Thursday, April 25, 2024

A vaccine to fight antibiotic resistance

MSU, Harvard Medical School team up to expand vaccine science’s role in the fight against MRSA and other infections

MICHIGAN STATE UNIVERSITY

Driven by the overuse of antimicrobials, pathogens are quickly building up resistances to once-successful treatments. It’s estimated that antimicrobial-resistant infections killed more than 1 million people worldwide in 2019, according to the World Health Organization.

“There are worries that at the rate things are going, in perhaps 20 or 30 years, few of our drugs will be effective at all,” said Xuefei Huang, a Michigan State University Research Foundation Professor in the departments of Chemistry and Biomedical Engineering.

“This would bring us back to the pre-antibiotic age.”

Now, in a new Nature Communications study, Huang and his collaborators have reported a breakthrough that will help tackle this global threat head-on. Specifically, the team has created a promising vaccine candidate for antibiotic-resistant bacteria.

Bacterial vaccines, along with antibiotics, are a crucial tool in the fight against deadly microbes.

In the latest paper, Huang announced several discoveries that will help the development of a carbohydrate-based vaccine for infections caused by Staphylococcus aureus and its “superbug” relative methicillin-resistant Staphylococcus aureus, or MRSA.

Staph aureus, or staph, and MRSA are among the most prevalent causes of bacterial infections.

Using an innovative delivery platform created by the Huang group at MSU, the team’s preclinical vaccine formulation offered high levels of immunity from lethal levels of staph and MRSA in animal trials.

With this work, Huang and his team have expanded the frontiers of vaccine science, equipping fellow researchers with new knowledge to improve and refine future bacterial vaccines.

Carbohydrate hurdles

To develop a vaccine, researchers must identify an effective antigen. This is a substance or molecule that the body flags as foreign, helping to trigger an immune response and the creation of antibodies that will fight future infection.

While most vaccines rely on protein antigens, Huang is an expert in the chemistry and biology of carbohydrates. These are chemical compounds comprised of saccharides, or sugars.

Developing carbohydrates to use as antigens in vaccines comes with its own unique challenges and advantages.

“Sugar structures are very specific to certain bacteria,” Huang explained. “A vaccine that works against one bacterium might not work at all against another, even if they’re very similar.”

This is why a single dose of a bacterial vaccine can contain many different antigens. For instance, the “20” in Pfizer’s PREVNAR 20 pediatric pneumonia vaccine refers to the 20 unique strains of bacteria it protects against.

If researchers can develop an antigen that’s shared among many — if not all — bacteria, vaccination coverage would be greatly improved.

Gerald Pier, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital and a collaborator on the latest MSU-led paper, has studied one such antigen candidate for years.

Polysaccharide poly-β-(1−6)-N-acetylglucosamine, or PNAG, is a carbohydrate found on the cell wall of staph, many other bacteria and even fungi. This prevalence makes it extremely useful, offering potential protection against numerous pathogens at once.

By examining PNAG as an antigen candidate for staph, Pier, Huang and their colleagues are unlocking the secrets needed to make a more effective vaccine.

A molecular mosaic

Imagine creating a mosaic made from multicolored tiles.

Arrange these tiles in a precise pattern and you’ll end up with a striking work of art. Move just a few tiles around, however, and you’ll find yourself looking at a very different image.

PNAG — and carbohydrates in general — are kind of like mosaics. There are myriad ways to arrange their individual pieces, but only a select few have the effects that researchers desire.

Just as changing a few tiles in a mosaic can give you a completely different image, swapping out these pieces or even changing their location within a PNAG molecule changes its performance as a potential antigen.

“We were very interested in this molecule and these different patterns,” Huang said.

“We wanted to know: Was there a best combination to improve Staph aureus vaccine efficiency, and does the arrangement matter?”

The pieces that Huang and his colleagues were most interested in were biologically active molecular components known as amines and acetyl groups that adorn PNAG’s sugary backbone.

PNAG molecules can contain many amines. These amines can be acetylated, meaning they’re modified with an acetyl group, or they can be free and not bound to anything else.

Currently, most researchers investigating PNAG as an antigen focus on forms of the sugar that are either fully free or fully acetylated.

