Viruses Can Have Immune Systems: A Pirate Phage Commandeers the Immune System of Bacteria

Artist's concept of bacteriophage infecting bacteria. (Credit: iStockphoto)

A study published today in the journal Nature reports that a viral predator of the cholera bacteria has stolen the functional immune system of bacteria and is using it against its bacterial host.

The study provides the first evidence that this type of virus, the bacteriophage ("phage" for short), can acquire a wholly functional and adaptive immune system.

The phage used the stolen immune system to disable -- and thus overcome -- the cholera bacteria's defense system against phages.

Therefore, the phage can kill the cholera bacteria and multiply to produce more phage offspring, which can then kill more cholera bacteria.

The study has dramatic implications for phage therapy, which is the use of phages to treat bacterial diseases.

Developing phage therapy is particularly important because some bacteria, called superbugs, are resistant to most or all current antibiotics.

Until now, scientists thought phages existed only as primitive particles of DNA or RNA and therefore lacked the sophistication of an adaptive immune system, which is a system that can respond rapidly to a nearly infinite variety of new challenges.

Phages are viruses that prey exclusively on bacteria and each phage is parasitically mated to a specific type of bacteria.

This study focused on a phage that attacks Vibrio cholerae, the bacterium responsible for cholera epidemics in humans.

Howard Hughes Medical Institute investigator Andrew Camilli, Ph.D., of Tufts University School of Medicine led the research team responsible for the surprising discovery.

First author Kimberley D. Seed, Ph.D., a postdoctoral fellow in Camilli's lab, was analyzing DNA sequences of phages taken from stool samples from patients with cholera in Bangladesh when she identified genes for a functional immune system previously found only in some bacteria (and most Archaea, a separate domain of single-celled microorganisms).

To verify the findings, the researchers used phage lacking the adaptive immune system to infect a new strain of cholera bacteria that is naturally resistant to the phage.

The phage were unable to adapt to and kill the cholera strain. They next infected the same strain of cholera bacteria with phage harboring the immune system, and observed that the phage rapidly adapted and thus gained the ability to kill the cholera bacteria.

This work demonstrates that the immune system harboured by the phage is fully functional and adaptive.

"Virtually all bacteria can be infected by phages. About half of the world's known bacteria have this adaptive immune system, called CRISPR/Cas, which is used primarily to provide immunity against phages.

Although this immune system was commandeered by the phage, its origin remains unknown because the cholera bacterium itself currently lacks this system.

What is really remarkable is that the immune system is being used by the phage to adapt to and overcome the defense systems of the cholera bacteria.

Finding a CRISPR/Cas system in a phage shows that there is gene flow between the phage and bacteria even for something as large and complex as the genes for an adaptive immune system," said Seed.

"The study lends credence to the controversial idea that viruses are living creatures, and bolsters the possibility of using phage therapy to treat bacterial infections, especially those that are resistant to antibiotic treatment," said Camilli, professor of Molecular Biology & Microbiology at Tufts University School of Medicine and member of the Molecular Microbiology program faculty at the Sackler School of Graduate Biomedical Sciences at Tufts University.

Camilli's previous research established that phages are highly prevalent in stool samples from patients with cholera, implying that phage therapy is happening naturally and could be made more effective.

In addition, a study published by Camilli in 2008 determined that phage therapy works in a mouse model of cholera intestinal infection.

The team is currently working on a study to understand precisely how the phage immune system disables the defense systems of the cholera bacteria.

This new knowledge will be important for understanding whether the phage's immune system could overcome newly acquired or evolved phage defense systems of the cholera bacteria, and thus has implications for designing an effective and stable phage therapy to combat cholera.

Meet "Flame", The Massive Spy Malware Infiltrating Iranian Computers

A massive, highly sophisticated piece of malware has been newly found infecting systems in Iran and elsewhere and is believed to be part of a well-coordinated, ongoing, state-run cyberespionage operation.

The malware, discovered by Russia-based anti-virus firm Kaspersky Lab, is an espionage toolkit that has been infecting targeted systems in Iran, Lebanon, Syria, Sudan, the Israeli Occupied Territories and other countries in the Middle East and North Africa for at least two years.

