How cadmium-induced inflammation increases the severity and mortality of lung infections

Description of this mechanism offers a promising therapeutic target to limit lung injury and death. Lower respiratory tract infections, including bacterial pneumonia, are the fourth-leading cause of death worldwide, with 120 million to 156 million cases a year

Peer-Reviewed Publication

UNIVERSITY OF ALABAMA AT BIRMINGHAM

 

IMAGE: A. BRENT CARTER view more 

CREDIT: UAB

BIRMINGHAM, Ala. – A key mechanism of cadmium-linked inflammation that increases severity and mortality of lung infections has been described, offering a promising therapeutic target to limit lung injury and death.

This study, led by University of Alabama at Birmingham researchers Jennifer L. Larson-Casey, Ph.D., and A. Brent Carter, M.D., is based on an underserved, primarily African American community that is proposed as a National Priorities List area by the United States Environmental Protection Agency, due to heavy metals, including cadmium, in the soil and air that have caused lung disease. This North Birmingham, Alabama, community historically housed people who worked in mines, coke plants and heavy industries.

Air pollution from tiny particulate matter less than 2.5 microns in size is linked to respiratory infections, and this pollution is often tainted with cadmium, a poisonous heavy metal emitted from sources like smelters, coal fired plants, coke factories and forest fires. Environmental cadmium is associated with higher risk of death from flu and pneumonia, and it doubles the risk of lung disease; but the mechanism of cadmium’s influence was not known.

Lower respiratory tract infections, including bacterial pneumonia, are the fourth-leading cause of death worldwide, with 120 million to 156 million cases and 1.4 million deaths a year. Streptococcus pneumoniae accounts for more than 55 percent of those deaths.

The UAB research, published in the journal JCI Insight, focused on bone marrow-derived macrophages that are recruited in large numbers to the lungs during infection to defend against respiratory pathogens. These immune cells are initially inflammatory to fight the pathogen, and then should become anti-inflammatory as the disease is controlled, so that continued inflammation does not damage the lung tissue. The Carter lab had previously shown that cadmium-mediated lung injury resulted in the persistence of the inflammatory, classically activated lung macrophages by inhibiting the nuclear localization of the transcription factor PPAR-gamma. Active PPAR-gamma is a negative regulator of the inflammatory response by inhibiting production of pro-inflammatory cytokines and reactive oxygen species.

An enzyme called extracellular signal-regulated kinase, or ERK, has been known to play a pivotal role in lung inflammation and mouse models of lung injury; but how it acts was not known. In the present study, Larson-Casey, Carter and UAB colleagues used a mouse model to describe how cadmium or S. pneumoniae infection impairs the activation of PPAR-gamma in macrophages that were recruited to the lungs.

The exposure to cadmium or S. pneumoniae led to ERK activation in only the recruited macrophages. Activated ERK increased the post-translational phosphorylation of PPAR-gamma at its serine 112 amino acid. That change led to PPAR-gamma degradation, canceling its anti-inflammatory role.

The researchers also showed that the experimental drug BVD-523 — an inhibitor of ERK that is currently in clinical testing to treat cancer — protected mice from lung injury after cadmium exposure or infection. They further found that human subjects, who live in industrial North Birmingham, had increased cadmium levels in their lung fluid. Those residents also showed PPAR-gamma inhibition, as compared to controls who live elsewhere, that was mediated, at least in part, by ERK activation.

“Although lung injury after respiratory infection is often unavoidable, identifying modifiable risk factors that predispose individuals to severe pneumonia is an unmet need,” Carter said. “Our observations suggest that the regulation of PPAR-gamma in monocyte-derived macrophages is a novel target to protect against the severity of lower respiratory tract infections secondary to lung injury mediated by air pollution.”

In the mouse model, mice were instilled intratracheally with cadmium chloride or saline, and S. pneumoniae was given five days later. All mice that were given just saline or cadmium alone were alive 15 days later; but only about 80 percent of the mice given saline and S. pneumoniae survived, and less than half the mice given both cadmium and S. pneumoniae survived. Cadmium-exposed mice had increased numbers of macrophage cells in the lungs, and that number increased further after the cadmium-exposed mice were given S. pneumoniae. Both cadmium- and S. pneumoniae-exposed mice showed lung injury, and the lung injury was significantly greater in cadmium-exposed mice that were infected with S. pneumoniae.

In other details, the UAB researchers used single-cell RNA sequencing of cells from the lung to show that the PPAR-gamma gene was expressed predominantly in macrophage cells rather than 13 other cell types detected from the lung. That gene expression was about the same in macrophages exposed to cadmium or S. pneumoniae alone, or to cadmium and S. pneumoniae together.

The researchers also found that cadmium and S. pneumoniae increased the production of pro-inflammatory TNF-alpha and interleukin-6, and decreased production of the anti-inflammatory interleukin-10. Activated PPAR-gamma is known to inhibit production of TNF-alpha and interleukin-6, and it increases expression of interleukin-10.

