Creative Minds: Complex Solutions to Inflammation

Posted on March 24, 2016 by Dr. Francis Collins

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.

Caption: Cryo-EM structure of the ASC protein, which is involved in signalosome assembly. The red, cyan and yellow each represent one strand of the triple-stranded helical assembly. The individual subunits are indicated by alternating darker and lighter shades.
Credit: Wu Lab

It’s long been assumed that innate immune cells possessed a simple signaling system that would be activated on encountering a microbe. But Wu and her colleagues discovered that the process wasn’t that simple. They found that the signal served as more of a first warning, causing proteins in the cell to aggregate into ordered clusters that they call a signalosome. These clusters, which are shaped like a helix and can be hundreds of nanometers to micrometers in diameter, serve as what Wu described as supramolecular organizing centers, or SMOCs. With multiple proteins teaming up to process the message, just as a full orchestra has greater potential for sound than a soloist, SMOCs can better amplify and modulate the signal, directly setting the parameters for the type of immune response, its intensity, and its duration.

Inflammation is part of fighting infection, but in other instances it can run amok and do damage to surrounding tissues. With the Pioneer Award, Wu and the members of her lab are developing small molecules or altered proteins that could be delivered to innate immune cells to prevent runaway inflammation by interfering with the assembly of the signalosome. If signalosomes don’t assemble to serve as SMOCs, inflammatory signals presumably couldn’t be sent.

Although excessive inflammation is a common problem for many human diseases, Wu will likely focus initially on stopping the chronic inflammation associated with gout, lymphoma, and possibly neurological disorders such as Alzheimer’s disease.

References:

[1] Death domain assembly mechanism revealed by crystal structure of the oligomeric PIDDosome core complex. Park HH, Logette E, Raunser S, Cuenin S, Walz T, Tschopp J, Wu H. Cell 2007 Feb 9;128(3):533-546.

[2] Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-IR signaling. Lin SC, Lo YC, Wu H. Nature 2010 Jun 17;465(7300):885-890.

Links:

Features of an Immune Response (National Institute of Allergy and Infectious Diseases/NIH)

Wu Lab (Harvard Medical School, Boston)

Wu NIH Project Information (NIH RePORTER)

NIH Director’s Pioneer Award Program

NIH Support: Common Fund; Eunice Kennedy Shriver National Institute of Child Health and Human Development