If you sampled all the chemical elements in the earth's crust, you'd find that hydrogen is the world leader, with 1.4 parts per million.

Way down the list, 57th in fact, is selenium, a trace element that counts 0.1 parts per million. But man, beast and plant life alike need their dietary fix of selenium-containing antioxidant proteins just to stay alive.

"The selenoproteins are ubiquitous in the world," observed virologist Bernard Moss, at the National Institute of Allergy and Infectious Diseases (NIAID), in Bethesda, Md. "Presumably, there are only a small number of them, but they're present in all types of organisms. We know," he added, "that selenium is essential to life because Japanese investigators recently tried to construct a knockout mouse unable to make a selenoprotein. It died in utero."

In the Chinese province of Keshan, the soil lacks selenium; hence, so do the crops its people eat. Several children have died of cardiac myopathy brought on by this selenium-deficiency "Keshan disease." It is claimed locally that dosing with selenium methionine acts as a preventative.

Proponents of alternative medicine urge people seeking health and wellness to consume 200mcg to 300mcg of selenium daily, and lifelong. Citing the trace element's antioxidant effect, a popular book by one of these advocates extols its "cancer-fighting benefits" and "reduced disease risk."

But the Merck Manual of Diagnosis and Therapy, a standard medical reference, notes that loss of hair and nails, as well as skin lesions and polyneuritis, have been attributed to selenium toxicity, "from the taking of 'health store' [selenium] tablets."

Oxygen-free radicals are the serial killers of cells exposed to too much sunshine, or the ravages of an over-zealous immune system. "Ultraviolet radiation and peroxides are cytotoxic," Moss observed, "causing cells to die through the process of apoptosis."

Macrophages are the designated hitters of the immune system for producing oxidative peroxides in the body, in order to fight infection. It's when they overproduce that target cells go belly-up in programmed death.

Moss and his NIAID coworkers have just discovered an unusual enzyme that appears to have protective effects against UV radiation and macrophage excesses. The kicker in their discovery is that the beneficiary of this protection against these oxidants is a particularly obnoxious virus.

An article in the Jan. 2, 1998, issue of Science reports their findings under the title: "Ultraviolet-induced cell death blocked by a selenoprotein from a human dermatotropic poxvirus."

The virus in question is Molluscum contagiosum, a close viral cousin of Orthopoxvirus, the now-conquered perpetrator of smallpox. That leaves M. contagiosum as the sole surviving member of the Poxviridae family that preferentially infects human beings.

Until the advent of AIDS, Molluscum infected mainly children (and wrestlers) with crops of relatively rare benign skin tumors, which went away spontaneously in a matter of months. The virus took care to spare its victims' lives, so these lesions — exclusively in skin cells — could provide a safe, steady haven in which it could replicate.

In HIV-positive people, M. contagiosum moved to a front burner, where it joined the other hitherto unusual and untreatable opportunistic infections, such as Kaposi's sarcoma and pneumocystic pneumonia, that suddenly flourished in the immunodeficient environment of incipient AIDS.

In mid-1996, Moss announced that his NIAID Laboratory of Viral Diseases had sequenced all 190,289 base pairs of the M. contagiosum genome. (See BioWorld Today, Aug. 13, 1996, p. 1.)

Analysis of that genome revealed a viral gene with a sequence very similar to the gene for the human enzyme glutathione peroxidase. This enzyme detoxifies the caustic hydrogen peroxide that macrophages unleash to fight infection.

Now, in the current Nature paper, Moss, its senior author, describes two new "significant findings. First, the M. contagiosum virus does indeed encode a selenoprotein. Second, that protein can protect cells against oxidative stress.

"From that," he went on, "one can infer that the selenoprotein protects the virus-infected cell from host immune cells — which use peroxide in order to kill target virus-infected cells — as well as ultraviolet radiation." When the researchers engineered human cells to express the Molluscum selenoprotein, these cells were largely protected from UV radiation and peroxides.

Anent the first finding, Moss made the added point that "although selenoproteins are present in bacteria, archaea and eukarya, it happens that M. contagiosum is the first virus in which this type of protein has been found."

Moss does not see "any therapeutic agent being derived from this protein." He explained: "Some proteins are secreted from cells, so one could make a purified protein reagent. But this selenoprotein is made inside the skin's keratinocytes, so I'm not sure there is any clinical application."

Detecting, Outmaneuvering Viral Play

Rather, he thinks "it's just a way to help us understand the strategies that viruses use to protect cells. This would seem to be a clever ploy," he continued, "for a virus that replicates in the epidermis."

That understanding has been blocked in the case of the Molluscum virus by two obstacles: It won't replicate in cell culture, and no animal model can manipulate its genetics. Moss and his lab are now suiting up for an end run around this interference.

"We're trying to do an animal-type experiment to see if that enzyme actually helps protect the virus in the skin," he said.

What his NIAID team has done is insert the virus's gene that encodes its selenoprotein enzyme into a vaccinia virus (VV), which is another member of the poxvirus family. "We're going to use the VV as a surrogate in animal studies," Moss said, "and see whether our predictions regarding its role in protecting this virus will be true. That vaccinia virus can replicate in normal mice, so we will first compare the normal VV with the one carrying the extra gene, and see if those mice can protect themselves from the oxidative cell damage.

"Whether or not the gene would be useful in some type of gene therapy," Moss concluded, "and here I may be getting off on too big a limb — or whether it just provides protection to cells in which one may wish to express some other genes, remains to be determined." *

No Comments