Dubbed “Flame” by Kaspersky, the malicious code dwarfs Stuxnet in size – the groundbreaking infrastructure-sabotaging malware that is believed to have wreaked havoc on Iran’s nuclear program in 2009 and 2010.

Although Flame has both a different purpose and composition than Stuxnet, and appears to have been written by different programmers, its complexity, the geographic scope of its infections and its behavior indicate strongly that a nation-state is behind Flame, rather than common cyber-criminals — marking it as yet another tool in the growing arsenal of cyberweaponry.

The researchers say that Flame may be part of a parallel project created by contractors who were hired by the same nation-state team that was behind Stuxnet and its sister malware, DuQu.

“Stuxnet and Duqu belonged to a single chain of attacks, which raised cyberwar-related concerns worldwide,” said Eugene Kaspersky, CEO and co-founder of Kaspersky Lab, in a statement.

“The Flame malware looks to be another phase in this war, and it’s important to understand that such cyber weapons can easily be used against any country.”

Early analysis of Flame by the Lab indicates that it’s designed primarily to spy on the users of infected computers and steal data from them, including documents, recorded conversations and keystrokes. It also opens a backdoor to infected systems to allow the attackers to tweak the toolkit and add new functionality.

The malware, which is 20 megabytes when all of its modules are installed, contains multiple libraries, SQLite3 databases, various levels of encryption — some strong, some weak — and 20 plug-ins that can be swapped in and out to provide various functionality for the attackers.

It even contains some code that is written in the LUA programming language — an uncommon choice for malware.

Kaspersky Lab is calling it “one of the most complex threats ever discovered.”

“It’s pretty fantastic and incredible in complexity,” said Alexander Gostev, chief security expert at Kaspersky Lab.

Flame appears to have been operating in the wild as early as March 2010, though it remained undetected by antivirus companies.

“It’s a very big chunk of code. Because of that, it’s quite interesting that it stayed undetected for at least two years,” Gostev said. He noted that there are clues that the malware may actually date back to as early as 2007, around the same time-period when Stuxnet and DuQu are believed to have been created.

Gostev says that because of its size and complexity, complete analysis of the code may take years.

“It took us half-a-year to analyze Stuxnet,” he said. “This is 20-times more complicated. It will take us 10 years to fully understand everything.”

Kaspersky discovered the malware about two weeks ago after the United Nations’ International Telecommunications Union asked the Lab to look into reports in April that computers belonging to the Iranian Oil Ministry and the Iranian National Oil Company had been hit with malware that was stealing and deleting information from the systems.

The malware was named alternatively in news articles as “Wiper” and “Viper,” a discrepancy that may be due to a translation mixup.

Kaspersky researchers searched through their reporting archive, which contains suspicious filenames sent automatically from customer machines so the names can be checked against whitelists of known malware, and found an MD5 hash and filename that appeared to have been deployed only on machines in Iran and other Middle East countries.

As the researchers dug further, they found other components infecting machines in the region, which they pieced together as parts of Flame.

Kaspersky, however, is currently treating Flame as if it is not connected to Viper, and believes it is a separate infection entirely. The researchers dubbed the toolkit “Flame” after the name of a module inside it.

Read more here

Early Detection of Immune Changes Prevents Painful Shingles in Astronauts

VZV infected MeWo cells showing typical herpes-virus-induced multinucleated giant cells. 

Cultures are stained with acrydine orange to identify RNA (red) in the cytoplasm. (NASA).

The physiological, emotional and psychological stress associated with spaceflight can result in decreased immunity that reactivates the virus that causes shingles, a disease punctuated by painful skin lesions.

NASA has developed a technology that can detect immune changes early enough to begin treatment before painful lesions appear in astronauts and people here on Earth.

This early detection and treatment will reduce the duration of the disease and the incidence of long-term consequences.

Spaceflight alters some elements of the human immune system: innate immunity, an early line of defense against infectious agents, and specific components of cellular immunity are decreased in astronauts.

Astronauts do not experience increased incidence or severity of infectious disease during short-duration spaceflight, but NASA scientists are concerned about how the immune system will function over the long stays in space that may be required for exploration missions.