Carter is a professor and Larson-Casey an assistant professor in the Division of Pulmonary, Allergy and Critical Care Medicine in the UAB Department of Medicine.

Co-authors with Carter and Larson-Casey in the study, “Impaired PPARɣ activation by cadmium exacerbates infection-induced lung injury,” are Shanrun Liu, UAB Department of Medicine, Division of Clinical Immunology and Rheumatology; Jennifer M. Pyles and Suzanne E. Lapi, UAB Department of Radiology; Komal Saleem and Veena B. Antony, UAB Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine; Manuel Lora Gonzalez, UAB Department of Pathology; and David K. Crossman, UAB Department of Genetics.

Support came from National Institutes of Health grants ES027723-03, a National Institute of Environmental Health Sciences Superfund grant that is determining the effects of heavy metals in lung disease, ES015981-15 and HL114470-10; Department of Veteran Affairs grant CX001715-04; and UAB.

At UAB, Medicine, Pathology, Radiology and Genetics are departments in the Marnix E. Heersink School of Medicine.

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JOURNAL

JCI Insight

DOI

10.1172/jci.insight.166608 

METHOD OF RESEARCH

Experimental study

SUBJECT OF RESEARCH

Animals

ARTICLE TITLE

Impaired PPARɣ activation by cadmium exacerbates infection-induced lung injury

Trim the sugar: New HIV vaccine design improves immune response

Scripps Research vaccine candidate headed for clinical trials.

Peer-Reviewed Publication

SCRIPPS RESEARCH INSTITUTE

 

IMAGE: A STRUCTURAL DEPICTION OF TWO HIV NANOPARTICLE VACCINES (E2P AND I3-01V9) AND A CLOSE-UP OF THE ENV PROTEINS THESE NANOPARTICLES DISPLAY ON THEIR SURFACES (HIV-1 BG505 UFO TRIMER). THE VACCINES ARE DESIGNED TO HAVE SHORTER SUGARS (OR GLYCANS) ON THE ENV PROTEIN. view more 

CREDIT: SCRIPPS RESEARCH

LA JOLLA, CA— A new HIV vaccine from Scripps Research has shown a significantly improved ability to neutralize the virus in preclinical tests, and it will soon be studied in healthy people who volunteer to participate in clinical trials.

The new and unique vaccine design, described in a paper in Nature Communications on April 9, 2023, uses tiny protein “nanoparticles” to display multiple copies of HIV’s surface protein Env, thus presenting itself to the immune system much as real HIV particles would without causing HIV infection. The key innovation that explains its effects has to do with flexible sugar molecules called glycans, which normally cover Env on the real virus but are shortened in the new design. After achieving promising preclinical results, the National Institutes of Health (NIH) has agreed to sponsor a future clinical trial.

“With this design we appear to have solved a big piece of the HIV vaccine puzzle,” says the paper’s senior author Jiang Zhu, PhD, an associate professor in the Department of Integrative Structural and Computational Biology at Scripps Research.

The co-first authors of the study were postdoctoral associates Yi-Nan Zhang, PhD and Aleksandar Antanasijevic, PhD; scientific collaborator Jennifer Paynter, PhD; and postdoctoral associate Joel Allen, PhD, from the laboratory of vaccinologist Max Crispin, DPhil, professor at the University of Southampton.

The Joint United Nations Programme on HIV/AIDS (UNAIDS) estimates that 38.4 million people worldwide are currently living with HIV, and 1.5 million people became newly infected with HIV in 2021 alone. Apart from very rare cases involving bone marrow transplants, there is no cure for the infection, which must be held in check indefinitely with antiviral drugs to keep it from progressing to the deadly immune deficiency condition known as AIDS.

One of the defense strategies the virus uses is to shield its most exposed structure, Env, with glycans. Glycans are simple, chain-like molecules that are made by human cells to carry out various essential functions. Env contains sites where glycans will automatically fasten, so that when it is inside a human host, it ends up largely covered by them.

Glycans are difficult for antibodies to grip, and anything coated in them appears less like a foreign invader to the immune system. At the same time, Env proteins typically leave some of their less critical, more mutable parts uncovered by glycans, harmlessly diverting much of the antibody response.

While the best way to present glycans on the Env proteins used in vaccines is still a subject of lively debate among researchers, Zhu and his team took their vaccine design in a unique direction: not by removing glycans or adding them to no-glycan regions as some designs do, but instead simply by shortening their lengths. They reasoned that this would reduce the decoy power of no-glycan regions by reducing their contrast with glycan-dense regions—while simultaneously making vulnerable sites on the virus more accessible to antibodies. They also suspected that the desirable antibodies that can use glycans to hit Env would still be able to grip the trimmed glycans.

