Ting Fu, previously a postdoctoral fellow at Salk and now an assistant professor at the University of Wisconsin-Madison.

Reference: “FXR mediates ILC-intrinsic responses to intestinal inflammation” by Ting Fu, Yuwenbin Li, Tae Gyu Oh, Fritz Cayabyab, Nanhai He, Qin Tang, Sally Coulter, Morgan Truitt, Paul Medina, Mingxiao He, Ruth T. Yu, Annette Atkins, Ye Zheng, Christopher Liddle, Michael Downes and Ronald M. Evans, 12 December 2022, Proceedings of the National Academy of Sciences.
DOI: 10.1073/pnas.2213041119

Other authors of the paper include Yuwenbin Li, Tae Gyu Oh, Fritz Cayabyab, Nanhai He, Qin Tang, Morgan Truitt, Paul Medina, Mingxiao He, Ruth T. Yu, and Ye Zheng of Salk; and Sally Coulter and Christopher Liddle of the University of Sydney.

The work was supported in part by the National Institutes of Health (DK057978, HL105278, and HL088093), the National Cancer Institute (CA014195), the National Health and Medical Research Council of Australia (grant 1087297) the Leona M. and Harry B. Helmsley Charitable Trust (2017PG-MED001), an SWCRF Investigator Award, a Hewitt Medical Foundation Fellowship, a Salk Alumni Fellowship, a Crohn’s & Colitis Foundation (CCFA) Visiting IBD Research Fellowship, a Stand Up To Cancer-Cancer Research UK-Lustgarten Foundation Pancreatic Cancer Dream Team Research Grant (SU2C-AACR-DT-20-16), the Howard Hughes Medical Institute, the NOMIS Foundation, and the National Institute of Environmental Health Sciences (P42ES010337).

Salk Institute

Microbiology

Research project obtains nearly seven million to study factors that affect human immune system in early life

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Dec 2 2022Reviewed by Aimee Molineux

The first few months and years of life are crucial to the development of the human immune system. This is an important phase as the immune system can define which diseases individuals might develop later in life. INITIALISE, a joint research project of ten universities, will study which environmental factors and mechanisms modify the human immune system in early life and whether targeted interventions could have a positive impact. The project obtained nearly seven million in funding from Horizon Europe.

Research project obtains nearly seven million to study factors that affect human immune system in early life
Professor Matej Orešič. Image Credit: Photographer/Author- Jasper Mattson, Örebro University

The research project is led from the University of Turku and it is coordinated by Professor Matej Orešič, who is also a group leader in the InFLAMES research flagship at the University of Turku, Finland.

The development of the human immune system starts already in the womb and continues after birth once the child is exposed to numerous bacteria, viruses, and other environmental factors. Exposure is important to the development of the immune system, but this stage of development is not without its risks.

“The first few months and years are a very delicate and vulnerable time. We already know that the development of the human immune system in early life is connected to the risks of several diseases later on, particularly allergies, asthma, and autoimmune diseases, such as type 1 diabetes. Yet, the mechanisms of immune imprinting in early life are still poorly understood,” says Professor Matej Orešič.

In a collaboration between ten universities, the INITIALISE project (Inflammation in human early life: targeting impacts on life-course health) will investigate which factors have an impact on the development of the human immune system and what is its significance for people’s health throughout the course of their lives.

A key question is if the immune system be modified so that the risks for different diseases would decrease.    

“Our shared view is that effective early-life interventions targeting the immune system will have a positive impact on life-course health,” says Orešič.

Focus on the impact of chemical exposure

As the immune system starts developing already before birth, the INITIALISE researchers are also interested in the mother’s diet, chemical exposures, and stress during pregnancy. After birth, the intricate interplay of environmental factors and genetics begins and their impact on the development of the immune cells is not yet well understood. In addition, the gut bacteria developed at the beginning of life have an impact on people’s health throughout their entire lifespan.

Furthermore, children have to face the chemical load in their environment with a still developing immune system.

“We are going to study how chemicals impact the immune system. Even a small exposure to chemicals can have significant consequences, and this also applies to other factors that shape our immune system. This is due to the fact that in our first few years, we develop and change quickly and constantly,” Orešič explains. 