Selecting one or more biomarkers or indicators of immunity in healthy individuals is difficult, but the herpes viruses have become valuable tools in early detection of changes in the immune system, based largely on the astronaut studies.

Eight herpes viruses may reside in the human body, and virtually all of us are infected by one or more of these viruses.

Herpes viruses cause diseases including common "fever blisters" (herpes simplex virus or HSV), infectious mononucleosis (Epstein-Barr virus or EBV) and chicken pox and shingles (varicella zoster virus or VZV).

In immune-suppressed individuals, herpes viruses may cause several types of cancer, such as carcinoma, lymphoproliferative disease and others.

According to the Centers for Disease Control and Prevention, one million cases of shingles occur yearly in the U.S., and 100,000 to 200,000 of these cases develop into a particularly painful and sometimes debilitating condition known as post-herpetic neuralgia, which can last for months or years.

The other seven herpes viruses also exist in an inactive state in different body tissues much like VZV, and similarly they may also reactivate and cause disease during periods of decreased immunity.

The most common cause of decreasing immunity is age, but chronic stress also results in decreased immunity and increases risk of the secondary disease, such as VZV-driven shingles.

Chemotherapy, organ transplants and infectious diseases, such as human immunodeficiency virus or HIV, also result in decreased immunity.

Thus, viral reactivation has been identified as an important indicator of clinically relevant immune changes.

Studies of immune-compromised individuals indicate that these patients shed EBV in saliva at rates 90-fold higher than found in healthy individuals.

The herpes viruses are already present in astronauts, as they are in at least 95 percent of the general adult population worldwide.

So measuring the appearance of herpes viruses in astronaut body fluids serves as a much-needed immune biomarker.

It is widely believed that various stressors associated with spaceflight are responsible for the observed decreased immunity.

USB stick can sequence DNA in seconds

It may look like an ordinary USB memory stick, but a little gadget that can sequence DNA while plugged into your laptop could have far-reaching effects on medicine and genetic research.

The UK firm Oxford Nanopore built the device, called MinION, and claims it can sequence simple genomes – like those of some viruses and bacteria – in a matter of seconds.

More complex genomes would take longer, but MinION could also be useful for obtaining quick results in sequencing DNA from cells in a biopsy to look for cancer, for example, or to determine the genetic identity of bone fragments at an archaeological dig.

The company demonstrated today at the Advances in Genome Biology and Technology (AGBT) conference in Marco Island, Florida, that MinION has sequenced a simple virus called Phi X, which contains 5000 genetic base pairs.

Proof of principle
This is merely a proof of principle – "Phi X was the first DNA genome to be sequenced ever," says Nick Loman, a bioinformatician at the Pallen research group at the University of Birmingham, UK, and author of the blog Pathogens: Genes and Genomes.

But it shows for the first time that this technology works, he says. "If you can sequence this genome you should be able to sequence larger genomes."

Oxford Nanopore is also building a larger device, GridION, for lab use. Both GridION and MinION operate using the same technology: DNA is added to a solution containing enzymes that bind to the end of each strand.

When a current is applied across the solution these enzymes and DNA are drawn to hundreds of wells in a membrane at the bottom of the solution, each just 10 micrometres in diameter.

Within each well is a modified version of the protein alpha hemolysin (AHL), which has a hollow tube just 10 nanometres wide at its core.

As the DNA is drawn to the pore the enzyme attaches itself to the AHL and begins to unzip the DNA, threading one strand of the double helix through the pore.

The unique electrical characteristics of each base disrupt the current flowing through each pore, enough to determine which of the four bases is passing through it. Each disruption is read by the device, like a tickertape reader.

Major Breathrough in TB Research: Questions answered!

After three decades of searching, the random screening of a group of compounds against the bacterium that causes pulmonary tuberculosis has led scientists to a eureka discovery that breaks through the fortress that protects the bacterium and allows it to survive and persist against treatments.

The two findings, which occurred at Colorado State University, are published today in Nature Chemical Biology.

The article describes the discovery of an important cell function in the mycobacterium that causes tuberculosis which allows the mycobacterium to survive. The researchers also discovered a compound that prevents this cell function.

