Infectious Diseases Archives - Sanford Burnham Prebys
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A strange research ecosystem: Discussing Lyme disease with Victoria Blaho

AuthorMiles Martin
Date

December 22, 2021

As an infectious disease immunologist studying Lyme disease, Victoria Blaho is one of a rare breed.

Sanford Burnham Prebys assistant professor Victoria Blaho, PhD, investigates the biochemical signals of the immune system and how they impact our bodies’ abilities to fight pathogenic infections, a branch of immunology that has become much less popular since the advent of antibiotics in the early 20th century.

Blaho’s disease of choice is Lyme disease, an unusual tick-borne bacterial infection that affects some 476,000 people in America each year, a number that is on the rise.

We caught up with Blaho to talk about why Lyme disease research is important, the progress being made and the work that remains in studying this strange and burdensome disease.

Why is Lyme disease research important?
Blaho: Lyme research is a very small field for a disease that is becoming bigger and bigger every year. Case counts are increasing for Lyme disease all over the world, and people get very sick from it. Some people are infected, take antibiotics and that’s the end of it. But others have chronic symptoms like arthritis or carditis that can last for years and become completely debilitating.

What makes Lyme difficult to study?
Blaho: One reason is that Lyme is an unusual infection from a microbiological standpoint. In the early days of Lyme research, there were studies showing that the bacteria that caused the disease, Borrelia burgdorferi, could change its physical form from a corkscrew shape to dormant blobs—and the blobs could be causing extended disease. This is a problem because scientists haven’t agreed on the true cause of chronic Lyme disease.

To make matters worse, a lot of the medical field still believes Lyme is easily curable with antibiotics, and if people are still having problems, then it’s psychosomatic. This makes it harder to get support for research into the longer-term inflammatory effects of Lyme. These politics make Lyme disease research a strange ecosystem of patients, physicians, researchers and funding agencies, and this is a barrier to learning more about the disease and helping people find relief.

How does your work enter the picture?
Blaho: I’ve been working on Lyme disease for over 15 years, since I was PhD student. It started because Celebrex was hugely popular at the time to treat arthritis, but nobody had ever studied it in the arthritis that emerges in Lyme disease. Celebrex inhibits an enzyme of the immune system that triggers inflammation, so we figured that Celebrex might work just as well in Lyme arthritis as in other types. But research on mice didn’t bear this out.
Inflammation doesn’t just peter out when an infections clears. The immune system has to clean up the mess. We discovered in mice that Celebrex inhibits the resolution of inflammation after Lyme disease has resolved, so the arthritis never went away.

Since then, my career has focused on exploring the signaling molecules that regulate inflammation and its resolution. These molecules affect all parts of the immune system and provide us with a whole host of different potential therapeutic targets for inflammatory diseases like chronic Lyme.

What are the next steps for your Lyme research and for the field at large? 
Blaho: My own immediate next step is to take the work I’ve been doing here at Sanford Burnham Prebys and connect it directly back to my original work with Lyme. My team here is currently working on a signaling molecule called S1P, and while we haven’t studied it in Lyme yet, we think there are connections between it and the immune mediators we first found through those Lyme studies.

Our next steps are to look for the protein that carries S1P in mice with Lyme disease. This protein is associated with disease susceptibility in other inflammatory illnesses like diabetes and cardiovascular disease, and we think it has a role to play in Lyme as well. We’re also planning to partner with the Bay Area Lyme Foundation to see if we can find changes in this protein in their collection of human samples.

More broadly, I think this field is hungry for innovation because there have been a small number of scientists focusing on it. If older ideas about Lyme being simple to treat were the complete picture, we’d already be able to better diagnose and treat patients. But we’re just not there yet.

Lyme may be a lot cleverer than we originally thought, but if we’re able to embrace new technologies and ideas and continue to push forward with new work, we’ll be able to find innovative approaches to fight Lyme and, ultimately, to help people suffering from this horrible disease.

Institute News

Ebola expert weighs in on news of a potential cure

AuthorMonica May
Date

August 13, 2019

Scientists recently reported that two treatments saved the lives of people infected with the Ebola virus—with the New York Times reporting that roughly 90% of newly infected patients were saved—suggesting we are ever so close to a cure. 

To place this news in context, we caught up with Ebola expert Sumit Chanda, PhD, whose team at Sanford Burnham Prebys is working to find a pill-based treatment for the deadly virus.

Tell us a bit more about Ebola and the recent outbreaks. 
Ebola is a virus responsible for severe, often fatal, hemorrhagic fevers in humans—meaning it damages blood vessels and can cause internal bleeding, among other symptoms. The mortality rate varies between 50% and 90%. The 2014 to 2016 West Africa epidemic has been of unprecedented scope, with more than 28,000 reported cases and more than 11,000 deaths. Exported cases were also documented in the U.S. and Europe. Since August 2018, a new outbreak is ongoing in the Democratic Republic of the Congo, with more than 2,800 total cases reported and more than 1,800 deaths. So far, no medication can treat people already sickened by Ebola (an experimental vaccine has shown effectiveness).