INITIALISE mobilises clinicians and scientists with diverse and complimentary expertise in immunology, paediatrics, microbiology, and metabolism. In addition, experts in metabolomics and lipidomics, proteomics, genetics, exposome, psychiatry, systems medicine, and bioinformatics participate in the study. 

Project lasts six years

INITIALISE includes eight prospective and longitudinal birth cohort studies, where the researchers follow groups of children for a long period of time to observe the development of immune-mediated diseases.

Towards the end of the research project, the researchers will conduct a clinical pilot study which aims to discover whether the immune system can be “altered” to prevent the development of diseases.

The clinical trial will target the gut microbiome in at-risk children. Our aim is to improve immune status and reduce disease risk.”

Professor Matej Orešič

The INITIALISE project starts at the beginning of 2023 and lasts six years. In addition to the University of Turku, the member organizations include Örebro University (SE), University of Naples Federico II (IT), Karolinska Institute (SE), University Medical Center Groningen (NL), Linköping University (SE), University of Helsinki (FI), University of Florida (US), Spanish National Research Council (ES), and University of Aberdeen (associated partner, UK).

Source:

University of Turku 

Microbiology

HIV infection leaves a ‘memory’ in cells

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Though antiretroviral therapy has made HIV a manageable disease, people living with HIV often suffer from chronic inflammation. This can put them at an increased risk of developing comorbidities such as cardiovascular disease and neurocognitive dysfunction, impacting the longevity and quality of their lives. Now, a new study in Cell Reports explains why chronic inflammation may be happening and how suppression or even eradication of HIV in the body may not resolve it.

In the study, researchers from the George Washington University show how an HIV protein permanently alters immune cells in a way that causes them to overreact to other pathogens. When the protein is introduced to immune cells, genes in those cells associated with inflammation turn on, or become expressed, the study showed. These pro-inflammatory genes remain expressed, even when the HIV protein is no longer in the cells. According to the researchers, this “immunologic memory” of the original HIV infection is why people living with HIV are susceptible to prolonged inflammation, putting them at greater risk for developing cardiovascular disease and other comorbidities.

“This research highlights the importance of physicians and patients recognizing that suppressing or even eliminating HIV does not eliminate the risk of these dangerous comorbidities,” Michael Bukrinsky,professor of microbiology, immunology, and tropical medicine at GW’s School of Medicine and Health Science and lead author on the study, said. “Patients and their doctors should still discuss ways to reduce inflammation and researchers should continue pursuing potential therapeutic targets that can reduce inflammation and co-morbidities in HIV-infected patients.”

For the study, the research team isolated human immune cells in vitro and exposed them to the HIV protein Nef. The amount of Nef introduced to the cells is similar to the amount found in about half of HIV-infected people taking antiretrovirals whose HIV load is undetectable. After a period of time, the researchers introduced a bacterial toxin to generate an immune response from the Nef-exposed cells. Compared to cells that were not exposed to the HIV protein, the Nef-exposed cells produced an elevated level of inflammatory proteins, called cytokines. When the team compared the genes of the Nef-exposed cells with the genes of the cells not exposed to Nef, they identified pro-inflammatory genes that were in a ready-to-be-expressed status as a result of the Nef exposure.

According to Bukrinsky, the findings in this study could help explain why certain comorbidities persist following other viral infections, including COVID-19.

“We’ve seen this pro-inflammatory immunologic memory reported with other pathogenic agents and often referred to as ‘trained immunity,'” Bukrinsky explains. “While this ‘trained immunity’ evolved as a beneficial immune process to protect against new infections, in certain cases it may lead to pathological outcomes. The ultimate effect depends on the length of this memory, and extended memory may underlie long-lived inflammatory conditions like we see in HIV infection or long COVID.”

The paper, “Extracellular vesicles carrying HIV-1 Nef induce long-term hyperreactivity of myeloid cells,” will be published in Cell Reports on November 14. The National Institute of Health’s National Heart, Lung, and Blood Institute supported this research.

Story Source:

Materials provided by George Washington University. Note: Content may be edited for style and length.

