Stem cells offer answers about a devastating brain infection—and a new view of the immune system

Why do some children develop severe encephalitis from herpes simplex virus 1, a virus that's usually innocuous? (Fred Murphy/CDC/Wikimedia Commons)

Herpes simplex virus-1 (HSV-1) is one of those viruses that’s found nearly everywhere: almost 60 percent of the U.S. population has been infected by it. Usually it causes little more than cold sores or occasional genital herpes.

But for a handful of children, it’s the source of one of the most devastating brain infections known—herpes simplex encephalitis (HSE)—causing fever, confusion, personality changes and seizures. If not caught and treated with high-dose antivirals, it’s highly fatal, and even with treatment most children are left with irreversible brain damage.

Why do some children develop HSE while everyone else just shrugs the virus off? The susceptibility is clearly genetic; indeed, Jean-Laurent Casanova, MD, PhD, at Rockefeller University several years ago identified genetic defects in a first-responder molecule known as TLR3 and in some of the molecules it interacts with. These defects prevent TLR3 from spotting viral RNA—the sign of an intrusion—and from producing interferon-alpha to help kill the virus.

Yet oddly, aside from the central nervous system, children with HSE are untouched by HSV-1. In fact, their white blood cells (whose job is to fight infection) are perfectly capable of responding to the virus and producing interferon-alpha.

Luigi Notarangelo, MD, at Boston Children’s Hospital, studies the origins of rare immune disorders and wanted to probe deeper. He proposed examining the TLR3 pathway specifically in cells from the central nervous system.

“Some life-threatening infections in kids are due to ‘holes’ in the immune system,” he says. “But why is only the brain affected in this case? There must be a cell type in the central nervous system that is absolutely requiring integrity of this pathway to defend against HSV-1.”

That’s where stem cells come in. For several years, Notarangelo and colleagues have been generating stem cells from patients with various immune disorders—like severe combined immune deficiency (aka “bubble boy disease”)—and turning them into different kinds of immune-system cells to figure out what’s going awry.

So Casanova sent Notarangelo skin cells from patients with HSE. With the help of the laboratory of George Daley, MD, PhD, at Boston Children’s, Notarangelo and colleagues from Rockefeller University and the Sloan-Kettering Institute for Cancer Research turned back the developmental clock, sending the skin cells back to an immature, embryonic-like state, capable of developing into any tissue.

Luigi Notarangelo is using iPS cells to probe the biology of immune deficiencies.

They then differentiated these so-called induced pluripotent stem cells (iPS cells) into neural stem cells, neurons, oligodendrocytes, astrocytes—all the cell types that make up the brain. “Working with iPS cells allowed us to model the infection and look at the mechanism, without touching the brain,” says Notarangelo.

When challenged with HSV-1, even small doses, the brain cells generated from HSE patients—especially neurons and oligodendrocytes—were unable to produce enough interferon to mount an effective defense, and died from infection. Brain cells generated from controls produced robust amounts of interferon and prevented HSV-1 from replicating.

The work, recently published in Nature, has allowed Notarangelo to uncover brain-specific genetic defects that could be tackled through completely new kinds of treatments. Most immediately, the missing interferon-alpha could be delivered into patients’ brains via an injection into the cerebrospinal fluid.

Notarangelo hopes to find the mechanisms behind heightened susceptibility to other viruses which, like HSV-1, lack a vaccine. His research and that of other groups may also help change the way we understand the immune system.

In addition to acquired immunity (based on recognition of invaders and production of pathogen-specific antibodies) and innate immunity (a rapid, generic response), scientists are increasingly recognizing something called intrinsic immunity that can block infection as soon as a virus enters the body.

And iPS cells, which earned a Nobel prize this year and have been used to model about 50 diseases to date, may help solve some other infectious disease mysteries, like why viral hepatitis or influenza can be rapidly fatal for some people but not others. Perhaps the genetic defect lies only in certain cells, like liver cells in the case of fulminant hepatitis or lung cells in the case of influenza.

“Each cell in the body has its way to protect itself against infections,” says Notarangelo. “With iPS cells, you can model the response in every cell type you are interested in.”