Jim Pipas and the Dangers of Mongrel Viruses

Posted on September 13, 2011 by

2


Borneo, Bali, Malawi, Pittsburgh. Dr Jim Pipas is a professor in the Department of Biological Sciences at Pitt, a singer, entertainer, and a bit of an adventurer.

[To be inserted here: photo of Jim that doesn’t make him ‘look like a convict.’ Thanks guys.]

Jim Pipas, Department of Biological Sciences, University of Pittsburgh

Right now, you are playing host to billions of viruses. If you’re unlucky, you might have the sniffles or some horrific intestinal disease, but more likely you don’t. Your viral guests are living quietly in your guts, on your mucus membranes, inside your cells and inside your genome. They live inside the countless bacteria and fungi that have colonized every nook and cranny of your body, as well as the plant cells you are digesting after eating that salad. Some of your viral guests may even be playing host to their own viruses.

And yet you are not the most complex viral landscape in the world. By one estimate, there are a few thousand kinds of viruses in a typical human, compared to a million kinds in a kilogram of seafloor. Jim Pipas has started taking stock of this dizzying viral diversity, sampling everywhere from Barcelona sewers to Phillipine bat caves, because he has a radical idea about one way that dangerous new viruses can arise. He thinks that all those millions of kinds of viruses are continually engaged in a haphazard game of gene mix-n-match, in which every so often, one hits the viral jackpot that lets them infect a new kind of host, wreaking havoc on that host’s defenses.

Simian Virus 40 (Wikimedia Commons)

Jim’s idea was born from his decades of studying how viruses manipulate hosts. Specifically, he studies how Simian Virus 40 (SV40) interacts with its host cells, inadvertently causing them to become cancerous. SV40 is a monkey virus that you might have heard of because millions of people were exposed to it from contaminated polio vaccines in the ’50s. I really wish the top Google hit for “SV40 polio vaccine” was this CDC site, rather than all the conspiracy theory sites. Despite the hysteria, it is unlikely to cause cancer in humans, although it does in rodents.

Scientists use this effect of SV40 to study the pathways that lead to cancer. Jim’s specialty is a veritable swiss-army-knife of a protein, called T-antigen, which SV40 uses to manipulate its host into replicating the virus genome. Recently, he has branched out to look for proteins in other viruses that are also used to manipulate hosts.  Actually ‘other viruses’ is an understatement; what I meant was all other viruses. Jim and his colleagues have searched all of the several thousand known virus genomes for clues as to which genes encode proteins that interact with host biology. They call these proteins ‘Host Interacting Proteins’ or HIPs, and the possession of certain host-specific HIPs is what allows a virus to infect its specific host.

But in the process of searching thousands of viral genomes for HIPs, they also kept finding evidence for the exchange of HIPs between completely unrelated viruses.

“Gene recombination across different virus families makes no sense, we don’t know how it happens,” he says. This phenomenon is nothing like the relatively orderly process of gene shuffling that gives the flu virus a new edge every year. This is more like genome butchery, with random bits of DNA from one virus being pasted into another’s genome. The strangest thing was that they saw evidence for this process even between viruses that cannot infect the same host cells. Contrary to what is normally assumed, Jim realized that in such gene exchange events, some of the DNA could come from an inactive virus.

“Only one virus has to be able to grow in the cell, the other one just has to be in the cell.”

This means that viruses that are dependent on completely different hosts could, in theory, be exchanging genes all the time, until one virus suddenly gains the ability to replicate in a new kind of host.

“Is this a mechanism for the emergence of new viruses? And where in nature does this mixing happen?” To answer these questions, Jim’s lab is preparing to take samples from all over the world, isolate all the viral DNA present, then sequence everything that comes out.

To help choose the environments that will most favor to the team’s ability to detect viral gene exchange, they used computational prediction based on features like biodiversity, species density, endemism and animal migration. For instance, one of the potential sites is Lake Chany in Siberia, an enormous shallow marsh that is a summer destination for migratory birds arriving from Africa and Asia. The area swarms with biting insects that feed on the summer visitors, as well as the local wildlife, all of which defecate into the waters of the lake. In contrast, another of their potential Siberian sites is much more biologically isolated; Lake Baikal is the largest freshwater lake in the world, but 40% of the species found there are found nowhere else. By choosing a variety of sites with different kinds of hosts, they hope to more easily spot gene exchange between very different kinds of viruses. Jim has spent several years visiting the sites, establishing collaborations with local scientists who can help collect and process the samples.

But even once the samples start arriving, the most challenging aspect will still be ahead of them: analyzing all the sequence data to find evidence for gene exchange. To test their sampling methods and start developing the computational tools for analysis, Jim and his lab have sequenced raw sewage from Ethiopia, Barcelona and Pittsburgh. So far they have identified 234 known viruses, which is almost 10% of all viruses ever detected previously. But they also found between 10,000 and 50,000 times as many kinds of unknown viruses. Most of them are viruses that infect bacteria, and 90% of the rest are plant viruses. Yes, that’s right, plant viruses. Apparently, animal stools contain enormous numbers of plant viruses from the diet. But because Jim thinks that gene exchange between different virus families doesn’t require infection, these plant viruses are fair game in their hunt for evidence of these events.

Eastern Barred Bandicoot, Australia. Wikimedia commons, http://www.noodlesnacks.com/

So what kind of evidence might they find? Maybe something like the virus that has been ravaging a cute, but endangered, Australian marsupial called the bandicoot. Efforts to protect the dwindling Bandicoot population have been hampered by the rapid spread of a disease that results in debilitating skin cancer-like masses. When scientists isolated the virus causing all the trouble they found a curious mongrel between a papillomavirus and a polyomavirus. Papillomaviruses are sometimes associated with particular cancers, like the human virus linked to cervical cancer. In contrast, polyomaviruses are mostly well-behaved house guests, only causing disease in hosts with compromised immune systems. The splicing of new combinations of genes in the bandicoot virus gave it the structure of a papillomavirus, but also bestowed it with a protein closely related to SV40’s T-antigen, the protein that causes cancer in SV40-infected mice.

To understand why such mixed-up viruses might be so dangerous, you first need to consider how viruses make their host sick. If you remember high school biology, you might be tempted to say it’s because viruses lyse the cells in which they reproduce. But in most cases the loss of these cells is insignificant; the real culprit behind the wooziness/snot/tingles/headaches/what-have-you is your own body’s response to invasion.

Viruses and hosts that have co-evolved have finely-tuned relationships, and in many cases a viral infection causes either mild symptoms (wooziness/snot/tingles etc) or no host response at all. In contrast, viruses that suddenly gain the ability to infect a new host are novice host manipulators. Until tuning-by-natural-selection has taken effect, such viruses might successfully infect the host, but with collateral damage: overstimulating the immune system, for example, or overstimulating cell division. In bandicoots infected with that mongrel virus, uncontrolled cell division eventually leads to tumors, debilitating pain, and sometimes death.

Very soon, Jim’s lab will start receiving their first samples from the Philippines and will begin the tough task of using gene sequences to piece together the evolutionary histories of countless unknown viruses. Whether or not Jim’s hypothesis about gene exchange survives this process, we will be gaining a fascinating glimpse into the viral landscape from which so many diseases emerge.

Advertisements
Posted in: In depth