Journal Reference:

  • Larisa Dubrovsky, Beda Brichacek, N.M. Prashant, Tatiana Pushkarsky, Nigora Mukhamedova, Andrew J. Fleetwood, Yangsong Xu, Dragana Dragoljevic, Michael Fitzgerald, Anelia Horvath, Andrew J. Murphy, Dmitri Sviridov, Michael I. Bukrinsky. Extracellular vesicles carrying HIV-1 Nef induce long-term hyperreactivity of myeloid cells. Cell Reports, 2022; 41 (8): 111674 DOI: 10.1016/j.celrep.2022.111674

    • George Washington University
    Microbiology

    Air pollution harms the brain and mental health, too – a large-scale analysis documents effects on brain regions associated with emotions

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    The Research Brief is a short take about interesting academic work.

    People who breathe polluted air experience changes within the brain regions that control emotions, and as a result, they may be more likely to develop anxiety and depression than those who breathe cleaner air. These are the key findings of a systematic review that my colleagues and I recently published in the journal NeuroToxicology.

    Our interdisciplinary team reviewed more than 100 research articles from both animal and human studies that focused on the effects of outdoor air pollution on mental health and regions of the brain that regulate emotions. The three main brain regions we focused on were the hippocampus, amygdala and the prefrontal cortex.

    In our analysis, 73% of the studies reported higher mental health symptoms and behaviors in humans and animals, such as rats, that were exposed to higher than average levels of air pollution. Some exposures that led to negative effects occurred in air pollution ranges that are currently considered “safe” by the Environmental Protection Agency’s standards. In addition, we discovered that 95% of studies examining brain effects found significant physical and functional changes within the emotion-regulation brain regions in those exposed to increased levels of air pollution.

    Most of these studies found that exposure to elevated levels of air pollution is associated with increased inflammation and changes to the regulation of neurotransmitters, which act as the brain’s chemical messengers.

    Research into the physical health effects associated with air pollution exposure, such as asthma and respiratory issues, have been well documented for decades.

    But only over the last 10 years or so have researchers begun to understand how air pollution can affect the brain. Studies have shown that small air pollutants, such as ultrafine particles from vehicle exhaust, can affect the brain either directly, by traveling through the nose and into the brain, or indirectly, by causing inflammation and altered immune responses in the body that can then cross into the brain.

    At the same time, researchers are increasingly documenting the association between air pollution and its negative effects on mental health.

    Unfortunately, research suggests that air pollution will only worsen as climate change intensifies and carbon emissions remain unregulated.

    For this reason, more research into the health effects of air pollution exposure that goes beyond respiratory health outcomes into the realm of biological psychiatry is badly needed. For instance, the neurobiological mechanisms through which air pollution increases risk for mental health symptoms are still poorly understood.

    In addition to our primary findings, our team also identified some notable gaps within the research that need to be addressed in order to paint a fuller picture of the relationship between air pollution and brain health.

    Relatively few studies examined the effects of air pollution exposure during early life, such as infancy and toddlerhood, and in childhood and adolescence. This is especially concerning given that the brain continues to develop until young adulthood and therefore may be particularly susceptible to the effects of air pollution.

    We also found that within the studies investigating air pollution effects on the brain, only 10 were conducted in humans. While research on animals has extensively
    shown that air pollution can cause a host of changes within the animal brain, the research on how air pollution affects the human brain is much more limited. What’s more, most of the existing brain studies in humans have focused on physical changes, such as differences in overall brain size. More research is needed that relies on a technique called functional brain imaging, which could enable researchers like us to detect subtle or smaller changes that may occur before physical changes.

    In the future, our team plans to use brain imaging methods to study how air pollution increases the risk of anxiety during adolescence. We plan to use a variety of techniques, including personal air monitors that children can wear as they go about their day, allowing us to more accurately assess their exposure.


    Clara G. Zundel

    The Conversation

    Microbiology

    Mitochondria transmit signals in the immune and nervous systems

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    Mitochondria are primarily known as the powerhouse of the cell. However, these cellular organelles are required not only for providing energy: Professor Konstanze Winklhofer and her group at the Faculty of Medicine at Ruhr University Bochum, Germany, recently discovered that mitochondria play an important role in signal transduction in innate immune pathways. They regulate a signalling pathway that helps to eliminate pathogens, but can cause damage through inflammation upon overactivation.