The bacterium that causes tuberculosis is extremely difficult to kill and current tuberculosis drugs on the market don’t do well to treat it. Six months of multiple antibiotics are generally required to treat tuberculosis in most people, and many current drugs no longer work because of resistant strains of the bacterium that causes tuberculosis. Scientists hope that finding new drugs to kill the bacteria in ways different than current drugs will help tackle those strains.

Cell envelopes form a virtually impenetrable bubble around the bacterium cell and protect it. Mycolic acids are key portions of this bacterium’s cell envelope. They are made inside the cell, but have to cross the cell membrane, with the help of a transporter, to reach their final location in the cell envelope.

“Without mycolic acids in the cell envelope, the bacteria die,” said Mary Jackson, one of the leading researchers on the project. Jackson is a professor in the Department of Microbiology, Immunology and Pathology.

“While randomly testing a group of compounds against the bacterium in the lab, we found one class of compounds that powerfully stops the growth of the bacterium, a significant finding on its own.

When we looked closer, we found that the compounds stopped a transporter from moving mycolic acids from inside to outside the cell, which also means this discovery identified a new method of killing the bacterium.

Scientists have been trying to find the transporter of mycolic acids for decades, knowing that understanding how to stop mycolic acids from reaching the surface of the cell could lead to new tuberculosis treatments.

“If mycolic acids cannot be transported, the tuberculosis bacterium cannot grow,” said Mike McNeil, co-researcher on the project with Jackson and also a professor in the Department of Microbiology, Immunology and Pathology at CSU.

“It is like a factory making bricks and no way to get them to the construction site. It is a long, hard road to develop new, badly-needed tuberculosis drugs. Still, we are optimistic that this research will strongly contribute to the worldwide crusade to diminish suffering and death caused by tuberculosis.”

Jackson, McNeil and partner researchers from CSU and St. Jude Children’s Hospital in Memphis also note that there are other potential transporters in the bacterium that resemble the one just found.

“We hope that our work also will pave the way to understanding what those transporters do in the cell and finding how to target them to kill the mycobacteria,” Jackson said.

Tuberculosis causes the death of more than 1.5 million people around the globe each year.

Drone mission control hit by self-cloning computer virus

How did a persistent computer virus come to haunt the pilots of the Predator drones attacking Al Qaeda targets in Afghanistan and Yemen?

No-one yet knows, and most likely we will never be told.

What we do know is that the top military technology of the age has proven vulnerable to a persistent keylogger, a virus that stores every keystroke made on a computer and which resists deletion.

It was found two weeks ago on the systems that ground pilots use to fly the Reaper and Predator drones at Creech Air Force Base in Nevada, and deleting the virus reportedly has no effect: it simply clones itself if deleted. "It keeps coming back," a Creech AFB operative complained to Wired.

It is most likely that the recent use of removable hard drives to update mission maps was the source of the malware, which appears to be hiding somewhere within the network at Creech. But since that network is not on the internet, the keylogged data should not be reaching any malefactor.

It is possible that top brass at the Pentagon, National Security Agency or the CIA are monitoring their own drone control staff using logging software - but given the mild panic its discovery has caused, that is unlikely.

Experts have also been warning for some time that counterfeit electronics could lead to such problems - and that will doubtless be investigated.

This episode shouldn't affect drone missions, however. They will still be as accurate or inaccurate as intelligence allows.

General Atomics, maker of the Predator, claims on its website that the aircraft has "a fault tolerant flight control system" that allows the plane to continue in safe flight even when contact with the remote control pilot is lost.

NPL Research: GeT-ting genes delivered

Confocal fluorescence micrograph of cells containing a gene delivered by GeT, encoding for the synthesis of green fluorescent protein.

NPL scientists have mimicked the ways viruses infect human cells and deliver their genetic material.

The research hopes to apply the approach to gene therapy – a therapeutic strategy to correct defective genes such as those that cause cancer.

Gene therapy is still in its infancy, with obvious challenges around targeting damaged cells and creating corrective genes. An equally important challenge is finding ways to transport the corrective genes into cells.

This is a problem, because of the poor permeability of cell membranes.