They designed experiments to test their predictions. Animal studies showed better antibody binding to key vulnerable sites on Env, and less binding to decoy sites. Moreover, in vaccinated animal models, the trimmed-glycan version of the vaccine induced strikingly stronger virus-neutralizing antibody responses compared to the non-trimmed-glycan version.

“In one test in mice, for example, seven out of eight immunized animal models generated robust neutralizing antibody responses, compared to only one of eight for the non-glycan-trimmed version,” Zhu says. “The difference with the glycan trimming was rather striking.”

The journey also extends beyond the lab and into the product development front. “As the exclusive licensee of this advanced vaccine platform technology, Uvax Bio is completing the GMP production of two vaccine candidates, namely, the wild-type Uvax-1197 and trimmed-glycan Uvax-1107,” added Ji Li, CEO of Uvax Bio.

In advance of the NIAID-supported clinical trial, Zhu and colleagues will do further experiments to confirm the specific antibodies, Env binding sites, glycan interactions and other vaccine components that are most important to test in this new vaccine candidate. A clinical trial may start as early as 2024.

“Single-component multilayered self-assembling protein nanoparticles presenting glycan-trimmed uncleaved prefusion optimized envelope trimers as HIV-1 vaccine candidates” was co-authored by Yi-Nan Zhang, Jennifer Paynter, Aleksandar Antanasijevic, Mor Eldad, Yi-Zong Lee, Jeffrey Copps, Linling He, Ian Wilson, Andrew Ward, and Jiang Zhu, of Scripps Research; Joel Allen, Maddy Newby, and Max Crispin of the University of Southampton; and Deborah Chavez, Pat Frost, Anna Goodroe, John Dutton, Robert Lanford and Christopher Chen of the Southwest National Primate Research Center.

Support for the research was provided by the International AIDS Vaccine Initiative (IAVI) (INV-008352/OPP1153692, INV-034657, INV-008352/OPP1153692), the Bill and Melinda Gates Foundation; the Scripps Consortium for HIV/AIDS Vaccine Development (CHAVD 1UM1 AI144462); the National Institutes of Health (P01 AI124337, R01 AI129698, R01 AI140844), the Southwest National Primate Research Center (P51 OD011133 and U42OD010442), Tulane National Primate Research Center (P51 OD011104), and UVAX BIO, LLC.

 

About Scripps Research

Scripps Research is an independent, nonprofit biomedical institute ranked one of the most influential in the world for its impact on innovation by Nature Index. We are advancing human health through profound discoveries that address pressing medical concerns around the globe. Our drug discovery and development division, Calibr, works hand-in-hand with scientists across disciplines to bring new medicines to patients as quickly and efficiently as possible, while teams at Scripps Research Translational Institute harness genomics, digital medicine and cutting-edge informatics to understand individual health and render more effective healthcare. Scripps Research also trains the next generation of leading scientists at our Skaggs Graduate School, consistently named among the top 10 US programs for chemistry and biological sciences. Learn more at www.scripps.edu.

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JOURNAL

Nature Communications

DOI

10.1038/s41467-023-37742-z 

ARTICLE TITLE

Single-component multilayered self-assembling protein nanoparticles presenting glycan-trimmed uncleaved prefusion optimized envelope trimers as HIV-1 vaccine candidates

UK

Cut council tax for green gardeners to help cities tackle climate change

Peer-Reviewed Publication

UNIVERSITY OF SHEFFIELD

• Homeowners should be rewarded to garden sustainably, new research by Professor of Environmental Horticulture at University of Sheffield, recommends
• Rewards for sustainable gardening could include reductions to council tax, water bills or assistance with resources
• Ensuring urban gardeners have the ability to have planted gardens will have numerous benefits for the environment and communities
• Banning environmentally damaging materials, such as pesticides; or practices such as installing astroturf, could also benefit the environment
• Research shows that some cities may have lost as much as 50 per cent of their green garden space over the last two decades, contributing to rising urban temperatures

Homeowners should be rewarded to garden sustainably, to help combat the damaging effects of climate change in cities and promote a healthier urban landscape.

According to new research from the University of Sheffield, policymakers should offer incentives, such as council tax or water bill discounts, to encourage gardeners to use environmentally sensitive techniques to help combat climate change in cities and boost communities' health and wellbeing.

The new study, published by Professor Ross Cameron in Urban Forestry and Urban Greening, highlights that, as gardens become increasingly important in the battle against the extreme effects of climate change, financial incentives should be considered to ensure gardens are well stocked with plants.

Professor Cameron said: “Gardens account for a third of all our urban areas and are vital spaces in terms of keeping our buildings and city environments cool in summer, absorbing rain to avoid flash flooding and providing an important refuge for wildlife.

“Gardens need to be green and full of plants to be beneficial to the local environment, and some types of garden are more beneficial than others.”