    Certain cytokines but also intracellular pathogens, such as viruses and some bacteria, activate the transcription factor NF-κB, which regulates the expression of various genes. “Depending on the stimulus and the cell type, NF-κB activation results in protection from cell death and increased synthesis of proteins required for the elimination of bacteria or viruses,” explains Konstanze Winklhofer. However, upon excessive and prolonged activation, this basically protective pathway can cause chronic inflammation. “Hence, a fine-tuned regulation of these signalling processes is of great medical relevance, in order to prevent pathophysiological conditions caused by either inefficient or overshooting NF-κB activation.”

    The new study has revealed that mitochondria play a crucial role in the regulation of the NF-κB signalling pathway. Within minutes after pathway activation, a signalling platform assembles at the outer mitochondrial membrane, resulting in the activation of NF-κB. “This allows signal amplification, based on the large surface of mitochondria,” says Konstanze Winklhofer. “Moreover, mitochondria have another capacity that qualifies them as organelles for signal transduction: they are mobile and can dock onto motor proteins in the cell.” The research team observed that mitochondria escort the activated transcription factor NF-κB to the nuclear membrane, thus facilitating the translocation of NF-κB into the nucleus.

    However, mitochondria are not only involved in the efficient activation of the NF-κB signalling pathway; they also contribute to the deactivation and thus regulation of the signal. This is accomplished by an enzyme located at the outer mitochondrial membrane, which counteracts ubiquitination, a posttranslational modification required for NF-κB activation.

    Two genes causally linked to Parkinson’s disease are involved in the mitochondrial regulation of the NF-κB signalling pathway: PINK1 and Parkin. “Our findings explain why mutations resulting in a loss of PINK1 or Parkin function promote neuronal cell death under stress conditions,” points out Konstanze Winklhofer. “Remarkably, our findings show that Parkinson’s disease patients with mutations in the PINK1 or Parkin gene show an increased vulnerability to various infections caused by intracellular pathogens. Thus, our study also helps to gain a better understanding of the interfaces between the nervous and immune system.”

    Story Source:

    Materials provided by Ruhr-University Bochum. Original written by Meike Drießen. Note: Content may be edited for style and length.

    Journal Reference:

  • Zhixiao Wu et al. LUBAC assembles a ubiquitin signaling platform at mitochondria for signal amplification and transport of NF-ĸB to the nucleus. EMBO Journal, 2022 DOI: 10.15252/embj.2022112006

    • Ruhr-University Bochum
    Microbiology

    “A Silent Killer” – COVID-19 Shown To Trigger Inflammation in the Brain Without Outward Symptoms for Years

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    Research led by The University of Queensland (UQ) in Australia has found COVID-19 activates the same inflammatory response in the brain as Parkinson’s disease.

    The discovery not only identified a potential future risk for neurodegenerative conditions in people who have had COVID-19, but suggested also a possible treatment.

    The UQ team was led by Professor Trent Woodruff and Dr. Eduardo Albornoz Balmaceda from UQ’s School of Biomedical Sciences, and virologists from the School of Chemistry and Molecular Biosciences.

    “We studied the effect of the virus on the brain’s immune cells, ‘microglia’ which are the key cells involved in the progression of brain diseases like Parkinson’s and Alzheimer’s,” Professor Woodruff said.

    “Our team grew human microglia in the laboratory and infected the cells with SARS-CoV-2, the virus that causes COVID-19.

    “We found the cells effectively became ‘angry’, activating the same pathway that Parkinson’s and Alzheimer’s proteins can activate in disease, the inflammasomes.”

    Dr. Albornoz Balmaceda said triggering the inflammasome pathway sparked a ‘fire’ in the brain, which begins a chronic and sustained process of killing off neurons.

    “It’s kind of a silent killer, because you don’t see any outward symptoms for many years,” Dr. Albornoz Balmaceda said.

