Creative Minds: Complex Solutions to Inflammation

Hao Wu

Hao Wu

For nearly 20 years, Hao Wu has studied innate immunity, our body’s first line of defense against infection. One of her research specialties is the challenging technique of X-ray crystallography, which she uses to capture the atomic structure of key molecules that drive an inflammatory response. But for this method to work, the proteins have to be coaxed to form regular crystals—and that has often proven to be prohibitively difficult. Wu, now at Boston Children’s Hospital and Harvard Medical School, can be relentless in her attempts to crystallize difficult molecular structures, and this quality has helped her make a number of important discoveries. Among them is the seminal finding that innate immune cells process and internalize signals to handle invading microbes much differently than previously thought.

Innate immune cells, which include macrophages and neutrophils, patrol the body non-specifically, keeping a look out for signs of anything unusual. Using protein receptors displayed on their surfaces, these cells can sense distinctive molecular patterns on microbes, prompting an immediate response at the site of infection.

Wu has shown that these cells form previously unknown protein complexes that mediate the immune response [1, 2]. She received an NIH Director’s 2015 Pioneer Award to help translate her expertise in the structural biology of these signaling complexes into the design of new kinds of anti-inflammatory treatments. This award helps exceptionally creative scientists to pioneer transformative approaches to major challenges in biomedical and behavioral research.

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Vaccine Research: New Tactics for Tackling HIV

HIV-infected Immune Cell

Caption: Scanning electron micrograph of an HIV-infected immune cell.
Credit: National Institute of Allergy and Infectious Diseases, NIH

For many of the viruses that make people sick—think measles, smallpox, or polio—vaccines that deliver weakened or killed virus encourage the immune system to produce antibodies that afford near complete protection in the event of an exposure. But that simple and straightforward approach doesn’t work in the case of human immunodeficiency virus (HIV), the virus that causes AIDS. In part, that’s because our immune system is poorly equipped to recognize HIV and mount an attack against the infection. To make matters worse, HIV has a habit of quickly mutating as it multiplies.That means, in order for an HIV vaccine to be effective, it must induce antibodies capable of fighting against a wide range of HIV strains. For all these reasons, the three decades of effort to develop an HIV vaccine have turned out to be enormously challenging and frustrating.

But now I’m pleased to report that NIH-funded scientists have taken some encouraging strides down this path. In two papers published in Science [1, 2] and one in Cell [3], researchers presented results of animal studies that support what most vaccine experts have come to suspect: the immune system is in fact capable of producing the kind of antibodies that should be protective against HIV, but it takes more than one step to get there. In effect, a successful vaccine strategy has to “take the immune system to school,” and it requires more than one lesson to pass the final exam. Specifically, what’s needed seems to be a series of shots—each consisting of a different engineered protein designed to push the immune system, step by step, toward the production of protective antibodies that will work against virtually all HIV strains.

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Ferreting Out Genomic Secrets

Ferret

Ferret in a Colorado conservation center, U.S. Fish and Wildlife Service

Not only is the ferret (Mustela putorius furo) adept at navigating a dirt field or threading electrical cables through piping (in New Zealand, ferrets can be registered as electrician assistants), this furry 5-pounder ranks as a real heavyweight for studying respiratory diseases. In fact, much of our current thinking about influenza is influenced by research with ferrets.

Now, the ferret will stand out even more. As reported online in Nature Biotechnology, NIH-funded researchers recently sequenced the genome of the sable ferret, the type that is bred in the United States as a pet. By studying this genetic blueprint like an explorer would a map, scientists can perform experiments to learn more systematically how the ferret copes biologically with common or emerging respiratory pathogens, pointing the way to improved strategies to preserve the health and well being of humans and ferrets alike.

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Using Tiny Sponges to Fight MRSA

Glowing image of MRSA toxin

Caption: MRSA toxin bound to nanosponge particles glows yellow inside a mouse immune cell. The cell membrane is stained red and the nucleus is stained blue.
Credit: Liangfang Zhang Laboratory, University of California, San Diego

Methicillin-resistant Staphylococcus aureus bacteria, commonly known as MRSA, pose a serious public health threat, causing more than 80,000 skin, lung, and blood infections and killing about 11,000 people annually in the United States [1]. This microbe wreaks its devastation by secreting a toxin, alpha-hemolysin, that punches holes in the membrane of cells, essentially causing them to leak to death. Now, NIH-funded researchers from the University of California, San Diego, have created tiny sponges capable of trapping and binding MRSA’s toxin [2]. When these toxin-laden sponges are injected into mice, they serve as a vaccine—that is, they stimulate the animal’s immune system in a way that protects them from the toxin’s deadly impact.

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Who Knew? Gut Bacteria Contribute to Malnutrition

Photo of an African girl with thin limbs and a distended abdomen.

A child suffering from kwashiorkor.
Source: CDC/Phil

Here’s a surprising result from a new NIH-funded study: a poor diet isn’t the only cause of severe malnutrition. It seems that a ‘bad’ assortment of microbes in the intestine can conspire with a nutrient poor diet to promote and perpetuate malnutrition [1].

Most of us don’t spend time thinking about it, but healthy humans harbor about 100 trillion bacteria in our intestines and trillions more in our nose, mouth, skin, and urogenital tracts. And though your initial reaction might be “yuck,” the presence of these microbes is generally a good thing. We’ve evolved with this bacterial community because they provide services—from food digestion to bolstering the immune response—and we give them food and shelter. We call these bacterial sidekicks our ‘microbiome,’ and the latest research, much of it NIH-funded, reveals that these life passengers are critical for good health. You read that right—we need bacteria. The trouble starts when the wrong ones take up residence in our body, or the bacterial demographics shift. Then diseases from eczema and obesity to asthma and heart disease may result. Indeed, we’ve learned that microbes even modulate our sex hormones and influence the risk of autoimmune diseases like type 1 diabetes. [2] Continue reading