Stories about: Program in Cellular and Molecular Medicine

When antibiotics fail: A potential new angle on severe bacterial infection and sepsis

bacterial infection sepsisBacterial infections that don’t respond to antibiotics are of rising concern. And so is sepsis — the immune system’s last-ditch, failed attack on infection that ends up being lethal itself. Sepsis is the largest killer of newborns and children worldwide and, in the U.S. alone, kills a quarter of a million people each year. Like antibiotic-resistant infections, it has no good treatment.

Reporting this week in Nature, scientists in Boston Children’s Hospital’s Program in Cellular and Molecular Medicine (PCMM) describe new potential avenues for controlling both sepsis and the runaway bacterial infections that provoke it.

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‘Hotspots’ for DNA breakage in neurons may promote brain genetic diversity, disease

DNA breakage brain
DNA breaks in certain genes may help brains evolve, but also can cause disease (Constantin Ciprian/Shutterstock)

As organs go, the brain seems to harbor an abundance of somatic mutations — genetic variants that arise after conception and affect only some of our neurons. In a recent study in Science, researchers found about 1,500 variants in each of neurons they sampled.

New research revealing the propensity of DNA to break in certain spots backs up the idea of a genetically diverse brain. Reported in Cell last month, it also suggests a new avenue for thinking about brain development, brain tumors and neurodevelopmental/psychiatric diseases.

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Genetic analysis backs a neuroimmune view of schizophrenia: Complement gone amok

schizophrenia C4
C4 (in green) located at the synapses of human neurons. (Courtesy Heather de Rivera, McCarroll lab)

A deep genetic analysis, involving nearly 65,000 people, finds a surprising risk factor for schizophrenia: variation in an immune molecule best known for its role in containing infection, known as complement component 4 or C4.

The findings, published this week in Nature, also support the emerging idea that schizophrenia is a disease of synaptic pruning, and could lead to much-needed new approaches to this elusive, devastating illness.

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Putting structure around the genetic basis of some immune diseases

The saying in the design world is that form follows function. But in biology, and protein biology in particular, it would be more correct to say that form begets function. Shape and structure are the foundation for most protein-based interactions in cells, and are why basic functions like receptor binding, antibody neutralization and gene transcription work.

Two enzymes in the immune system’s B cells, called RAG1 and RAG2, are a perfect example. Together, they form a complex that splices antibody-producing genes together in unique combinations through a process called V(D)J recombination. They do a similar job in T cells to build antigen-binding T-cell receptors (TCRs). In either case, the enzymes are essential to a robust immune response.

In a recent Cell paper, a team led by Hao Wu, PhD, of the Program in Cellular and Molecular Medicine (PCMM) at Boston Children’s Hospital and Maofu Liao, PhD, at Harvard Medical School used electronic microscopy to reveal how RAG1 and 2 interact at a structural level, both with each other and with DNA. The structural biology images they’ve created show plainly what mutations in the genes for these proteins do to cause disease.

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How our neutrophils might sabotage wound healing in diabetes

When you get a cut or a scrape, your body jumps into action, mobilizing a complicated array of cells and factors to stem bleeding, keep the wound bacteria-free and launch the healing process.

For most of us, that process is complete in a couple of weeks. But for many people with type 1 and type 2 diabetes, delayed wound healing can have permanent consequences. For example, between 15 and 25 percent of diabetes patients develop chronic foot ulcers. Those ulcers are the root cause of roughly two-thirds of lower limb amputations related to diabetes.

Why don’t these wounds close? Blame a perfect storm of diabetic complications, such as reduced blood flow, neuropathy and impaired signaling between cells. According to research by Denisa Wagner, PhD, of Boston Children’s Hospital’s Program in Cellular and Molecular Medicine, a poorly understood feature of our immune system’s neutrophils may be one more ingredient in the storm.

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Drawing a ring around antiviral immunity

Ubiquitin RIG-I innate antiviral immunity Sun Hur
Ubiquitin (pink ovals) doesn’t just tag proteins for recycling. It also may help keep our antiviral immune response in balance. (Image courtesy: Sun Hur)

If you follow cancer biology, then you’ve probably heard of ubiquitin before. Ubiquitin tags a cell’s damaged or used proteins and guides them to a cellular machine called the proteasome, which breaks them down and recycles their amino acids. Proteasome-blocking drugs like Velcade® that go after that recycling pathway in cancer cells have been very successful at treating two blood cancers—multiple myeloma and mantle cell lymphoma—and may hold promise for other cancers as well.

Less well known, however, is the fact that ubiquitin helps normal, healthy cells raise an alarm when viruses attack. Ubiquitin works with a protein called RIG-I, part of a complex signaling pathway that detects viral RNA and triggers an innate antiviral immune response.

Sun Hur, PhD, a structural biologist in Boston Children’s Hospital’s Program in Cellular and Molecular Medicine, has been studying RIG-I and other members of the innate cellular antiviral response for some time. And in a recent paper in Nature, she provided a structural rationale for how ubiquitin helps RIG-I do its job, and how that might help keep our immune system from getting out of hand.

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Catching platelets with NETs: Neutrophils and deep vein thrombosis

Sea cucumbers drive off attackers by expelling their innards. Neutrophils do the same, forming NETs to fight bacteria. But that same capability might also help fuel dangerous blood clots. (Anders Poulsen/Wikimedia Commons)

Sea cucumbers have an unusual way of defending themselves. When threatened, they ensnare their foes with sticky threads. Some even expel their own internal organs to repel attackers.

Immune system cells called neutrophils sometimes do much the same: When confronted with bacteria, they unravel and shoot out their chromatin—the tightly wound mix of DNA and proteins that keeps genes packaged in cells. The resulting molecular mesh, known as a neutrophil extracellular trap, or NET, traps and kills bacteria, providing an additional line of defense against bloodstream infections.

But neutrophils and NETs can go awry. Since 2010, Denisa Wagner, PhD, of the Program in Cellular and Molecular Medicine at Boston Children’s Hospital, has been studying NETs’ role in deep vein thromboses (DVTs)—blood clots that form in veins deep in the body where blood clots shouldn’t, usually in the legs.

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