Creative Minds: Interrogating a Master of Disguise

Monica Mugnier

Monica Mugnier

When I volunteered several years ago as a physician in a small hospital in West Africa, one of the most frustrating and frightening diseases I saw was sleeping sickness. Now, an investigator supported by the NIH Common Fund aims to figure out how this disease pathogen manages to evade the human immune system.

Monica Mugnier’s fascination with parasites started in college when she picked up the book Parasite Rex, a riveting, firsthand account of how “sneaky” parasites can be. The next year, while studying abroad in England, Mugnier met a researcher who had studied one of the most devious of parasites—a protozoan, spread by blood-sucking tsetse flies, that causes sleeping sickness in humans and livestock across sub-Saharan Africa.

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Find and Replace: DNA Editing Tool Shows Gene Therapy Promise

Neutrophil being edited with CRISPR/Cas9

Caption: This image represents an infection-fighting cell called a neutrophil. In this artist’s rendering,  the cell’s DNA is being “edited” to help restore its ability to fight bacterial invaders.
Credit: NIAID, NIH

For gene therapy research, the perennial challenge has been devising a reliable way to insert safely a working copy of a gene into relevant cells that can take over for a faulty one. But with the recent discovery of powerful gene editing tools, the landscape of opportunity is starting to change. Instead of threading the needle through the cell membrane with a bulky gene, researchers are starting to design ways to apply these tools in the nucleus—to edit out the disease-causing error in a gene and allow it to work correctly.

While the research is just getting under way, progress is already being made for a rare inherited immunodeficiency called chronic granulomatous disease (CGD). As published recently in Science Translational Medicine, a team of NIH researchers has shown with the help of the latest CRISPR/Cas9 gene-editing tools, they can correct a mutation in human blood-forming adult stem cells that triggers a common form of CGD. What’s more, they can do it without introducing any new and potentially disease-causing errors to the surrounding DNA sequence [1].

When those edited human cells were transplanted into mice, the cells correctly took up residence in the bone marrow and began producing fully functional white blood cells. The corrected cells persisted in the animal’s bone marrow and bloodstream for up to five months, providing proof of principle that this lifelong genetic condition and others like it could one day be cured without the risks and limitations of our current treatments.

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Simplifying HIV Treatment: A Surprising New Lead

CD4+ cells in the gut

Caption: PET/CT imaging reveals a surprisingly high concentration (yellow, light green) of key immune cells called CD4 T cells in the colon (left) of an SIV-infected animal that received antibody infusions along with antiviral treatment. Fewer immune cells were found in the small intestine (right), while the liver (lower left) shows a high level of non-specific signal (orange).
Credit: Byrareddy et al., Science (2016).

The surprising results of an animal study are raising hopes for a far simpler treatment regimen for people infected with the AIDS-causing human immunodeficiency virus (HIV). Currently, HIV-infected individuals can live a near normal life span if, every day, they take a complex combination of drugs called antiretroviral therapy (ART). The bad news is if they stop ART, the small amounts of HIV that still lurk in their bodies can bounce back and infect key immune cells, called CD4 T cells, resulting in life-threatening suppression of their immune systems.

Now, a study of rhesus macaques infected with a close relative of HIV, the simian immunodeficiency virus (SIV), suggests there might be a new therapeutic option that works by a mechanism that has researchers both excited and baffled [1]. By teaming ART with a designer antibody used to treat people with severe bowel disease, NIH-funded researchers report that they have been able to keep SIV in check in macaques for at least two years after ART is stopped. More research is needed to figure out exactly how the new strategy works, and whether it would also work for humans infected with HIV. However, the findings suggest there may be a way to achieve lasting remission from HIV without the risks, costs, and inconvenience associated with a daily regimen of drugs.

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Imaging Advance Offers New View on Allergic Asthma

Healthy vs. Allergic Asthma Airways

Caption: OR-OCT images of the airways of a healthy person (left) and a person with allergic asthma (right). The colorized portion highlights airway smooth muscle, with thinner areas in purple and black and thicker areas in yellow and orange. Credit: Cho et al., Science Translational Medicine (2016)

You probably know people who sneeze a little when they encounter plant pollens, pet dander, or other everyday allergens. For others, however, these same allergens can trigger a serious asthma attack that can make breathing a life-or-death struggle. Now, two NIH-funded research groups have teamed up to help explain the differences in severity underlying the two types of reactions.

In the studies, researchers at Massachusetts General Hospital, Boston, used an innovative imaging tool to zoom in on a person’s airways safely in real time to gain an unprecedented view of how his or her body reacts to allergens [1,2]. The imaging revealed key differences between the asthma and non-asthma groups in the smooth muscle tissue that surrounds critical airways, and is responsible for constriction. In a complementary series of experiments, researchers also uncovered heightened immune responses in the airways of folks with allergic asthma. The findings offer important new clues in the quest to better understand and guide treatment for asthma, a condition that affects more than 300 million people around the world.

The factors driving airway constriction in people with asthma have been poorly understood in part because, until now, there hasn’t been a way to view airway smooth muscle in action. As described in the journal Science Translational Medicine, Melissa Suter and colleagues adapted an established form of imaging called optical coherence tomography (OCT) to help fill this gap. Standard OCT produces an image by measuring the amount of light reflected back from body tissues, but such images aren’t sufficient to distinguish airway smooth muscle from other tissues.

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Mouse Study Finds Microbe Might Protect against Food Poisoning

T mu in a mouse colon

Caption: Scanning electron microscopy image of T. mu in the mouse colon.
Credit: Aleksey Chudnovskiy and Miriam Merad, Icahn School of Medicine at Mount Sinai

Recently, we humans have started to pay a lot more attention to the legions of bacteria that live on and in our bodies because of research that’s shown us the many important roles they play in everything from how we efficiently metabolize food to how well we fend off disease. And, as it turns out, bacteria may not be the only interior bugs with the power to influence our biology positively—a new study suggests that an entirely different kingdom of primarily single-celled microbes, called protists, may be in on the act.

In a study published in the journal Cell, an NIH-funded research team reports that it has identified a new protozoan, called Tritrichomonas musculis (T. mu), living inside the gut of laboratory mice. That sounds bad—but actually this little wriggler was potentially providing a positive benefit to the mice. Not only did T. mu appear to boost the animals’ immune systems, it spared them from the severe intestinal infection that typically occurs after eating food contaminated with toxic Salmonella bacteria. While it’s not yet clear if protists exist that can produce similar beneficial effects in humans, there is evidence that a close relative of T. mu frequently resides in the intestines of people around the world.

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