Department of Microbial Pathogenesis posts displayed by tag

Researcher of the Year Ernst Recounts Quest To Thwart Sepsis

Davidge Hall has been witness to some enlightening presentations over its 205 years, but chances are few foes discussed there have been more formidable than sepsis, which Robert K. “Bob” Ernst, PhD, addressed in his Founders Week Researcher of the Year presentation on Oct. 17.

A death from sepsis occurs every two minutes in the United States. Hospitals spend $23 billion on it annually, making it the most expensive condition treated in U.S. hospitals.

Ernst, professor and vice chair of the Department of Microbial Pathogenesis at the University of Maryland School of Dentistry (UMSOD), and his colleagues are engineering rationally designed mimetics based on bacterial surface molecules that will inhibit the ability of the body to mount the damaging immune response present in sepsis.

In particular, he is at the forefront of innovative research studying the molecular basis by which bacteria modify the lipid component of their membrane, specifically lipopolysaccharide (LPS), and how these alterations affect normal host innate immune system responses, potentially resulting in septic shock.

Before his presentation Ernst was saluted by University of Maryland, Baltimore President Jay A. Perman, MD, and School of Dentistry Dean Mark A. Reynolds, DDS, PhD, MA. “We recognized Dr. Ernst at the Gala Saturday night, but now he needs to work for it,” said Perman, eliciting laughter from the 100-plus Ernst colleagues, students, faculty, and staff on hand. Perman praised Ernst not only for his “groundbreaking body of work” but also as “a generous collaborator, entrepreneur, and very dedicated mentor.”

When Perman spoke of the scientist inspiring the “next generation of Bob Ernsts” an “oh, no” from the crowd brought another round of laughter, with the jovial Ernst leading the way.

Indeed, Reynolds said Ernst’s “enthusiasm for science and mentoring is contagious,” which he showed in his 45-minute presentation “Structure Matters — Making Bacterial Molecules Work for Us.”

Without notes, the award winner chronicled the journey his research has taken. He thanked a long list of collaborators and funders, saying “you can’t just rely on NIH,” which has supported Ernst and his team with $3 million in the last decade. UMB’s seed grant program and MedImmune also have provided strong support.

He discussed E coli, pattern recognition receptors, and the “bar code” in bacterial molecules. “Pathogens are detected by pattern recognition receptors on host cells that recognize structures that are broadly shared by pathogens,” Ernst said. “These bacterial patterns represent a signature or ‘bar code’ that informs the host on the level of danger of the invading organism and how to respond.”

Ernst came to UMB in the fall of 2008, moving his laboratory from the University of Washington in Seattle. David R. Goodlett, PhD, who worked closely with Ernst in Seattle studying the structure function relationships of lipid A, also came to UMB and is now a professor of pharmaceutical sciences in the University of Maryland School of Pharmacy.

In 2016, Ernst and Goodlett co-founded a startup diagnostic company called Pataigin. Last fall, the company received a $25,000 Maryland Department of Commerce Life Award for its patented test called “BACLIB” that inexpensively identifies bacteria- and fungi-causing infections in less than an hour, allowing clinicians to make decisions in the hospital at the “point-of-care.”

“Thank you to Jim Hughes and the UMB tech transfer office for all their help,” Ernst said.

When he turned to sepsis, Ernst’s tone turned more serious. “Each hour delay in antibiotic treatment the mortality rate goes up 7 percent,” he said.

Ernst admits he’s willing to talk to anyone in his quest for research advances. That approach has taken him to Maastricht in the Netherlands to utilize multimodal imaging, tracking where the blood flow is in sepsis. “They’re among the best in the world, with an image every 20 minutes instead of every three to six hours.”

Ernst was the picture of a passionate scientist, enthused and lifted when he discussed advances with E coli and the LPS, bemoaning the setbacks, praising “unheard of” assistance from the Food and Drug Administration, and recognizing his colleagues in the professional schools at UMB.

“Absolutely, this is the most collegial university that I’ve been associated with. The Department of Microbiology and Immunology in the School of Medicine and our department work together hand in glove. We are now branching out to do work with cancer researchers at UMB, MedImmune, and the National Cancer Institute, as they are also looking for novel mechanisms to attack cancer cells in the body.”

Ernst concluded his presentation with thanks to his many colleagues and a final PowerPoint slide:
Yes, structure does matter

Modulation of the host innate and adaptive immune systems
– Adjuvant development

Just the tip of the iceberg
– We are expanding our library rapidly
– We’ve neglected the carbohydrate portion – core and O-antigen

The potential for a novel antisepsis therapeutic is promising
– Inhibiting at the earliest intervention point

Asked earlier if a cure for sepsis in his lifetime is a realistic possibility, Ernst responded, “Cure, no, there will always be infections. But being able to modify the host response to give physicians a better chance to treat the symptoms associated with sepsis, potentially.”

