By David N. Leff

"It may come as a surprise to many," observed virologist and immunologist Glenn Rall, "that measles causes annually as many deaths worldwide as HIV."

Something else the two pathogens have in common, he added, "is that both infect only humans. You can infect apes as well with the measles virus, but there are no good animal models for looking at that virus." At the Fox Chase Cancer Center, in Philadelphia, Rall heads a laboratory that focuses on viral pathogenesis in the central nervous system.

In 1993, researchers discovered the human receptor that gives the measles virion entry to infect its target cells in the human body.

This receptor, CD46, hangs out on the surface of virtually every cell in the human body. Like a cop on the beat, its day job is to catch and inactivate any bad-cell-killing components of the body's complement system that happen to land on a good cell by mistake. "If it does that," Rall pointed out, "it can initiate the whole complement cascade, and result in lysis of cells that have been, essentially, innocent bystanders."

But CD46's far-from-innocent part-time gig is to open wide the gates and admit infectious measles virions to their target human cells. "The measles virus," Rall said, "infects lymphocytes, neurons, epithelial and endothelial cells; it's quite a ubiquitous infection."

Quite the contrary of the receptor's complement-inactivating mission, Rall continued, "the measles virus binds to the virion's outer protein, hemagglutinin. That association doesn't result in inactivation of the virus; rather, it results in its internalization. These two functions," he continued, "appear to be quite different. I'm not sure about the distinction between what CD46 does normally and how it serves as a receptor for measles."

That highly contagious childhood disease spreads from victim to victim via the respiratory tract, mainly by coughing, sneezing, even breathing.

In 1962, the year an effective vaccine made its debut in the U.S., half a million preschool and school-age kids suffered the dusky red rash, fever and congestion of measles. By 1977, cases were down to 35,000, and by 1983, 99 percent of American infants had been vaccinated and fewer than 1,497 came down with measles.

In the underdeveloped Third World, the story was — and still is — different.

"In countries where the measles vaccine is either never delivered, or administered at the wrong time," Rall pointed out, "people are still susceptible to infection. The disease itself causes a transient immunosuppression, so they become more vulnerable to life-threatening opportunistic pathogens."

The measles virus itself causes a 100 percent lethal infection in a statistically small proportion of measles victims.

Measles Backlashes In Brain

"This infection of the central nervous system [CNS] that we're studying," Rall said, "occurs very rarely. It's called subacute sclerosing panencephalitis (SSPE), and strikes from one in 10,000 to one in 100,000 cases of acute measles infection in Third World countries. If you do the math," he continued, "if you assume one million people annually, even ten million, are getting acutely infected with measles virus, you may have 10 to 100 individuals dying of SSPE each year."

In the U.S., he said, "there are virtually no more cases of SSPE; vaccination has been pretty much 100 percent effective in eradicating it."

Prime targets for the brain infection are infants who have had classical measles before the age of two. Then the virus hibernates, and emerges after several asymptomatic years of latency to inflict a succession of psychoneurological SSPE symptoms: personality changes, seizures, myoclonus (muscle spasms), ataxia (wobbly gait), light sensitivity and eye abnormalities, spasticity, coma.

"If you begin to develop such signs," Rall observed, "there's no way to intervene; even though SSPE is rare, it's 100 percent lethal."

Rall is lead author of a paper in the current Proceedings of the National Academy of Sciences (PNAS), dated April 29, 1997. Its title: "A transgenic mouse model for measles virus infection of the brain."

He and his co-authors engineered these animals to mimic the SSPE infection. "That was our motivation," Rall observed, "to develop an animal model for measles virus infection of a very specific cell type, the neuron."

As reported in PNAS, the team coupled the CD46 measles receptor gene to a promoter that specifically drives transcription of CNS cells. They microinjected this linear piece of DNA into early-stage embryonic cells.

"A number of founder mice were born," Rall recounted, "and we did studies to characterize expression of the CD46 proteins on the surface of neurons. They proved that the receptor molecule is expressed on neurons in the transgenic mice, but not on non-transgenic ones."

The group's initial hope, he went on, "was that we would have an in vivo model for measles infection. So we infected adult transgenic mice intracerebrally with measles virus, expecting that we would get a raging brain infection, and these mice would start dropping dead."

In fact, none of those adults died, and very few of their CNS neurons were infected with virus. After a period of disappointment that their intended model had fallen by the wayside, Rall played a hunch and infected newborn animals rather than grown-ups.

"We got a very, very widespread CNS infection," he recalled. "So the implication is that there are differences between neonatal and adult mice with respect to susceptibility to disease.

"SSPE," Rall explained, "is a disease of kids. Even though adults get acute measles and die of the immunosuppression, rarely do adults get the brain infection. So what we were seeing in the animal system might be a parallel to what is actually occurring in the human condition as well."

He continued: "We're hoping that these human-CD46-expressing transgenics are not just a model system for measles virus infection in the brain, but for a number of neurodegenerative diseases, because the major CNS lesion that's caused by this infection is a massive drop-out of neurons. This so-called 'decortication' accompanies a large number of CNS diseases in humans that are much more prevalent that SSPE -- such as Alzheimer's disease, for example.

Rall concluded: "We have no evidence that there are parallels between this and any neurodegenerative diseases of humans that affect people in the U.S. But we're certainly considering that as an option." *