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Saturday, November 01, 2014

A Virus Where It Shouldn't Be

Words like "bizarre" and "unexpected" hardly suffice when describing the results published this week in PNAS (one of the most respected journals in all of science) by Robert H. Yolken and 17 coworkers from Johns Hopkins, University of Nebraska, and Baltimore's Sheppard Pratt Health System, who wrote about finding a peculiar virus in the noses of a number of individuals. The virus they found (through DNA metagenome analysis) was something called ATCV-1, a large DNA virus normally associated with the freshwater alga Chlorella.

ATCV-1 virions attached to a Chlorella cell.
Just to bring you up-to-date quickly: The scientists in question stumbled onto the fact that DNA from the ATCV-1 virus appears to exist in the noses and throats of a surprising fraction (43%) of randomly chosen individuals. The study population of 92 people is not large, however, and we should not be too quick to jump to conclusions. Nevertheless, the mere finding of this virus's DNA in that many people's noses is shocking, because this is a virus that, until now, was thought to occur only in algae, not higher life forms (and certainly not in humans).

To understand how shocking this is, you have to realize that viruses are generally extremely highly adapted to specific hosts. A virus that attacks tobacco plants only attacks tobacco plants. A virus that infects bacteria only infects bacteria, and generally only a specific species of bacterium. Viruses coevolve very closely with their hosts, developing extremely intricate, fine-tuned adaptations to a specific organism. For a virus to cross species lines (let alone Kingdoms) is unusual, to say the least. And thank goodness! Otherwise, you might come down with pox from an insect bite, or get any number of deadly diseases from eating ordinary foods.

As it turns out, ATCV-1 (Acanthocystis turfacea Chlorella virus) has appeared in this blog once before, back in March, in a post I did called "A Virus, a Worm, and a Louse Walk into a Bar." The point of that post (ironically) was to show that while most virus genes tend to have a great deal of DNA homology with their host counterparts, the genes of certain algae viruses actually appear to have greater homology with genes in the human body louse. Which perhaps should have been a tipoff, of sorts, to the Yolken et al. findings. Certainly, it adds more color to the story, knowing (as we do) that phycodnavirus DNA may have have crossed species lines before. ("Phycodnavirus" is the name scientists have given to the family of large DNA viruses that infect algae.)

What do we know about ATCV-1? It's fairly large, as viruses go, with a genome of 288,047 base pairs, encompasssing as many as 860 genes. The fact that the genome has been fully sequenced doesn't mean we know how it works, though. In fact, we don't know what most of the 860 genes do. Some of the genes are (as in many king-size viruses) devoted to DNA-synthesis functions of a type commonly associated with nuclear-expressed genes in the host, meaning that the virus appears well adapted to take over the nucleus of a cell. This is not always the case; some viruses are adapted to thrive in the cytoplasm, away from the nucleus.

Intriguingly, the Yolken group conducted tests of cognitive function among enrollees in its study and found that there was a statistically significant reduction in cognitive ability (on the particular measures tested) in the group of people that tested positive for ATCV-1. To determine if this was just a fluke, researchers evaluated the effects of the virus on mice. As it happens, inoculated rodents showed deficits in recognition memory and attention while navigating mazes. In other words, exposure to the virus is associated with cognitive deficits in both humans and an animal model.

This is remarkable, since (if true) it would suggest that the virus traveled through the blood (of humans and mice), crossed the blood-brain barrier, gained entry to brain cells, and expressed its DNA inside brain cells (a type of cell the virus would presumably never encounter in its normal habitat of freshwater marshes and lakes). It all sounds (and is) very unlikely. But there you are: PNAS is one of the most esteemed science journals in the world. They published the result. It's as real as can be.

Of course, the work needs to be replicated and extended. And I'm sure it will be.

And I think what we'll find is that phycodnaviruses have been crossing species boundaries for some time. If you go back to my original blog about this, you'll see an example of a particular gene, encoding a ribonucleoside reductase, in another Chlorella virus (called PBCV-1), which shows greater homology to the ribonucleoside reductase of the human body louse than to the same gene in the virus's "normal" host, Chlorella. (The homology between PBCV-1 and louse reductases is 53%, versus 48% for virus and Chlorella. These are protein-sequence homology numbers.)

If we check the ATCV-1 reductase for homology with reductases in other organisms, we find that the highest scoring non-viral match (53%) occurs not with Chlorella (the virus's host), but with Lichtheimia corymbifera, a fungus found in soil and decaying plant matter. Interestingly, this fungus is known to cause pulmonary, CNS, and rhinocerebral infection in animals and humans. (But there is no known association whatsoever between ATCV-1 and the fungus.) One wonders whether the fungus has learned a few tricks from marine viruses; or perhaps vice versa?

If you're wondering how the people in the Yolken et al. study could have come in contact with ATCV-1, maybe the answer is as simple as taking a drink of water from a mountain stream, or drinking unfiltered water from a well, or swimming in a lake, or perhaps just walking in a marsh.

Suffice it to say, a good deal more remains to be learned regarding the ecology and life cycles of the phycodnaviruses, and cross-species infection/transfection generally. I feel certain the recent results of Yolken et al. will stimulate a great amount of much-needed followup research.

In the meantime, would you grab me a bottled water?

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