“The paradox is that many gardens are not actually green and some trends in garden design can be very damaging for the urban environment. We have paved them over to house the car, or provide sterile patio space; factors that increase urban temperatures and increase flooding risk.”

The study calls for policy-makers to promote more sustainable garden management and to help foster gardening activities that help us meet important environmental and sustainability targets.

Professor Cameron outlines potential incentives that could be offered by policymakers to ensure gardens remain green and well-planted, including:

• Offering financial rewards – such as a reduction in council tax or water bills – for house owners with more than 50 per cent of their garden space planted
• Offering financial incentives to plant or maintain trees in gardens, with appropriate choices based on size of garden
• Banning or restricting features that damage environmental processes e.g. having a maximum area artificial grass can cover and banning synthetic pesticides for home garden use
• Acknowledging that gardens with a high proportion of plants act as a health facility, and that planning processes should have mandatory requirements to include and protect, well-planted areas

Will Teare, 32, from Norton Lees, and his family have been planting a garden that provides a home for wildlife as well as a space for them to enjoy at the same time.

He said: “When we moved into our house, we thought about how we could create a garden that would help us be more connected to nature, so the most important thing for us has been that it benefits wildlife.

“Humans are responsible for a lot of the loss of habitat for wildlife and we wanted to invite it back into the garden. Everything we try in the garden, whether it is the plants we use, or having a go at creating different habitats in the garden, say with a woodland type area or pond, needs to have value for the wildlife.

“The family gets a lot of enjoyment out of it, the birds coming to nest, or watching the frogs and newts around the pond; it brings the garden to life, and is a source of excitement for the kids.”

“I think like us, everyone can work with what space they have, have a small tree, unusual plants, or create different habitats; basically anything other than hard paving can be an asset to wildlife, and benefits us as well. So I think incentives to plant a garden will definitely get people to think about it!”

Unlike previous eras, where private garden management has largely been left to the discretion of the homeowner, Professor Cameron argues that radical changes in policy and practice are now required if local authorities are to deal effectively with the impacts of climate change and biodiversity loss at a city level.

He said: “Our research shows that some cities may have lost as much as 50 per cent of their ‘green’ garden space over the last two decades. Many residents use artificial grass that kills much of the soil life underneath it, and when real plants are present, we wrongly assume we need to hit them with a cocktail of chemicals to keep them alive and free of pests. These chemicals pollute our watercourses and damage the ecological function of our gardens”. 

The research suggests well-planted gardens not only provide a quality habitat for wildlife, but also improves local air quality, improves health and well-being, provides people with the opportunity to grow their own food, connect with nature and reduce energy bills by better insulating homes.

Professor Helen Woolley, Head of the Department of Landscape Architecture at the University of Sheffield, said: “The value of this research is it categorically states the value of a particular landscape type and how that links to different socio-environmental agendas. Many citizens quickly realised the value of their home gardens during the pandemic lockdowns, and this academic paper builds on and reinforces what we learned then. It is important that policy makers and planners take note.” 

Professor Ross Cameron is also the author of a new book exploring the science behind how introducing plants into your life and space, irrespective of how much outdoor space you actually have, can promote a powerful, long-lasting and positive impact on your well-being.

‘How plants can save your life’ will be published by Quercus on 25 May 2023.

 

ENDS

Media contact: Rebecca Ferguson, Media & PR Officer, 0114 222 3670, r.l.ferguson@sheffield.ac.uk

Notes to editors:

• Read the full study at ScienceDirect: https://www.sciencedirect.com/science/article/pii/S1618866722003636?via%3Dihub
• Image asset available for ‘How plants can save your life’, please contact the Media & PR Officer

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JOURNAL

Urban Forestry & Urban Greening

DOI

10.1016/j.ufug.2022.127820 

ARTICLE TITLE

“Do we need to see gardens in a new light?” Recommendations for policy and practice to improve the ecosystem services derived from domestic gardens

A myth no more: Cranberry products can prevent urinary tract infections for women

New medical evidence shows consuming cranberry products is an effective way to prevent a UTI

Peer-Reviewed Publication

FLINDERS UNIVERSITY

Drinking cranberry juice has long been a mythical prevention strategy for women who develop a urinary tract infection – and new medical evidence shows consuming cranberry products is an effective way to prevent a UTI before it gets started.

A global study looking at the benefits of cranberry products published in Cochrane Reviews has determined cranberry juice, and its supplements, reduce the risk of repeat symptomatic UTIs in women by more than a quarter, in children by more than half, and in people susceptible to UTI following medical interventions by about 53%. 

Cranberry juice and healthcare supplements that commonly include the fruit, such as capsules and tablets, have long been promoted as a readily available solution to ward off the infection but the most recent review in 2012, with evidence from 24 trials, showed no benefit from the products.

