Of all the senses, perhaps none is more evocative than the sense of smell. The merest whiff of a familiar scent can bring back the past and rouse sleeping emotions. That’s because a relay of neurons connects the nose directly to the brain. But unfortunately, viruses also travel this bridge: for example, the viruses that cause rabies, West Nile disease, and some influenzas infect the brain through the olfactory pathway. New research shows that a lesser-known virus called human herpesvirus-6 (HHV-6) may take the same route to play a role in multiple sclerosis (MS). The finding may point the way toward new treatments and may help reveal how MS and other neurological diseases develop.
In MS, an overzealous immune system mistakenly attacks the myelin sheath, a fatty insulation that wraps around axons (the projections along which neurons send messages). Though myelin-producing cells called oligodendrocytes re-build the sheath, in many patients the loss of myelin eventually becomes permanent. The axons begin to degenerate, slowing down signal transmission among neurons, which can lead to paralysis and blindness.
Exactly how the disease begins is not fully understood, although patients are assumed to have a genetic susceptibility. “The jury is still out on whether MS is triggered by something in the environment, like a virus,” says virologist Steven Jacobson of the National Institute of Neurological Disorders and Stroke (NINDS).
Evidence of a role for HHV-6 has been mounting for many years, Jacobson says. The virus is everywhere, and most people carry traces of it in their systems without ever suffering harm. But elevated levels of HHV-6 have been found in the blood and cerebrospinal fluid of MS patients, as well as in the lesions, or scars, that appear in their brains.
HHV-6 is also known to infect both the myelin-producing oligodendrocytes and other cells called astrocytes, which assist in the repair process in the brain and spinal cord. Perhaps not coincidentally, cells very similar to astrocytes are found in the nasal cavity. Called olfactory-ensheathing cells (OECs), these cells help guide newly formed neurons from the nasal passageway into the brain. In laboratory experiments, OECs have been shown to help axons regenerate.
To see if HHV-6 infects these cells to take the nasal route into the brain, Jacobson first checked for the virus’s presence in the olfactory pathway. Working with colleagues at NINDS and at the Center for Molecular Nutrition and Sensory Disorders in Washington, DC, Jacobson obtained brain tissue taken from autopsies of eight patients with MS and five others who had had cancer. Amounts of viral DNA were found throughout the brains of these patients, but levels were highest in the olfactory bulb (the part of the brain nearest the nasal cavity and the point at which smell information enters the brain). Elevated viral presence was also found in nasal secretions collected from 126 people with MS or loss of smell, and from healthy individuals. The results were published in the Aug. 16 Proceedings of the National Academy of Sciences.
The amount of virus detected was similar among those who had MS and those who didn’t—showing that the virus entered the brain through the olfactory route but shedding no light on what it did once it got there. It was the next phase of the study that raised suspicion for a role in MS. The investigators infected cultured OECs with two strains of the virus and found that one version, HHV-6A, has a strong affinity for infecting these cells—just as it does for the cells that help to regenerate axons—suggesting that it may play a role in a disease that features myelin loss and neurodegeneration.
“To our knowledge, this is the first study to show that this virus readily infects OECs,” says Jacobson. “It’s a piece of the puzzle.” And the puzzle of MS is complex—involving a scrambled immune system response, loss of myelin, and a failure to re-myelinate, which eventually leads to neurodegeneration. The next question, Jacobson says, is where the virus fits in.
Does size matter?
The answer may lie in the virus’s considerable size. A virus is not an organism like a bacterium, with its own, internal life-support equipment, but simply a package of genes that contain the codes for proteins. Once the virus penetrates a host cell, its DNA takes over that cell’s machinery, and the cell starts producing the proteins encoded by the virus’s genes. HHV-6 is a big virus, containing the codes for approximately 100 proteins. Much smaller viruses can inflict devastating, even lethal damage; the human imunosuppressive virus has nine genes encoding 19 proteins, while the polio virus encodes only10. “There’s a good chance that if HHV-6 gets into a cell it will mess it up somehow,” says Jacobson.
Unfortunately, HHV-6 is “the new agent on the block,” says Jacobson, having been discovered only in 1985. Researchers studying it have to develop their own tests, tools, and chemicals. It is also not yet possible to study the virus’s effects in mice, since it isn’t a virus that mice get.
Even with these obstacles, “The work has major implications,” says virologist Samantha Soldan of the University of Pennsylvania, who has collaborated with Jacobson on past research but was not involved in the current study. “Many studies have shown an association between HHV-6 and MS, but this is the first to show how the virus enters the central nervous system.” Soldan says the research may open new treatment possibilities or new ways to target the virus in the brain. Although some antiviral drugs are partially effective against HHV-6, she says, using them long-term, which would be necessary for a chronic condition like MS, would result in serious kidney damage.
She also believes that a better understanding of the virus might clear up the biggest question of all—why a virus that everyone has only causes disease in comparatively few people.
Jacobson adds that HHV-6 has been implicated in other neurological conditions including a form of epilepsy and some types of encephalitis—such as “limbic dementia,” which occurs when the virus is re-activated by drugs given to suppress the immune system after bone marrow transplants. Finding ways to stop the virus from replicating or figuring out what makes it re-activate are on the agenda for the future, he says—along with the hope that any treatments discovered could be delivered through a nasal spray.