Describe the study and key findings for us. 
Last November, several potential treatments were evaluated in clinical trials in the outbreak area. Two of these treatments, mAb114 (Ridgeback Biotherapeutics) and REGN-EB3 (Regeneron Pharmaceuticals), were found to be highly effective in reducing Ebola-related deaths. These drugs are monoclonal antibodies, which are protein-based therapies—the same kind that are currently being used to treat cancers, autoimmune and other diseases. 

What is your reaction? Is this big news? Or is more research needed?
This is a very important result. For the first time, a clinical therapy significantly reduced mortality after Ebola exposure—especially when given early after infection. While it cannot be called a “cure,” since not everyone taking the therapy survived, it represents a hugely important advance by the scientific community and brings hope to people exposed to this virus and in the outbreak regions. 

What does this advance mean for people infected with the Ebola virus?
People impacted by Ebola have so far been skeptical about medical treatment, especially considering the low success rate of previous treatments. We expect that the high survival rate associated with these two treatments will encourage infected individuals to go to Ebola treatment centers. This will increase the number of people receiving the treatments, reducing the total amount of deaths and helping contain the spread of the virus.

What does this news mean for the quest to find an Ebola treatment?
This remarkable achievement gives me hope that a cure is possible, potentially by combining these therapies with additional drugs. There is more work to be done, however. These antibody-based treatments require administration by a medical professional in a specialized Ebola treatment center and can be expensive. An Ebola therapy that comes in the form of a low-cost pill—the focus of my lab’s work—will be easier to deploy to patients, especially in areas that do not have access to advanced facilities. Since it appears that early treatment is important, easy availability to a medicine will benefit rural patients who are usually at the epicenter of an outbreak—and will help prevent an epidemic from taking root in the first place. 

Anything else you’d like to add? 
We are now, more than ever, hugely optimistic that efforts to develop an Ebola antiviral drug, especially one that is low cost and can be easily distributed in affected regions, will be part of a complete cure regimen for Ebola.

 

Sumit Chanda, PhD, is the professor and director of the Immunity and Pathogenesis Program at Sanford Burnham Prebys. His team works to find new treatments for infectious diseases, including influenza A (flu), human immunodeficiency virus (HIV) and Ebola virus, by unraveling the cellular machinery that allows these viruses to thrive.

Institute News

The search for new anthrax treatments isn’t over

AuthorJessica Moore
Date

October 5, 2016

A bioterror attack using virulent anthrax would be nearly as deadly today as it was in 2001, when anthrax spores sent through the mail killed five people. Even with aggressive treatment, only about half of those who breathe anthrax spores survive because the bacterium rapidly produces huge amounts of deadly toxins.

To inform future therapies, the lab of Robert Liddington, PhD, professor in the Bioinformatics and Structural Biology Program, examined how toxins enter cells. Their new study, published in the Journal of General Physiology, shows that the bacterial toxin is remarkably efficient at getting across cell membranes.

“When we pushed the system to its limit, we found that the pore formed by the toxin is incredibly robust,” said Liddington. “It acts like a ‘conveyer belt,’ continuously feeding toxic enzymes across the membrane.”

During anthrax infections, the bacterium Bacillus anthracis secretes a three-unit toxin: two enzymes named lethal factor (LF) and edema factor (EF) and a third protein called protective antigen (PA). After they’re engulfed by cells, they’re contained within membrane-bound acid baths (vesicles) that they have to escape to avoid being broken down. To do that, the PA proteins link together to form a pore across the membrane, allowing LF and EF to be transported into the interior of the cell. There, they wreck signals that would alert other cells to the presence of the bacteria, eventually causing the cell to die.

Liddington’s lab teamed with Isabelle Rouiller, PhD, and her group at McGill University, using a cutting-edge high-resolution imaging technique called cryo-electron microscopy to build a three-dimensional map of the “pre-pore” complex. The map showed seven PA proteins surrounding a narrow pore, with three LF molecules perched at the rim, ready to be moved across. As well as binding to the PA subunits, each LF molecule also bound to its neighbor.

The team hopes that these new findings will aid the development of better treatments for anthrax infection. “By identifying new interactions between different parts of the toxin, our findings suggest new ways to thwart toxin entry,” explained Liddington. “That might allow us to design new antitoxins that work better than or in combination with the two that have been approved by the FDA.”

This post is based in part on a press release from the Journal of General Physiology.

The paper is available online here.