The medical scientists behind this updated review from Flinders University and The Children’s Hospital at Westmead aimed to update these findings, as an important step in determining the effectiveness of cranberry products by looking at 50 more recent trials that included almost 9000 participants.

“This incredible result didn’t really surprise us, as we’re taught that when there’s more and better evidence, the truth will ultimately come out. UTIs are horrible and very common; about a third of women will experience one, as will many elderly people and also people with bladder issues from spinal cord injury or other conditions,” says the study lead author Dr. Gabrielle Williams.

“Even back in 1973, my mum was told to try cranberry juice to prevent her horrible and frequent UTIs, and for her it’s been a saviour. Despite me niggling in her ear about evidence, she’s continued to take it daily, first as the nasty sour juice and in recent years, the easy to swallow capsules. As soon as she stops, wham the symptoms are back. As usual, it turns out that mum was right! Cranberry products can help some women prevent UTIs.”

Flinders University epidemiologist Dr. Jacqueline Stephens, a co-author of the study, says if the UTI persists untreated it can move to the kidneys and cause pain and more complications, including sepsis in very severe cases, so prevention is the most effective way to reduce risks.

“Most UTIs are effectively, and pretty quickly, treated with antibiotics, sometimes as little as one dose can cure the problem. Unfortunately, in some people UTIs keep coming back. Without being sure if or how it works, some healthcare providers began suggesting it to their patients.  It was a harmless, easy option at the time. Even centuries ago, Native Americans reportedly ate cranberries for bladder problems, leading somewhat more recently, to laboratory scientists exploring what it was in cranberries that helped and how it might work.”

“The studies we looked at included a range of methods to determine the benefits of cranberry products. The vast majority compared cranberry products with a placebo or no treatment for UTI and determined drinking cranberries as a juice or taking capsules reduced the number of UTIs in women with recurrent cases, in children and in people susceptible to UTi’s following medical interventions such as bladder radiotherapy.”

“It’s also important to consider that few people reported any side effects with the most common being tummy pain based on the results. We also did not find enough information to determine if cranberry products are more or less effective compared with antibiotics or probiotics in preventing further UTIs.”

The data also doesn’t show any benefit for elderly people, pregnant women or in people with bladder emptying problems. 

Senior Author, Professor Jonathan Craig, Vice President and Executive Dean of the College of Medicine & Public Health at Flinders University, says the real benefits of cranberry products became clear when the researchers expanded the scope of the review to include the most recently available clinical data.

“This is a review of the totality of the evidence and as new evidence emerges, new findings might occur. In this case, the new evidence shows a very positive finding that cranberry juice can prevent UTI in susceptible people,” says Professor Craig.

“We have shown the efficacy of cranberry products for the treatment of UTIs using all the evidence published on this topic since the mid-nineties. The earlier versions of this review didn’t have enough evidence to determine efficacy and subsequent clinical trials showed varied results, but in this updated review the volume of data has shown this new finding.”

The study authors conclude that while cranberry products do help prevent UTIs in women with frequent recurrence, more studies are needed to further clarify who with UTI would benefit most from cranberry products.

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JOURNAL

Cochrane Database of Systematic Reviews

DOI

10.1002/14651858.CD001321.pub6 

METHOD OF RESEARCH

Systematic review

SUBJECT OF RESEARCH

People

ARTICLE TITLE

Cranberries for preventing urinary tract infections

Osteoarthritis sufferers swing their way to better health

Peer-Reviewed Publication

UNIVERSITY OF SOUTH AUSTRALIA

Golf is acknowledged as a sport allowing players to blow off steam and enjoy the outdoors, but a new study led by the University of South Australia shows it may also have significant benefits for people with chronic disease osteoarthritis.

UniSA researcher Dr Brad Stenner from the Alliance for Research in Exercise, Nutrition and Activity (ARENA) and a team of academics from Australia and the UK found that golfers with the degenerative condition experience lower psychological distress and better general health compared to the general population.

The same was found with golfers without osteoarthritis.

The findings are reported in the Journal of Science and Medicine in Sport.

Osteoarthritis affects more than two million Australians who suffer joint pain and stiffness most commonly in their hands, neck, lower back, knees, or hips, contributing to a lower likelihood of meeting physical exercise guidelines.

Osteoarthritis is the most common form of arthritis, the leading cause of chronic pain and the second most common cause of disability.

In a survey of 459 golfers with osteoarthritis more than 90% of participants rated their health as good, very good or excellent, compared to just 64% of the general population with the condition.

Almost three times as many non-golfers (22%) reported high to very high levels of psychological distress compared to golfers with osteoarthritis (8%).

Dr Stenner, a lecturer and occupational therapist, says regular golfers are kept active due to the amount of walking required and they can also experience a range of social benefits.

“People who play golf are often walking 8-10km per round and, as such, are regularly meeting or exceeding recommended physical activity guidelines, which is known to reduce the risk of cardiovascular disease, diabetes, obesity and improve metabolic and respiratory health,” he says.

