mBiosphere

One at a time, please! One herpes virus per compartment in infected cells

Herpes viruses are very effective at deploying a host's cellular machinery to do their bidding. Once they infect a cell (human OR animal - I just learned pigs, cows, horses, cats, ducks, and other creatures all have their own herpes strains), herpes viruses use the cell's resources to create replication compartments - distinct nuclear foci for making copies of their genomes - to prepare for repackaging as new viruses. And even if a cell is bombarded with many different herpes viruses, only a limited number of those viruses are expressed once the cell is blown up to release the new viruses. Many types can go in, but only a few types come out. Why?

In their paper in mBio this week, Kobiler et al. explain that it's because replication compartments are like little private rooms: each one only contains one kind of viral genome. Using mixtures of isogenic pseudorabies viruses that express three different fluorescent proteins, the authors determined that each replication compartment probably initiates from a single incoming viral genome. Only a few types of viruses come out of a lysed cell because only a few viruses create replication compartments.

New discovery: how the body fights dengue fever

We don’t hear a whole lot about dengue fever here in the U.S., but it is a really big problem: worldwide, dengue fever strikes roughly 50 million people every year and takes the lives of thousands, but there are currently no specific treatments and no vaccine to prevent infection with the dengue virus. A study published in mBio this week describes a new discovery about how the body fights the dengue virus, a finding that could explain differences in the ability to fight off the virus and help in developing a drug to boost this response.

Avirutnan et al. report that a part of the immune system called mannose-binding lectin (MBL) is involved in targeting dengue viruses for destruction. MBL recognizes sugar molecules present on the outsides of many different kinds of viruses and bacteria. When it finds these sugars, MBL can activate the complement system, which targets foreign materials in the body for destruction in any of a number of cruel ways. Scientists have suspected that the complement system may play a role in causing dengue disease, but until now no one knew that it may also be involved in getting rid of the virus and contributing to protection against this infection.

“Before, people thought the complement system was involved primarily in dengue pathogenesis,” says Sujan Shresta, an Associate Professor at the La Jolla Institute for Allergy and Immunology, who reviewed the paper and was not involved in the work. “This paper is the first to look at the role of the complement system in the context of protection” from the dengue virus, says Shresta.

This is an important discovery in terms of human health, says Shresta, because different people naturally make different amounts of MBL. Some people have high levels of MBL, some people have low levels, a fact that may help explain why some individuals are able to fight off the virus while others are not. Individuals with low MBL levels or low MBL activity are more susceptible to variety of other infectious diseases than individuals with high MBL levels or activity.

The authors showed that blood samples with high levels of MBL neutralized dengue more efficiently than samples with lower levels of MBL. This finding suggests that people with high MBL levels in their blood could well be better at fighting dengue infection.

Shresta says this is a clue that could help create therapies for the disease. “You could develop antivirals that work through a similar mechanism,” to deactivate dengue viruses, says Shresta. Vaccines could also be designed to activate this pathway, she says, helping boost the normal functions of the immune system to fight off infection.

Needs-Based Assistance for Outer Membrane Proteins

How do outer membrane proteins (OMPs) make it from the interior of the cell, through the periplasm, and into the outer membrane? In Pseudomonas aeruginosa, Bam and Lol proteins are big helpers that get some, but not all, OMPs where they need to go. The authors of a study in mBio explain this spotty service may be due to individual differences in the membrane proteins. In short, some folks need the help more than others.

By depleting cells of certain components of either targeting pathway, Bam or Lol, Hoang et al. demonstrated which targeting pathway works for which OMP. Hits to the Bam pathway affected the ability of a membrane protein with a β-barrel structure to get to the outer membrane (including OprF, pictured at left - click on the image to view animation**). Knocking down the Lol pathway, on the other hand, affected the movement of all lipoproteins to the outer membrane. But neither pathway seemed necessary to get the protein XcpQ to the outer membrane.

The results indicate that intrinsic properties of OMPs determine which localization factors OMPs rely on and how much help they need, say the authors. Proteins with strong β-barrel structural features all seem to rely on some form of the OM translocation system, but non- β-barrel proteins may be targeted into the OM by an alternative machinery. The authors think the transit through the periplasm is critical: structural features of OMPs determine their tendency to misfold during periplasmic transit, and thereby influence the extent to which those proteins rely on the Bam machinery to help them through. β-barrel proteins could be more prone to misfolding during periplasmic transit and insertion into the outer membrane, and are thus more reliant on Bam machinery.

(**Thanks to R.E.W. Hancock Laboratory at the University of British Columbia and to Fiona Brinkmann, who created the animation.)

mBio Study: New compound to control Listeria

Cantaloupe contaminated with the bacterium Listeria monocytogenes killed 29 people in the U.S. this year in the deadliest foodborne outbreak since 1924, but the pathogen usually strikes in less public ways, quietly sickening an average of 1,600 people per year, according to the CDC. The authors of a study in mBio this week screened 57,000 small molecules to find one compound that can stop Listeria in its tracks. This needle-in-the-haystack approach has turned up a compound that could lead to novel therapeutics for listeriosis and other infections.

Palmer et al. targeted an Achilles tendon for many Gram positive bacteria, the stress responsive alternative sigma factor “σB”, since it poses a small target that, when struck, could bring down the entire pathogen. In Listeria, the σB gene controls the transcription of more than 150 other genes, many of which contribute to virulence and survival inside the human host. After screening tens of thousands of different small molecules, both synthetic and natural, for their activity against σB, the authors settled on fluoro-phenyl-styrene-sulfonamide (FPSS), a compound that specifically inhibits activity of σB and doesn’t pack any nasty side effects for mammalian cells. This shuts down many of Listeria’s virulence factors and inhibits invasion of the intestinal lining. As a bonus, FPSS could well prove effective against other pathogens that rely on σB, including Staphylococcus aureus (the cause of a wide range of maladies, from pimples to pneumonia) and Bacillus anthracis (the delightful bacterium that brought you Anthrax).

The authors point out that FPSS could serve not only as a therapeutic, but also as a tool for studying the regulatory networks that enable Listeria and other Gram-positive pathogens to invade and take advantage of the human host. An ongoing problem that has come to the public’s attention only when hundreds were sickened in the outbreak earlier this year, perhaps listeriosis is overdue for this exploration and for some new antibiotic therapy options.