Posts Tagged ‘Jennifer Brown’

BY: JENNIFER BROWN

More than 200,000 U.S. soldiers serving in the Middle East have experienced a blast-related traumatic brain injury, making it a common health problem and concern for that population.

Traumatic brain injury (TBI) can have various harmful long-term neurological effects, including problems with vision, coordination, memory, mood, and thinking. According to the Centers for Disease Control and Prevention, TBI from a head injury is a leading cause of death and disability in the United States, and close to 5 million Americans—soldiers and non-soldiers alike—are currently living with a TBI-related disability. Current therapy for these patients involves supportive care and rehabilitation, but no treatments are available that can prevent the development of chronic neurological symptoms.

Researchers from the University of Iowa believe they may have identified a potential approach for preventing the development of neurological problems associated with TBI. Their research in mice suggests that protecting axons—the fiber-like projections that connect brain cells—prevents the long-term neuropsychiatric problems caused by blast-related traumatic brain injury.

In a recent study, the UI team led by Andrew Pieper, professor of psychiatry at the UI Carver College of Medicine, investigated whether early damage to axons—an event that is strongly associated with many forms of brain injury, including blast-related TBI—is simply a consequence of the injury or whether it is a driving cause of the subsequent neurological and psychiatric symptoms.

To answer that question, the researchers used mice with a genetic mutation that protects axons from some forms of damage. The mutation works by maintaining normal levels of an important energy metabolite known as nicotinamide adenine dinucleotide (NAD) in brain cells after injury.

When mice with the mutation experienced blast-mediated TBI, their axons were protected from damage, and they did not develop the vision problems, or the thinking and movement difficulties that were seen when mice without the mutation experienced blast-related TBI. The findings were published Oct. 11 in the online journal eNeuro.

“Our work strongly suggests that early axonal injury appears to be a critical driver of neurobehavioral complications after blast-TBI,” says Pieper, who also is a professor of neurology, radiation oncology, and a physician with the Iowa City Veterans Affairs Health Care System.

“Therefore, future therapeutic strategies targeted specifically at protecting or augmenting the health of axons may provide a uniquely beneficial approach for preventing these patients from developing neurologic symptoms after blast exposure.”

In confirming the critical relationship between axon degeneration and development of subsequent neurological complication, the new study builds on previous work from Pieper’s lab. The researchers also have discovered a series of neuroprotective compounds that appear to help axons survive the kind of early damage seen in TBI. These compounds activate a molecular pathway that preserves neuronal levels of NAD, the energy metabolite that has been shown to be critical to the health of axons. Pieper’s team previously demonstrated that these neuroprotective compounds block axonal degeneration and protect mice from harmful neurological effects of blast-TBI, even when the compound are given 24 to 36 hours after the blast injury.

In addition to Pieper, the research team included Terry Yin, Jaymie Voorhees, Rachel Genova, Kevin Davis, Ashley Madison, Jeremiah Britt, Coral Cinton, Latisha McDaniel, and Matthew Harper. Pieper also is a member of the Pappajohn Biomedical Institute at the UI.

https://now.uiowa.edu/2016/10/study-traumatic-brain-injury

by Jennifer Brown

The recent Ebola outbreak in West Africa has claimed more than 11,300 lives—a stark reminder of the lack of effective options for treating or preventing the disease.

Progress has been made on developing vaccines, but there is still a need for antiviral therapies to protect health care workers and local populations in the event of future outbreaks.

Now, a new study suggests that gamma interferon, an FDA-approved drug, may have potential as an antiviral therapy to prevent Ebola infection when given either before or after exposure to the virus.

The findings, published in the journal PLOS Pathogens, show that gamma interferon, given up to 24 hours after exposure, inhibits Ebola infection in mice and completely protects the animals from death.

Ebola infection appears to be a stepwise process. First, the virus targets and infects macrophages or dendritic cells, two types of immune system cells found in the liver, spleen, and lymph nodes. Ebola then replicates in those cells. Following this initial infection, which happens at day 3 or 4 in non-human primates, Ebola virus is released into the blood and infects a plethora of other different cell populations.

“It goes from an early stage with a very targeted infection of only these few cell types, to everything being infected,” says Wendy Maury, professor of microbiology at the University of Iowa.

“We think what’s happening with gamma interferon is that it’s targeting macrophages and blocking the infection of those initial cell targets so you don’t get the second round of infection.”

The University of Iowa does not have a specializing BioSafety Level 4 (BSL4) lab that is required for experiment using Ebola virus, so the researchers made their initial findings using a surrogate virus, which targets and infects the same cells as Ebola, but does not cause the disease.

This Ebola lookalike—a sheep in wolf’s clothing—consists of a less dangerous vesicular stomatitis virus (VSV) that expresses Ebola glycoproteins on its surface.

All of the results found using the surrogate virus were then repeated using mouse-adapted Ebola virus in the BSL4 lab of Maury’s longtime collaborator Robert Davey at Texas Biomedical Institute in San Antonio, Texas.

Gamma interferon inhibits the virus’s ability to infect human and mouse macrophages, in part by blocking virus replication in the cells. Pre-treating mice with interferon gamma 24 hours before exposure protects the animals from infection and death. The researchers were surprised to find that treatment up to 24 hours after what would have been a lethal exposure also completely protected the animals from death, and they could no longer detect any Ebola virus in the mouse’s cells.

The findings suggest that interferon gamma may be useful both as a prophylaxis and post-exposure treatment against Ebola. The team still has to determine how late gamma interferon can be given to the mice and still prevent infection. However, the results suggest a window of time after exposure when gamma interferon may be an effective antiviral therapy.

“My guess is that if you delay the gamma interferon too much, you miss this window of opportunity to block the infection in macrophage cells and the gamma interferon can no longer provide protection,” Maury says.

Maury and colleagues investigated how gamma interferon might be helping the cells fight off the Ebola virus. They identified that the expression of more than 160 genes in human macrophages is stimulated by gamma interferon. Introduction of some of these genes into cells was sufficient to prevent Ebola infection.

“This mechanistic information might suggest more precise drug targets rather than the broad effects, including adverse side-effects, that are produced by gamma-interferon,” she says.

Gamma interferon is already approved by the FDA to treat chronic granulomatous disease (an immune disease) and severe malignant osteopetrosis.

In addition to moving the studies into larger animal models, Maury next plans to study the ability of gamma interferon to inhibit Ebola infection in conjunction with other developing antivirals.

“Right now, there are no FDA-approved antiviral therapies for Ebola, but there are some being developed that target virus entry,” she says. “We know that gamma interferon blocks replication but not entry into cells. So combining an entry inhibitor with gamma interferon may allow us to reduce amount of gamma interferon needed and target two different steps in the virus’s life cycle, which has been shown in HIV to be critically important for controlling the virus.”

http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1005263

http://now.uiowa.edu/2015/12/fda-approved-drug-protects-mice-ebola