    “It may explain why some people who’ve had COVID-19 are more vulnerable to developing neurological symptoms similar to Parkinson’s disease.”

    The researchers found the spike protein of the virus was enough to start the process and was further exacerbated when there were already proteins in the brain linked to Parkinson’s.

    “So if someone is already pre-disposed to Parkinson’s, having COVID-19 could be like pouring more fuel on that ‘fire’ in the brain,” Professor Woodruff said.

    “The same would apply for a predisposition for Alzheimer’s and other dementias that have been linked to inflammasomes.”

    But the study also found a potential treatment.

    The researchers administered a class of UQ-developed inhibitory drugs that are currently in clinical trials with Parkinson’s patients.

    “We found it successfully blocked the inflammatory pathway activated by COVID-19, essentially putting out the fire,” Dr. Albornoz Balmaceda said.

    “The drug reduced inflammation in both COVID-19-infected mice and the microglia cells from humans, suggesting a possible treatment approach to prevent neurodegeneration in the future.”

    Professor Woodruff said while the similarity between how COVID-19 and dementia diseases affect the brain was concerning, it also meant a possible treatment was already in existence.

    “Further research is needed, but this is potentially a new approach to treating a virus that could otherwise have untold long-term health ramifications.”  

    The research was co-led by Dr. Alberto Amarilla Ortiz and Associate Professor Daniel Watterson and involved 33 co-authors across UQ and internationally.

    The study was published on November 1 in Nature’s Molecular Psychiatry.

    Reference: “SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia through spike protein” by Eduardo A. Albornoz, Alberto A. Amarilla, Naphak Modhiran, Sandra Parker, Xaria X. Li, Danushka K. Wijesundara, Julio Aguado, Adriana Pliego Zamora, Christopher L. D. McMillan, Benjamin Liang, Nias Y. G. Peng, Julian D. J. Sng, Fatema Tuj Saima, Jenny N. Fung, John D. Lee, Devina Paramitha, Rhys Parry, Michael S. Avumegah, Ariel Isaacs, Martin W. Lo, Zaray Miranda-Chacon, Daniella Bradshaw, Constanza Salinas-Rebolledo, Niwanthi W. Rajapakse, Ernst J. Wolvetang, Trent P. Munro, Alejandro Rojas-Fernandez, Paul R. Young, Katryn J. Stacey, Alexander A. Khromykh, Keith J. Chappell, Daniel Watterson and Trent M. Woodruff, 1 November 2022, Molecular Psychiatry.
    DOI: 10.1038/s41380-022-01831-0

    University of Queensland

    Microbiology

    Researchers shed light on the key functions of innate immune cells

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    Reviewed by Emily Henderson, B.Sc.Nov 3 2022

    Inflammation and increased mucus production are typical symptoms of worm infections and allergies. This immune response involves our innate immune cells, but their exact functions are not yet fully understood. A research team from Charité – Universitätsmedizin Berlin has now shed light on the key tasks that these cells perform. In the study, which has been published in the journal Nature, the researchers also identify potential therapeutic approaches for the treatment of allergies.

    The human immune system is made up of two interconnected branches: the adaptive immune system, which learns something new with every infection and constantly develops over the course of a lifetime, and the innate immune system, which is less specialized but reacts particularly quickly and effectively. The cells of the innate immune system are located in the mucous membranes of the respiratory tract and the intestine, where they form a first line of defense at the point of entry for pathogens. These cells include group 2 innate lymphoid cells (ILC2s for short), which are active in the intestine in the case of parasitic diseases, and in the respiratory tract in the case of allergies.

    “Innate lymphoid cells were discovered a decade or so ago and we already know a lot about them, but their exact function in the machinery of the immune system is not yet completely understood,” explains Dr. Christoph Klose, who heads the Emmy Noether Independent Junior Research Group on the regulation of type 2 immune responses by neuropeptides and neurotransmitters at the Institute of Microbiology, Infectious Diseases and Immunology at Charité. “There is a group of adaptive immune cells – namely the T cells – that carry out some similar functions as part of the type 2 immune response, so it was previously thought that the role of ILC2s may be redundant and could be easily taken over by the T cells.”