Huang and his colleagues believed there were promising opportunities in the understudied in-between space where there’s a mixture of free and acetylated amines.

For its research, the team created a library of 32 different PNAG structures. The structures were all pentasaccharides — made from five saccharides — but they differed in how they were decorated with amines and acetyl groups.

By screening these 32 structures with antibody studies, they made their discovery.

“The fine pattern matters quite a bit,” Huang said. “And the impact is drastic.”

An MSU mutant

The team identified two PNAG combinations that were especially promising. Going a step further, the researchers attached them to a groundbreaking vaccine delivery platform.

The platform is based on a bacteriophage, which is a virus that infects bacteria, called Qbeta, also written as Qβ (pronounced “cue beta”). Huang’s team modified the bacteriophage, giving it the power to deliver antigens for carbohydrate-based pathogens.

PNAG and other carbohydrates typically don’t provoke strong immune responses in our bodies, but the mutant Qbeta, or mQβ, helps create an enhanced reaction.

This breakthrough delivery platform — which also has vaccine applications for cancer and even opioid addiction — earned Huang MSU’s 2024 Technology Transfer Achievement Award.

When coupled with mQβ, Huang and his collaborators found that the two most promising PNAG pentasaccharides offered high levels of protection in mice against staph and MRSA.

In animal studies, the team’s new vaccine construct outperformed another PNAG-vaccine delivery system that is currently in human trials.

The team also found their formulation had minimal impact on the biochemistry of the gut microbiome in tests.

As the team prepares for future tests of their new vaccine candidate, Huang is looking forward to the role bacterial vaccines will play in the larger fight against antibiotic resistance.

“Vaccines reduce the overall infection rate, which means there’s less of a need for antibiotics,” Huang said. “This reduces the chance for bacteria to develop resistance, breaking the cycle.

“The two go hand in hand.”

JOURNAL

Nature Communications

DOI

10.1038/s41467-024-47457-4

METHOD OF RESEARCH

Experimental study

SUBJECT OF RESEARCH

Animals

ARTICLE TITLE

A comprehensive synthetic library of poly-N-acetyl glucosamines enabled vaccine against lethal challenges of Staphylococcus aureus

ARTICLE PUBLICATION DATE

24-Apr-2024

UZH acquires important Richard Wagner manuscript

UNIVERSITY OF ZURICH

Manuscript "A message to my friends" by Richard Wagner — IMAGE:
IMAGE OF TWO PAGES OF THE WORKING MANUSCRIPT "A MESSAGE TO MY FRIENDS" BY RICHARD WAGNER.
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CREDIT: (IMAGE: ZENTRALBIBLIOTHEK ZÜRICH)

The University of Zurich has made a spectacular acquisition of an important manuscript by Richard Wagner (1812 to 1883). In Eine Mitteilung an meine Freunde (“A Message to My Friends”), the composer takes autobiographical and artistic stock and looks to the future. The manuscript, which was written in Zurich, will now undergo further scholarly analysis at UZH.

Zurich was an important stage in Richard Wagner’s life and work. After taking part in the failed May Uprising in Dresden (1849) against the Saxon King Friedrich August II, Wagner lived in exile in Zurich from 1849 to 1858. The time in Zurich marked a turning point and reorientation in his life and work. Here he not only worked on his famous tetralogy The Ring of the Nibelung, but also wrote groundbreaking works of music and drama theory.

Returning to Zurich after 170 years

Some 170 years later, the original working manuscript of one of these writings, entitled Eine Mitteilung an meine Freunde (“A Message to My Friends”), has now returned to the place where it was created. UZH acquired the manuscript at an auction at Sotheby’s. The acquisition was possible thanks to donations from UBS Culture Foundation (Zurich), the Bareva Foundation (Vaduz) and the UZH Foundation, the foundation of the University of Zurich.

“The purchase of the Wagner manuscript is of great importance for Zurich, UZH and scholarly work,” says UZH President Michael Schaepman. Musicologist Laurenz Lütteken, co-director of the University of Zurich’s Department of Musicology, is also excited about the successful acquisition: “Wagner manuscripts of such high caliber are otherwise scarcely available on the free market.” The work of Richard Wagner is one of the focal points of the Department of Musicology’s research.