“There are also significant benefits to mental health and wellbeing.

“Our research has highlighted the important role that golf has in building friendships, contributing to community, and bringing a sense of belonging, all of which are known to contribute to mental health and wellbeing.”

Staying active and exercising regularly is one of the most important aspects of managing osteoarthritis.

“Lower impact activity such as golf can assist in maintaining activity whereas higher impact activities such as running, jogging and gym may place significant stress on the joints, contributing to increased symptoms and pain,” Dr Stenner says.

“There is a growing body of evidence that golf reduces the risk of many chronic conditions such as obesity, diabetes, and cardiovascular disease, and may contribute to the management of these illnesses, which in turn may lower the longer term health and medical costs.

“From a mental health point of view, playing golf is associated with improved wellbeing and lower levels of psychological distress, and this is an important consideration for older adults.”

Dr Stenner says there is a gap in the known literature on the topic despite it being one of the most popular sporting activities for older adults.

“Very little is known about the relationship between golf and health and there is so much more we need to find out,” he says.

Notes to Editors

The study was undertaken by researchers from the University of South Australia, University of Dundee, University of Oxford, University of Melbourne and University College London.

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JOURNAL

Journal of Science and Medicine in Sport

DOI

10.1016/j.jsams.2023.02.005 

METHOD OF RESEARCH

Survey

SUBJECT OF RESEARCH

People

ARTICLE TITLE

Australian golfers with and without osteoarthritis report reduced psychological distress and improved general health compared to a general population-based sample

The University of Liège and Mithra pharmaceuticals are intensifying their collaboration for the production of biosourced estetrol

This research led by the CiTOS Lab at ULiège will enable the development of an innovative process for the production of a key intermediate in the contraceptive product estetrol while reducing the environmental footprint

Peer-Reviewed Publication

UNIVERSITY OF LIEGE

 

IMAGE: COMPUTATIONAL CHEMISTRY AS AN ACCELERATOR FOR THE INTENSIFICATION OF CONTINUOUS FLOW PROCESSES view more 

CREDIT: MICHAËL SCHMITZ, CITOS

Researchers at CiTOS - Center for Integrated Technology and Organic Synthesis of the University of Liège (Belgium) and  Mithra Pharmaceuticals have devised a continuous process for preparing a key intermediate of estetrol. The process is based on a thermolysis reaction feeding upon an estrone sulfoxide derivative. Estrone is a bio-based steroid compound sourced from the soybean industry. This successful collaboration relies on a pioneering approach developed at CiTOS, which features synergy between computational chemistry and intensified continuous flow processes. 

Estetrol is a natural biogenic estrogen derivative with breakthrough potential in hormone-dependent treatments and, in particular, for the oral contraceptive market. Estetrol was approved in 2021 by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) in combination with drospirenone as an active pharmaceutical ingredient for fifth-generation oral contraceptives. Estetrol is one of the flagship products of Mithra Pharmaceuticals, a pharmaceutical and biotechnology company based in Liège focused on women's health. In view of estetrol’s market expansion, research efforts toward cost-effective and intensified large-scale synthesis were engaged.

Mithra Pharmaceuticals R&D team has teamed up with CiTOS to develop a process towards a key enone intermediate. “Our R&D team has been collaborating for almost three years with Prof. Jean-Christophe Monbaliu under the umbrella of his technology flow platform,” says Amaury Dubart, Industrial Synthesis Associate at Mithra. "We present an applied study relying on a unique methodology, where quantum chemical calculations give an experimental design framework. It allows a priori assessment of the feasibility of a reaction in micro-/ and mesofluidic reactors”, comments Pauline Bianchi, F.R.S- FNRS PhD at CiTOS and lead author of the study. Such a priori benchmarking assessment affords a preselection of reaction conditions and suitable combinations of reagents. It positively impacts the reduction of waste generated during optimization phases. "This last point is a significant improvement to accelerate the development of innovative conditions while minimizing the overall environmental footprint, particularly when compounds with high hormonal activity are at stake", indicates Jean-Christophe Monbaliu.

The collaboration focused on the thermolysis of a key sulfoxide derivative of estrone, which was carefully tailored to minimize by-products and to improve its robustness and productivity. “After optimization, the thermolysis process was transposed into a production pilot, leading to an unprecedented productivity of ~1 kg every three hours. With these metrics transposed to the entire estetrol production scheme, a forecast of several million doses (15 mg formulation) is therefore achievable with a minimal global footprint,” concludes Jean-Christophe Monbaliu.

The successful outcome of this project, funded by the FRS-F.N.R.S. as part of Pauline Bianchi's PhD fellowship, relies on a multidisciplinary approach at the interface between organic chemistry, new process technologies and computational chemistry. This program belongs to one of the priority areas of research at CiTOS, with the ambition of using chemical and technological innovations to accelerate the development of processes with a minimal environmental footprint.