— Chris Zang

  
Chris Zang Clinical Care, Education, People, Research, UMB NewsOctober 26, 20170 comments
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Feng

Research Professor Wins Entrepreneurial Award

In 2007, Hanping Feng, PhD, then a research assistant professor at Tufts University Cummings School of Veterinary Medicine, decided to transition from basic research to translational research. “I wanted to do something that had a direct impact on human health,” he says.

A decade later, he hasn’t changed his mind. Now a professor in the Department of Microbial Pathogenesis at the University of Maryland School of Dentistry (UMSOD), he is a co-founder of Fzata, Inc., an antibody technology startup company, which in June was named “Best Life Sciences Company” at the Maryland Incubator Company of the Year awards ceremony. Now in its 16th year, the honor is presented annually by a committee of regional leaders and early-stage investors in recognition of promising fledgling technology companies in Maryland.

Feng’s research is focused on the development of novel diagnostics, vaccines, and antibody-based immunotherapies for Clostridium difficile infection (CDI). More than 29,000 deaths in the United States are caused annually by antibiotic-resistant C. difficile; globally the infection is considered an urgent public health threat.

“It’s a huge problem particularly in westernized countries,” says Feng. “It develops frequently in hospitals where antibiotics are administered. Patients expose spores and then develop an infection. The problem is that currently there’s no prevention nor good treatment strategy.”

Feng’s team has developed a highly innovative and multi-specific antitoxin antibody that has been shown to be effective in neutralizing both clostridial toxins and blocking the disease. Based on this research, Feng and FZata team is developing two candidate drug products: an intravenous, fully humanized, tetra-specific, antibody product (FZ001) designed to treat ongoing infection and to prevent recurrence, and an oral, probiotic, yeast product (FZ002) that secretes the antitoxin at the site of infection.

Both drug candidates have been evaluated in animal models of human infection and reveal superior efficacy against the infection than competitors.

In 2015, Feng and co-founder Zhiyong Yang, PhD, a former research scientist, formed FZata to fast track drug candidates by creating a viable pathway toward clinical trials, and ultimately commercial production. “There’s a big gap between University bench work and clinical study for biologics,” Feng says. “The process is expensive and the large pharmaceutical companies don’t want to invest at an early stage because it’s risky.”

The early success of Fzata gives Feng hope that his model can be successful. “We’ve been able to get support because it’s innovative, and it’s centered on a major public health issue.”

Since 2011, when he came to UMSOD from Tufts University, Feng’s research has been supported by 14 grants or contracts totaling $15 million. Most recently, FZata received a $5.6 million National Institutes of Health grant to enable development of lead therapeutics against CDI.

  
Scott Hesel Bulletin Board, Contests, People, Research, TechnologyJuly 24, 20170 comments
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Krantz and Das

Dentistry-led Anthrax Study in Prestiguous Journal

The University of Maryland School of Dentistry’s research team achieved an unprecedented breakthrough with the acceptance of a recent manuscript into the publication Proceedings of the National Academy of Sciences of the United States of America (PNAS). ‌

This manuscript, “Peptide and Proton Driven Allosteric Clamps Catalyze Anthrax Toxin Translocation across Membranes,” is the first such paper to be accepted into this prestigious journal in the history of UMSOD. The paper was co-authored by Bryan Krantz, PhD, associate professor, and Debasis Das, PhD, a postdoctorate fellow, both in the Department of Microbial Pathogenesis (pictured).

The primary focus of the research centered on the components of the anthrax toxin protein. The anthrax toxin contains three components. One component forms a channel – or pore – in the cell membrane. The other component goes through that pore into the cell. Once that second component (referred to as the ‘substrate’) makes it into the cell, it carries out reactions that disrupts the cell’s functions.

Working from a foundation provided by researchers at the University of California, Berkeley, Das and Krantz discovered evidence that this translocation mechanism is under allosteric control. Allosteric regulation is a process wherein proteins transmit the effect of binding at one site to another, often at a location other than the enzyme’s active site. In the case of the Anthrax toxin, when the pore part of the protein binds, the substrate part that is disrupting the cell binds tighter as well, despite being at a different location.

“This tells us how the anthrax pore functions,” said Krantz, “there are huge implications because this is an entirely new way of thinking about the translocation mechanism.”

Previously, there had been no documented evidence showing that the mechanism of translation carried out by the pore protein was under allosteric control. The importance of this discovery is a major reason why the manuscript was accepted into PNAS, according to Krantz.

“This is a landmark discovery that may find its way into textbooks,” said Patrik Bavoil, PhD, professor and chair in the Department of Microbial Pathogenesis, “this is a model for how all proteins, not just the anthrax toxin, translocate across membranes.”

This accomplishment caps off a successful two months for UMSOD research efforts. On May 29, Vineet Dhar, PhD, in the Department of Pediatrics won the Paul P. Taylor award from the American Academy of Pediatric Dentistry (AAPD) for his paper evaluating the evidence of effectiveness of interventions for Early Childhood Carries (ECC).

For Krantz and Das, the next steps will include additional research into their discovery through grants awarded by the National Institutes of Health.

  
Scott Hesel ResearchJuly 22, 20160 comments
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