Taking autobiographical and artistic stock

Eine Mitteilung an meine Freunde was written in August 1851 in the “Zum Abendstern” building in Zurich’s Enge district (roughly the location of today’s Lavaterstrasse 76), shortly before Wagner’s move to the Vordere Escherhäuser premises (Zeltweg 11). The text was published in the same year as the supplement and foreword to the libretti of the operas The Flying Dutchman, Tannhäuser and Lohengrin.

The message is a kind of autobiographical stocktaking, with reference to the works before the revolution and the great post-revolutionary Ring project. “Wagner provides an interpretation of his work to date and a succinct summary of what ‘musikdrama’ should achieve in the future,” explains Laurenz Lütteken. At the very end, there is also a sketch of the tetralogy in progress, as well as a plan for a performance “in the course of a specifically designated three-day festival plus a preceding evening.” It is therefore also the first sketch of the festival idea that Wagner later brought to fruition with the Ring of the Nibelung.

UZH investigates writing of text

The extensive autograph of this important Wagner work, which will now be kept at Zentralbibliothek Zürich, is not simply returning to its place of origin. It will continue to occupy researchers at UZH. Until now, the text has only been available in the first printing and the version published in Richard Wagner’s collected writings and poems. The handwritten version, on the other hand, reveals intensive effort. The manuscript is written in dark brown ink and contains extensive deletions, corrections, revisions and additions. The musicologists at UZH have now embarked on an extensive research project to analyze and trace the genesis of the text. This analysis will provide new findings and insights into the work, thinking and influence of Richard Wagner in Zurich.

Once the research at UZH has been completed, the manuscript will be made available by the Zentralbibliothek Zurich (ZB) library. The working manuscript of Eine Mitteilung an meine Freunde is another gem in the important collection of Wagneriana at the ZB, which includes music and text manuscripts, music prints, printed matter and letters.

Narcissistic CEOs appoint other narcissists to the management board

Professor from TU Dortmund University has analyzed more than 11,000 LinkedIn profiles

TU DORTMUND UNIVERSITY

Narcissism manifests itself in different forms in leadership situations – from self-confidence and charisma to destructive self-focus and lack of consideration for others. While this character trait in individual CEOs is already the subject of research, very little is known so far about its impact on the wider composition of senior management.

This was the starting point for the study conducted by Professor Graf-Vlachy’s team, which analyzed LinkedIn profiles of top managers. “Narcissists want to show a broader audience that they are superior. Earlier studies have found that this is also reflected in corporate press releases or letters to shareholders, among other things,” says Professor Graf-Vlachy. Elements that are indicative of narcissism include, for example, the size of an executive’s picture in the annual report or the frequency with which a manager’s name appears in a company’s press releases.

In their study, the authors used the same approach to analyze individuals’ digital presence on social media. “We have demonstrated that we can reliably measure the narcissism of managers on the basis of their LinkedIn profiles by analyzing the number of pictures of the manager, the length of the text in the ‘About’ section, and the skills, certificates, and career steps listed,” says Professor Graf-Vlachy.

Increased fluctuation can be expensive for companies

In total, the team analyzed 11,705 LinkedIn profiles of top managers of US companies. The study reveals an astonishing tendency: CEOs with a higher degree of narcissism appoint members to their management board who mirror their own character traits – in other words, who also display a narcissistic streak. An increase in the narcissism of a CEO by one standard deviation leads to an 18 percent higher level of narcissism in each newly appointed executive.

This also has an impact on the dynamics and stability of the team, as management boards with more narcissistic managers have a significantly higher turnover rate, which can mean sizeable costs for a company. “Narcissists want to dominate each other, which leads to conflicts on the board, and these in turn lead to more fluctuation in the executive team,” summarizes Professor Graf-Vlachy.

“The results of the study show that it is important for CEOs and supervisory boards to understand the dynamics in their executive teams better and to review the selection process for managers,” the researchers conclude. “This can be achieved if the personality traits of managers are also viewed in a balanced way.”