Intensified preparation of a key enone intermediate toward estetrol

CREDIT

Michaël Schmitz, CiTOS

JOURNAL

Reaction Chemistry & Engineering

DOI

10.1039/D3RE00051F 

ARTICLE TITLE

Metal-free synthesis of an estetrol key intermediate under intensified continuous flow conditions

Diatoms provide an attractive habitat for bacteria

New study reveals complex colonization patterns

Peer-Reviewed Publication

UNIVERSITY OF OLDENBURG

 

IMAGE: THIS IMAGE TAKEN BY A CONFOCAL LASER SCANNING MICROSCOPE SHOWS ALGAL CELLS (STAINED BLUE AND RED) COLONIZED BY BACTERIA (GREEN). view more 

CREDIT: UNIVERSITY OF OLDENBURG

Unicellular algae are an attractive and surprisingly diverse habitat for marine bacteria. A research team led by microbiologist Professor Dr. Meinhard Simon from the University of Oldenburg has now shown for the first time how different species of bacteria tend to colonise different parts of a common microscopic diatom from the North Sea. The team presents the results of its study in the current issue of the Journal of Phycology, shedding light on the complex interactions between algae and bacteria which are of fundamental importance for material cycles and food webs in marine environments.

Diatoms are an important type of phytoplankton – the mostly microscopic, single-celled algae that live in the world's oceans. Enclosed in a solid silicate shell, diatoms produce about a fifth of the oxygen in the Earth's atmosphere and also convert carbon dioxide from the air into biomass during photosynthesis, binding more CO2 than the tropical rainforests, which is why they play a key role in the carbon cycle and for the climate. "Diatoms live in close association with bacteria, yet little is known about many aspects of their interactions," Simon explained. The biologist and his team have now taken a closer look at these microscopic interactions which are of vital importance for the ecology and biochemistry of the oceans.

The Oldenburg team led by Professor Simon, Dr Sara Billerbeck and doctoral candidate Tran Quoc Den selected a commonly occurring diatom called Thalassiosira rotula and used various microscopy methods to conduct a detailed analysis of its colonisation by bacteria. Dr Thomas Neu from the Helmholtz Centre for Environmental Research in Magdeburg was also involved in the study.

3D images of algal surfaces

Using fluorescent dyes, the researchers were able to demonstrate that the surface of this alga displays distinct microscale biochemical variations. They used lectins – complex biochemical compounds that bind very specifically to certain protein-carbohydrate complexes – to mark the different areas on the surface of the alga, stain them, and with the help of a special microscope make them visible as 3D images. The scientists also found out that different species of bacteria specialise in colonising different areas of the algae. The observed bacteria belonged mainly to the Roseobacter group and the Flavobacteria strain.

"The cell surface of diatoms is surprisingly diverse in its structure. We hadn't expected the colonisation by the different bacterial species to be so finely tuned to this structure," Simon explained. The team also observed that certain bacterial species are more commonly found on fine hairs or "threads" on the surface of the algae. "The colonisation patterns reflect the highly diverse metabolic properties of different bacterial species and their abilities to colonise surfaces," said Simon, summarising the team's findings.

These results are also interesting because they provide an insight into the diatoms' microenvironment. Known as the "phycosphere", this environment is rich in organic substances excreted by the algal cells. "Previous studies have shown that the algae use this to attract certain bacteria that produce substances which are vital for their survival, for example vitamins – similar to the way plants attract bees with their flowers," Simon explained. "Building on these new findings, future studies could examine in greater detail the precise function of the different bacterial species in the phycosphere," he added.

The current study was conducted as part of the Transregional Collaborative Research Centre (CRC) Roseobacter, which is funded by the German Research Foundation (DFG). In the 13 years since the establishment of the CRC, more than 60 researchers from Oldenburg, Braunschweig, Göttingen and Bonn have studied the bacteria of the Roseobacter group. These bacteria occur in all marine environments – from the tropics to the polar seas and from the surface layer to the deep sea. The researchers have discovered many new strains and described the interactions of representatives of this group with other microorganisms and their distribution and functional biogeography in the oceans around the world for the first time. In total, more than 250 published scientific articles are based on research conducted in the context of the CRC Roseobacter.

CAPTION

The scanning electron micrograph shows thin filaments connecting two algal cells. On the surface of the algae mostly rod-shaped bacteria are attached. The scale is 10 micrometers.

CREDIT

University of Oldenburg

JOURNAL

Journal of Phycology

DOI

10.1111/jpy.13308 

METHOD OF RESEARCH

Observational study

SUBJECT OF RESEARCH

Not applicable

ARTICLE TITLE

Distinct glycoconjugate cell surface structures make the pelagic diatom Thalassiosira rotula an attractive habitat for bacteria

Gut bacteria could be behind weaker immune responses to COVID-19 vaccine

Digestion of fucose sugar by bacteria in our digestive tract could be hampering how effectively we respond to the COVID-19 mRNA vaccine.