The research addresses this challenge by describing a model peptide sequence, dubbed GeT (gene transporter), which wraps around genes, transports them through cell membranes and helps their escape from intracellular degradation traps. The process mimics that which viruses use to infect human cells.

To prove the concept, the researchers used GeT to transfer a synthetic gene encoding for a green fluorescent protein that can be seen and monitored using fluorescence microscopy.

The design can serve as a potential template for non-viral gene delivery systems and future treatments of genetic disorders.

This research is part of the NPL-led international research project 'Multiscale measurements in biophysical systems', which is jointly funded by NPL and the Scottish Universities Physics Alliance.

Read the full article detailing this research published in Chemical Communications – the flagship journal of the Royal Society of Chemistry.

More on NPL’s work in Biotechnology

For more information please contact Max Ryadnov

Borna Virus: Hunting Fossil Viruses in Human DNA

The borna virus is at once, obscure and grotesque. It can infect mammals and birds, but scientists know little about its effects on its victims.

In some species it seems to be harmless, but it can drive horses into wild fits. The horses sometimes kill themselves by smashing in their skulls.

In other cases, they starve themselves to death. Some scientists have even claimed that borna viruses alter human behavior, playing a role in schizophrenia and bipolar disorder, although others say there is no solid evidence of a link.

The virus now turns out to have an intimate bond with every person on Earth. In the latest issue of Nature, a team of Japanese and American scientists report that the human genome contains borna virus genes. The virus infected our monkey-like ancestors 40 million years ago, and its genes have been passed down ever since.

Borna viruses are not the only viruses lurking in our genome. Scientists have found about 100,000 elements of human DNA that probably came from viruses. But the borna virus belongs to a kind of virus that has never been found in the human genome before. Its discovery raises the possibility that many more viruses are left to be found.

Scientists who hunt for these viruses think of themselves as paleontologists searching for fossils. Just as animals get buried in rock, these viruses become trapped in the genomes of their hosts. While their free-living relatives continue to evolve, fossil viruses are effectively frozen in time.

“We can really dig fossils out of the genome and literally put them back together,” said Cédric Feschotte, a genome biologist at the University of Texas, Arlington. “It’s like putting a hominid back together and asking it if it can walk upright.”

When scientists sequenced the human genome in 2001, they noticed many segments that bore a striking resemblance to genes in retroviruses, a class of viruses that includes H.I.V.

Retroviruses carry their genetic material in a single-stranded version of DNA, called RNA. To make new viruses, they make DNA versions of their genes, which are inserted into a host cell’s genome. The cell then reads the retrovirus’s genes as if they were its own, and manufactures new retroviruses.

Scientists speculated that every now and then a retrovirus inserted itself into a host cell and then failed to turn it into a virus factory. If the trapped retrovirus happened to be in sperm or egg cells, its DNA might be passed down to the host’s descendants. From generation to generation, the virus’s DNA would mutate. It would lose its ability to produce normal viruses. For a while it might be able to make new viruses that could re-infect the same cell, but over enough time, the viruses would become disabled.

In recent years, scientists have found several lines of evidence to support this idea. . Koala retroviruses, for example, appear to be in the middle of the journey. The viruses can move from one koala to another. But in some populations of koalas, the virus’s DNA is permanently lodged in their genomes.

Thierry Heidmann of the Gustave Roussy Institute in France and his colleagues put the fossil virus hypothesis to a spectacular test: they tried to resurrect a dead retrovirus. They first identified a number of copies of the same virus-like stretch of DNA in the human genome. Each version had its own set of mutations that it acquired after the virus had invaded our ancestors.

By comparing the copies, Dr. Heidmann and his colleagues were able to figure out what the original sequence of the virus’s genes had been. When they synthesized the genes from scratch and injected the genetic material into cells, the cells produced new viruses.

“It was a tour-de-force of an experiment,” said John Coffin, an expert on fossil viruses at Tufts University.

Click here to read the full article

Deadly Bullet-shaped rhabdoviruses

Gallery - Picture of the day - Image 1 - New Scientist

Some viruses are our friends, some are our deadly enemies. The bullet-shaped rhabdoviruses are both. On one plus side, there's vesicular stomatitis virus (VSV), the core of several promising new vaccines. Then there's rabies, among the deadliest viruses known.

