2004 Home Page Stories

 
A Breath of Fresh Care

 

It’s 2 a.m. and that bundle of joy who climbed into bed hours ago is now crying at the bedroom door. Clutching a teddy bear for comfort, the tot sounds like Darth Vader with a bad cough. It’s the unmistakable, harsh bark of croup.

No medicines are available to treat the infection, and current remedies—which involve breathing shower steam or sniffing cool, dry midnight air—are helpful interventions, but not curative.

Scientists at St. Jude Children’s Research Hospital hope to use unlikely allies—viruses—to make vaccines that prevent such respiratory nightmares. They’re even using viruses to create new treatments for fighting cancer.

Waking the soldiers

Although the human immune system is highly skilled at fighting infection, its soldiers, called B-cells and T-cells, sometimes need to be nudged into action.

“They’re like a sleeping army,” says Julia Hurwitz, PhD, of the St. Jude Immunology Department. “B-cells each make different weapons called antibodies that appear on the cell surface and that can be shed into the blood. An antibody will latch onto a virus, using a lock-and-key type interaction, and block virus infection. If the body has never been attacked before by a particular virus, the immune cells responsive to that virus may be off guard, allowing viruses to slip past them and cause disease.” A vaccine’s job is to wake up the cells by way of a decoy.

“We want to find something that looks like the virus in question, but that is not dangerous,” Hurwitz says. “This safe mimic can bind onto the antibodies on a B-cell surface and trigger the B-cell to multiply, giving rise to a huge army of activated soldiers. The cells will also release antibodies into the circulation. If the real virus appears later, antibodies will bind and destroy it.”

St. Jude studies are targeted toward members of a family of viruses called Paramyxoviridae, which are common pathogens of infants and children. Viruses in this family include the Sendai virus; respiratory syncytial virus; Newcastle disease virus; and the human parainfluenza virus-1 (hPIV-1), which causes croup. Although the Sendai virus causes severe, flu-like disease in mice, it does not cause disease in humans. Because its structure so closely resembles hPIV-1, the Sendai virus is the perfect candidate for a vaccine against hPIV-1.

A St. Jude vaccine currently under study uses an unmodified laboratory strain of the Sendai virus as a vaccine to prevent hPIV-1 infection. It’s a seemingly simplistic approach, but there is reason to be optimistic: the eradication of smallpox occurred in the same way. 

Helping history repeat itself

When a deadly scourge of smallpox swept through his English town in the 1790s, Edward Jenner noticed that milkmaids didn’t get sick. He found that they were naturally immunized against smallpox because they had been exposed to the virus that causes cowpox. This mild, bovine virus looks a lot like the smallpox pathogen, yet does not harm humans. So the milkmaids’ fortified immune systems could recognize and thwart smallpox without getting the disease. Jenner’s studies led to mass vaccinations, and the World Health Organization declared the world free of epidemic smallpox in 1980.

“That was the first truly effective vaccine,” says Hurwitz. “We’re using the same strategy to target hPIV-1.”

Jerry Shenep, MD, of St. Jude Infectious Diseases has patterned the St. Jude clinical studies after Jenner’s design. This trial is the first human study of Sendai virus in the world. Results have been promising: the vaccine was well-tolerated in all adults who volunteered for testing. St. Jude is now planning to test the vaccine in healthy children.

Karen Slobod, MD, also of St. Jude Infectious Diseases, says an hPIV-1 vaccine could indirectly benefit patients who have weakened immune systems from cancer or other catastrophic illnesses. “The overall goal is to eradicate the virus from the healthy community,” she says. “If you can eradicate it from the healthy population, chances are greatly reduced that patients would have to worry about catching the virus, either.”

Tweaking the process for RSV

Not all Paramyxoviridae viruses have structural twins that can be used to prevent disease. For example, unmodified Sendai virus will not protect against its relative, respiratory syncytial virus (RSV), the leading cause of breathing diseases such as bronchitis and pneumonia in infants less than 6 months old.

But with a few genetic modifications, the Sendai virus can elicit immune responses to RSV.

“We’re now building on the hPIV-1 findings and looking at a vaccine where the Sendai virus acts as a carrier,” says Allen Portner, PhD, of St. Jude Infectious Diseases.

Portner is leading studies that use a technique called reverse genetics to convert the Sendai virus’ RNA into DNA. “At this stage, we can put any gene we want into this Sendai virus DNA,” Portner says. Using this technique, Toru Takimoto, PhD, and Sateesh Krishnamurthy, PhD, inserted genes for specific RSV proteins into Sendai virus, thereby generating a vaccine specific for the RSV.

Portner says the St. Jude vaccine research using Sendai virus could eventually translate into protection for some of the world’s most common respiratory diseases. “There isn’t a population out there that isn’t touched by such infections.” he says. “Just like mumps and measles, this is another disease for which kids could get vaccines.”

Newcastle Disease Virus: A tumor-killing virus

Another member of the Paramyxoviridae family— Newcastle disease virus (NDV)—actually kills cancer cells while sparing healthy cells. Portner’s team is trying to figure out why.

Although the idea of killing tumors with viruses has been explored for decades, the mechanism behind NDV has remained an enigma. Newcastle disease occurs naturally in birds and can be fatal to them. But although it can cause mild flu-like symptoms and conjunctivitis in some people, NDV is largely harmless to humans. Portner and Krishnamurthy have confirmed earlier studies that Newcastle disease virus kills tumor cells. “But we’re not seeing anything in scientific literature telling us that anyone is looking into the very important question of why normal cells are spared,” Portner says.

The answer could have huge implications for cancer treatment. A tumor-killing virus that spares healthy tissue could someday support surgery, chemotherapy and radiation therapy.

Figuring out how NDV selectively destroys tumor cells may even offer clues to other biological agents that can act in the same way, says Krishnamurthy, who leads NDV research in Portner’s lab. Like rummaging for the tip of a needle lost in a microscopic haystack, Krishnamurthy has painstakingly traced the virus’ progression. He has found that NDV initially launches attacks on healthy and tumor cells, causing both cell types to secrete an antiviral protein called interferon-beta (IFN ß) before the cells die. The IFN ß then works its way through each cell’s signaling pathway—the chain of command within cells—to elicit the response necessary to ward off the virus.   

Krishnamurthy discovered that the signaling pathways work fine in both cell types after infection, yet the tumor cells are not protected by the IFN ß as are the healthy cells. Thus vulnerable to NDV, the tumor cells release new copies of the virus and spread the infection among themselves.

Krishnamurthy thinks the key difference between the reactions of healthy and tumor cells to NDV lies with one of the antiviral proteins that are generated in response to INF ß. These proteins sound the cell’s alarm bell to thwart an attacking virus. This alarm system seems to be jammed in tumor cells—an ironic boon to patients battling tumors.

“By knowing what’s going on, we can perhaps exploit these essential differences—as the virus does—to the patient’s advantage,” Portner says. “Just about every person in this world knows someone fighting cancer. A virus that attacks tumors gives us another bullet to fight the disease.”

Reprinted from Promise magazine, winter 2004