Peer-Reviewed Publication

OKINAWA INSTITUTE OF SCIENCE AND TECHNOLOGY (OIST) GRADUATE UNIVERSITY

 

IMAGE: HIGH ACTIVITY OF FUCOSE DIGESTION BY BACTERIA IN THE GUT IS ASSOCIATED WITH HIGHER EXPRESSION OF TWO AP-1 TRANSCRIPTION FACTORS, FOS AND ATF3 IN BLOOD IMMUNE CELLS, AND WITH A LOWER T-CELL RESPONSE TO THE COVID-19 VACCINE. view more 

CREDIT: OKINAWA INSTITUTE OF SCIENCE AND TECHNOLOGY (OIST)

Gut bacteria that break down a sugar called fucose could be dampening our immune response to the COVID-19 mRNA vaccine, according to a study led by researchers from the Okinawa Institute of Science and Technology (OIST). 

The scientists report that increased fucose digestion by bacteria in the gut before vaccination was associated with lower numbers of T-cells activated by vaccination. T-cells are an important type of blood immune cell that are activated by a specific strain of bacteria or virus, and then multiply to fight the infection. 

The findings, published 20 April in Communications Biology, illustrate the important impact that the trillions of bacteria in our gut — collectively called our ‘gut microbiome’— have on our immune health and adds a missing piece to the puzzle of why vaccination varies in effectiveness from person to person.  

“Not everyone who gets the same vaccine receives an equal level of protection, but we still don’t really understand why people respond so differently,” said Professor Hiroki Ishikawa, who leads the OIST Immune Signal Unit. “If we can get to the bottom of what causes this variation, we could predict how an individual might respond to a vaccine, and perhaps find new strategies to promote the immune response.” 

While this research focused on the response to the COVID-19 Pfizer mRNA vaccine, the researchers believe their results could also be relevant for other mRNA vaccines in development that protect against other infectious diseases, and even cancer. 

In this study, Prof. Ishikawa and his colleagues took a stool sample and multiple blood samples from 96 healthy participants living in Okinawa, starting before the first dose of the vaccine, and ending a month after the second dose. 

They then did a broad analysis, looking at all the genes from immune cells in the blood and bacteria in the gut to see if there was any association with an individual’s T-cell and antibody levels. 

The researchers did not find a significant link to antibody levels, but they did find that individuals that had a lower T-cell response also had a gut microbiome with a high activity of fucose digestion. 

The team also found that individuals with a reduced T-cell response had higher expression of two genes, FOS and ATF3, prior to vaccination. These genes are expressed by blood immune cells, and code for proteins that are part of a larger group, called AP-1 transcription factors. Previous research has shown that different AP-1 transcription factors control T-cell survival and activity, but the exact role and function of these two proteins remains unknown. 

Individuals with higher expression of FOS and ATF3 prior to vaccination also had microbiomes with high activity of fucose digestion, suggesting that the gut’s impact on the immune system is through a pathway that involves FOS and ATF3. 

“The mechanism is not yet proven, but we propose that fucose digestion leads to increased baseline expression of FOS and ATF3 in blood immune cells, which in turn weakens the response to the COVID-19 vaccine,” said Masato Hirota, first author and PhD student in the Immune Signal Unit. “It’s clear that the gut bacteria have an important impact on the overall health of the immune system.” 

The team now plans to experimentally manipulate the gut bacteria in mice and investigate the exact mechanism of FOS and ATF3, to further understand the link between the microbiome, blood immune cells and the overall immune response. 

Left to right: Professor Hiroki Ishikawa, Miho Tamai, and Masato Hirota from the Immune Signal Unit looked for associations between genes and proteins from blood immune cells and gut bacteria, and an individual’s immune response.

CREDIT

Okinawa Institute of Science and Technology (OIST)

The study was carried out as a collaboration between the OIST, Naha Medical Association and KIN Oncology Wellness Clinic. From OIST, Prof. Hiroaki Kitano, Prof. Matthias Wolf, and former Provost Mary Collins contributed to the study. This was supported by COVID-19 AI and Simulation Project (Cabinet Secretariat) to Prof. Ishikawa, the Platform Project for Supporting Drug Discovery and Life Science Research (BINDS) from AMED to Prof. Wolf, and JST COI-NEXT to Prof. Kitano.   

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JOURNAL

Communications Biology

DOI

10.1038/s42003-023-04755-9 

METHOD OF RESEARCH

Observational study

SUBJECT OF RESEARCH

People

ARTICLE TITLE

Human immune and gut microbial parameters associated with inter-individual variations in COVID-19 mRNA vaccine-induced immunity

ARTICLE PUBLICATION DATE

20-Apr-2023