Feeling Seasick?

Ocean Virus Found In Human Blood Samples

By Jen Schripsema

Alvin Smith's search for zoonotic marine illnesses, those that spread from animals to humans, began in 1972 while serving in the military. The Navy was using marine mammals in military operations; as a veterinarian, Smith was responsible for keeping the animals and controlling diseases that could be transmitted to their trainers. He found that one peculiarly flexible viral genus, Vesivirus, was causing a wide range of symptoms in a very wide range of animals, from shellfish to sea lions.

The unique adaptability of these viruses intrigued Smith, so his attention shifted from large mammals to small viruses. He is now a professor of veterinary medicine at Oregon State University in Corvallis and one of the world's foremost authorities on the Caliciviridae family of viruses, which includes Vesivirus and three other genera.

A few years ago, when Vesivirus infection caused blistering in two scientists, one working with marine Vesivirus in the lab and another with marine mammals in the field, Smith started to wonder how prevalent Vesivirus was in the general human population. Because infection does not cause a very specific set of symptoms, it was very likely being attributed to some other cause. "[If] you don't know it's there, and you don't know to test for it, then it simply doesn't exist," says Smith.

Smith's team of researchers from Oregon State University, the Center for Pediatric Research at Eastern Virginia Medical School in Norfolk, and AVI BioPharma of Portland, Oregon, tested over 700 blood samples from eight western states for antibodies to Vesivirus, which indicate a previous infection, and presence of the virus itself, which indicates an active infection. The results from this study, published in the online edition of the Journal of Medical Virology in March, suggest that we have not found Vesivirus simply because no one has looked before.

Blood samples were acquired from a laboratory processing blood donations intended for transfusion. Twelve percent of normal blood donations later used in transfusions had antibodies to Vesivirus. In donors with liver damage, as evidenced by a liver enzyme test, 21 percent had antibodies. Based on these preliminary data, researchers obtained blood samples from patients with clinical hepatitis, or inflammation of the liver. In these samples, 29 percent had antibodies. Finally, in people who developed hepatitis of an unknown cause after being transfused, 47 percent had antibodies to Vesivirus.

Subsequent testing to find evidence for an active Vesivirus infection by amplifying the viral genome also showed a correlation between the virus and liver damage. Only five percent of normal blood donors had evidence of Vesivirus in their blood; 11 percent of those with liver damage had the virus present. Although this study cannot prove conclusively that Vesivirus infection causes hepatitis in humans, "there is no reason to believe that it doesn't," says Smith.

Based on the study results, researchers estimate that approximately 1 in 10,000 blood donors may have an active Vesivirus infection causing sub-clinical hepatitis, which could be transmitted via transfusion and potentially cause clinical hepatitis for the blood recipient. Smith is currently working on strengthening the evidence of a link between Vesivirus and hepatitis so he can push for Vesivirus screening of the blood supply.

Despite increasing evidence showing that Vesivirus infection is common in a variety of land animals including cattle, horses, and now people, Vesiviruses are classified as marine viruses because they are exceedingly common in marine animals. Adult marine mammals will typically have antibodies to many strains of Vesivirus. Of the 40 known serotypes, or strains, of Vesivirus, all but one is known to have primary marine presence.

Oceans cover most of our planet, yet we know very little about the plants and animals in marine ecosystems and even less about their pathogens and how they might infect us. "This in fact is a paradigm shift. I know of no other virus that has a primary reservoir in the ocean that has been shown to be a human pathogen. It's a terribly under-examined source," says Smith. "Many of the diseases we see that are emerging probably aren't really emerging. What is emerging is our knowledge."

Vesivirus is one of four genera of viruses within the Caliciviridae family. Caliciviruses are known for their unusual ability to cause disease in widely unrelated animal species. For example, one Vesivirus serotype can infect fish, seals, shellfish, pigs, cattle, primates, and humans.

The ability of Caliciviruses to infect a broad range of species is an adaptive trait that has developed based on their replication mechanisms. Like a number of other viruses, their genetic information is coded with RNA, not DNA. RNA replication lacks the proofreading inherent in DNA replication, making Vesivirus very error-prone. Every virus replicated will have one to ten mistakes in the genetic code. Thus, the children from a single parent will virtually all be unique variants. This genetic looseness makes classification a little tricky.

Like all viruses, Caliciviruses can only reproduce inside a host cell. Vesivirus has the ability to infect a wide variety of tissue types, causing a wide range of symptoms. An infected cell can yield up to 10,000 viruses after only four to eight hours. The combination of genetic flexibility and large attack numbers creates a virus that can theoretically adapt to new host species.

"If you think about it, the ocean is a much easier place for a virus to get around anyway. When the viruses are shed, they're in basically a big bag of saline, so they can move around pretty freely and don't decay nearly as rapidly as they might on land," says Smith. The virus can become airborne by erupting in bubbles at the surface of the water, much like the spray that comes off a freshly poured glass of soda.

Environmental exposure may put people at some risk, but don't cancel your beach vacation just yet. It is always wise to keep a safe distance from animals that appear to be sick, but researchers believe the greater risk for exposure is probably contaminated meat, seafood, or drinking water. Smith advises against eating undercooked or raw seafood.

Biotech company, AVI BioPharma, is investigating the use of their proprietary NeuGene antisense compound as an anti-Vesiviral treatment, according to Patrick Iversen, co-author of the study and senior vice president of research and development at the company. This technology uses a synthetic compound that binds closely with the start codons of the RNA sequence, or points along the code that signal the virus to begin replication. "You set the antisense down straddling that so it's like blocking a zipper," says Smith.

NeuGene drugs developed using this technology successfully stopped an outbreak of fatal Calicivirus in cats. The company is developing several other drug candidates for treatment of other RNA viruses including hepatitis C, influenza, and West Nile virus. This technology may signal the beginning of the end of the "wait and see" approach to viral infection treatment.

Jen Schripsema earned a B.A. in biology from Colorado College. She is currently pursuing a Master's degree in technical communication at the University of Washington.

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Feline Calicivirus, a relative of Vesivirus, can infect all cat species. Photo: Erskine Palmer, CDC