It has never before been clear how these viruses' three structural proteins and RNA genome come together to form their bullet shape.

Now, using ultra-fine electron microscopy, Z. Hong Zhou at the University of California, Los Angeles, and colleagues have shown that the RNA and proteins wind together in a precise order, starting at the top of the bullet, to form two nested helices. Such structural insights may one day help us fight VSV's less benign cousins (Science, vol 327, p 689, DOI: 10.1126/science.1181766).

(Image: Z. Hong Zhou/Science)

Viruses use 'Hive Intelligence' to spread Infection

A tactic familiar from insect behaviour seems to give viruses the edge in the eternal battle between them and their host – and the remarkable proof can be seen in a video.

The video catches viruses only a few hundred nanometres in size in the act of hopping over cells that are already infected. This allows them to concentrate their energies on previously uninfected cells, accelerating the spread of infection fivefold.

Geoffrey Smith and his team of virologists at Imperial College London were curious about the vaccinia virus, and set up a video microscope to watch how the virus spreads through cells.

Vaccinia and Smallpox
Vaccinia was used in the vaccine that rid the world of smallpox some 35 years ago. It doesn't cause disease in humans or any other animal, and its origin is unknown.

Spreading Infection
The traditional idea of how viruses spread goes like this. A virus first enters a cell and hijacks its machinery to make its own viral proteins and replicate. Thousands of replicated viruses then spread to neighbouring cells to wreak havoc.

When Smith watched the vaccinia virus infecting monkey liver cells, he thought that it was spreading far too quickly. "It takes 5 to 6 hours for the virus to replicate, but it was spreading from cell to cell within 1 or 2 hours," he says.

Spread of Vaccinia
Vaccinia is known to spread from cell to cell in a characteristic way. After attaching to the cell membrane of its target, it releases a protein that enters the cell, where it communicates with actin – a protein that helps maintain the cell's structure.

The actin responds by growing longer, and then attaches itself to the virus, still sitting on the surface of the cell, as a so-called "actin tail". This tail helps the virus take off from the cell and find the next victim.

Marking the Virus
Smith's team labelled the virus with green fluorescent protein, and labelled some – but not all – cells with a red marker that tagged the actin. They found, to their amazement, that a virus leaving a cell would travel to another cell and merely bounce off it if it already contained the virus.

Virus Changes
The researchers could tell that a single virus had travelled over more than one cell because some viruses which left a cell with an uncoloured actin tail picked up a red actin tail from another cell. "This means that the viruses can change their actin tails as they bounce along the surfaces of cells," says Smith. "This allows the virus to reach distant cells really quickly."

Smith reckons that two viral proteins which are presented on the surface of the infected cell effectively tell the virus not to bother reinfecting that cell. When he looked at virus strains lacking each of these proteins, the virus spread at the slower rate that would expected without the "bouncing infection" mechanism.

"It's as if the proteins are telling the virus: 'Hey guys, there's no point in coming in here'," says Smith. "If you think about it, it makes sense – it's very Darwinian."

The Full article is available here .........

Natural human protein could prevent H1N1: study

Natural human protein could prevent H1N1: study

A strain of natural human proteins have been found to help ward off swine flu and other viruses including West Nile and dengue, in a discovery that could spur more effective treatments, US researchers said Thursday.

In cultured human cells, researchers lead by the Howard Hughes Medical Institute (HHMI) found that these certain proteins have powerful antiviral effects by blocking the replication of viruses.

The findings, reported Thursday in an online article from the journal Cell, "could lead to the development of more effective antiviral drugs, including prophylactic drugs that could be used to slow influenza transmission," the team said.

The influenza virus, along with the other viruses, must take over proteins in cells to sustain itself. In their study, researchers found some 120 genes that are needed by H1N1 -- commonly known as swine flu.

"But in the process of figuring that out, we found this other class of genes that actually have the opposite effect, so that if you get rid of them, influenza replicates much better," according to HHMI team leader Stephen Elledge at the Harvard Medical School.