    However, the recently published study has now disproved this theory. Using an animal model and state-of-the-art molecular methods such as single-cell sequencing, which allows scientists to zoom into individual cells and analyze their molecular state, they have shed light on the central functions of ILC2s.

    A certain type of immune cells called eosinophils were not able to develop properly when ILC2s were absent. This relationship was previously unknown and came as a big surprise.”

    Dr. Christoph Klose,  Charité – Universitätsmedizin Berlin

    Eosinophils are involved in inflammatory processes in the tissue. The scientists also found that ILC2s have a major effect on the ability of epithelial cells to promote mucus production and expel parasites, such as worms, from the body. “The absence of ILC2s was clearly noticeable in our tests examining the immune response to worm infections. There was only limited mucus production in the tissue and the parasites could no longer be combated effectively,” says Dr. Klose, summarizing the results of the study.

    In further experiments, the researchers examined the symptoms of allergic asthma and found that these improved when ILC2s were absent. “This could be a starting point for future studies aimed at developing potential allergy therapies,” says Dr. Klose. “With our study, we were able to show that group 2 innate lymphoid cells are essential cogs in the machinery of the immune system and cannot be replaced without compromising the immune response.” In future research projects, Dr. Klose and his team would like to investigate whether the innate lymphoid cells regulate other aspects of the immune response.

    Source:

    Charité – Universitätsmedizin Berlin

    Journal reference:

    Jarick, K.J., et al. (2022) Non-redundant functions of group 2 innate lymphoid cells. Nature. doi.org/10.1038/s41586-022-05395-5.

    Microbiology

    Shingles, or herpes zoster (HZ), is caused by the varicella zoster virus, which is the same virus that …

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    Shingles, or herpes zoster (HZ), is caused by the varicella zoster virus, which is the same virus that causes chicken pox. Varicella zoster virus may infect people as children, then it can hide away in ganglionic neurons. If the virus reactivates later in life, it can cause a rash and excruciating pain. Scientists have found that shingles can raise the risk of stroke, particularly for people younger than 40. There is a vaccine for shingles, but it has not yet been approved for use in people under age 50.

    Varicella-zoster Virus / Credit: NIAID

    Now researchers have found that tiny sacs in cells called exosomes, which move cargo like proteins and genetic sequences around cells, can link stroke and shingles. The findings have been reported in The Journal of Infectious Diseases.

    While most people are familiar with the painful rash that shingles can cause, many may not know that the risk of a stroke increases in the year after infection, noted corresponding study author Andrew Bubak, Ph.D., an assistant research professor at the University of Colorado School of Medicine. “Importantly, the rash is often completely healed and individuals feel normal but nonetheless are walking around with this significant elevation in stroke risk.”

    People who get a shingles facial rash face the highest risk of stroke, which may be related to its proximity to the brain.

    The investigators wanted to known if exosomes may be involved, because these sacs can carry dangerous cargo that may cause thrombosis and inflammation far from the site of where an infection is actually occurring, Bubak explained. “That could ultimately lead to a stroke in patients.”

    In this study, the researchers obtained plasma from thirteen shingles patients and ten healthy individuals. The plasma samples were collected when the patients had an infection, as well as three months later for some patients. Exosomes were isolated from the samples and analyzed.

    The scientists identified blood clot-causing prothrombotic exosomes in the shingles patients. The follow-up samples taken three months later also contained proinflammatory exosomes that could increase the risk of stroke.

    Bubak suggested that in some shingles patients, the virus does not become dormant again, or there are persistently circulating exosomes that prolong a prothrombotic state, even after therapy has concluded and the shingles rash is gone. A combination therapy that includes antiviral drugs, and antiplatelet and anti-inflammatory medications may be helpful in those cases, Bubak added.

    However, more work will be needed to affirm the conclusions of this small study. If that happens, “this could change clinical practice,” said Bubak.

    Physicians are often unaware that shingles and stroke are linked, even though it is important and easy to prevent. There is a vaccine for shingles, and when someone gets it, they should be treated with antiplatelet agents, Bubak noted.

    Sources: CU Anschutz Medical Campus, The Journal of Infectious Diseases


    Carmen Leitch