Fighting Zika Virus with Mosquito Genetics

 

By  John McLaughlin

 

The Zika virus burst into the news last year when a dramatic increase in microcephaly cases was reported throughout several states in Brazil. This frightening birth defect quickly became associated with the mosquito-borne virus, carried by Aedes mosquitos; Aedes aegypti, which also carries Dengue, is the main vector in the current Zika outbreak. While Zika virus usually affects adults with fairly mild symptoms such as fever, rash, and joint pain, it can have severe or fatal consequences for the fetuses being carried by infected females. In fact, The World Health Organization (WHO) has recently reported a scientific consensus on the theory that Zika is the cause of the large number of Brazilian microcephaly cases.

 

In January of 2016, a Hawaiian baby born with microcephaly became the first case of Zika reported in the United States. And the U.S. National Institute of Allergy and Infectious Diseases has recently stated that a wider outbreak of the virus within the United States will likely occur soon. Naturally, mosquito containment has become a top priority for health officials in both infected areas and those likely to be impacted by the virus. The standard list of mosquito control protocols includes pesticide repellents, mosquito nets, eliminating stagnant open water sources, and long-sleeved clothing to limit skin exposure. In addition to these, health authorities are considering a number of new strategies based on genetic engineering technologies.

 

One such technique employs the concept of gene drive, the fact that some “selfish” gene alleles can segregate into gametes at frequencies higher than the expected Mendelian ratios. In this scenario, gene drive can be exploited to spread a disease resistance gene quickly throughout a population of mosquitoes. Recently, a team at the University of California tested this idea by using CRISPR technology to engineer the mosquito Anopheles stephensi with a malarial resistance gene drive. After integration of the resistance gene cassette and DNA targeting with CRISPR, this gene was successfully copied onto the homologous chromosome with high efficiency, thus ensuring that close to 100% of its offspring will bear resistance. Possibly, similar techniques could be exploited to engineer Zika resistance in Aedes mosquitoes.

 

In contrast to engineering disease resistance, an alternative defense strategy is to simply reduce the population of a specific mosquito species, in the case of a Zika outbreak, Aedes aegypti. The WHO has recently approved a GM mosquito which, after breeding, produces offspring that die before reaching adulthood. This technique can dramatically reduce an insect population when applied in strategic locations. The British biotech firm Oxitech has also developed its own strain of sterile Aedes aegypti males. In laboratory testing, these GM mosquitoes compete effectively with wild males for female breeding partners. The short-term goal is receiving approval to test these sterile males in the wild; ultimately, a targeted release of these mosquitoes will reduce the Aedes aegypti population in Zika hot spots without affecting other species.

 

In parallel to mosquito engineering, other work has focused on studying the mechanisms underlying Zika’s dramatic affects on the brain. To study the process of Zika infection in vitro, scientists at Johns Hopkins cultured 3-D printed brain organoids and demonstrated that the virus preferentially infects neural stem cells, resulting in reduced cortical thickness owing to the loss of differentiated neurons. This neural cell death may explain the frequent microcephaly observed in fetuses carried by infected mothers.

 

Much like the recent outbreak of Ebola in several African countries, this event helps underscores the importance of basic research. A recent New York Times article drew attention to this fact by highlighting the need for more complete genome sequences of the mosquito species that carry Zika. With a complete genome sequence at hand, researchers might be able to piece together information in answering questions such as: why are some Aedes mosquitoes vectors for Zika and others aren’t? Species differences in genome sequence may provide some answers. Nevertheless, greater knowledge of the mosquito’s biology will yield more options for human intervention. This is an excellent case study in how ‘basic’ and ‘translational’ research projects can co-evolve in special situations.

 


Genome

How Low Can You Go? Designing a Minimal Genome

By Elizabeth Ohneck, PhD

How many genes are necessary for life? We humans have 19,000 – 20,000 genes, while the water flea Daphnia pulex has over 30,000 and the microbe Mycoplasma genitalium has only 525. But how many of these genes are absolutely required for life? Is there a minimum number of genes needed for a cell to survive independently? What are the functions of these essential genes? Researchers from the J. Craig Venter Institute and Synthetic Genomics, Inc., set out to explore these questions by designing the smallest cellular genome that can maintain an independently replicating cell. Their findings were published in the March 25th version of Science.

The researchers started with a modified version of the Mycoplasma mycoides genome, which contains over 900 genes. Mycoplasmas are simplest cells capable of autonomous growth, and their small genome size provides a good starting point for building minimal cells. To identify genes unnecessary for cell growth, the team used Tn5 transposon mutagenesis, in which a piece of mobile DNA is introduced to the cells and randomly “jumps” into the bacterial chromosome, thereby disrupting gene function. If many cells were found to have the transposon inserted into the same gene at any position in the gene sequence, and these cells were able to grow normally, the gene was considered non-essential, since its function was not required for growth; such genes were candidates for deletion in a minimal genome. In some genes, the transposon was only found to insert at the ends of the genes, and cells with these insertions grew slowly; such genes were considered quasi-essential, since they were needed for robust growth but were not necessary for cell survival. Genes which were never found to contain the transposon in any cells were considered essential, since cells that had transposon insertions in these genes did not survive; these essential genes were required in the minimal genome.

The researchers then constructed genomes with various combinations of non-essential and quasi-essential gene deletions using in vitro DNA synthesis and yeast cells. The synthetic chromosomes were transplanted into Mycoplasma capricolum, replacing its normal chromosome with the minimized genome. If the M. capricolum survived and grew in culture, the genome was considered viable. Some viable genomes, however, caused the cells to grow too slowly to be practical for further experiments. The team therefore had to find a compromise between small genome size and workable growth rate.

The final bacterial strain containing the optimized minimal genome, JCVI-syn3.0, had 473 genes, a genome smaller than any autonomously replicating cell found in nature. Its doubling time was 3 hours, which, while slower than the 1 hour doubling time of the M. mycoides parent strain, was not prohibitive of further experiments.

What genes were indispensable for an independently replicating cell? The 473 genes in the minimal genome could be categorized into 5 functional groups: cytosolic metabolism (17%), cell membrane structure and function (18%), preservation of genomic information (7%), expression of genomic information (41%), and unassigned or unknown function (17%). Because the cells were grown in rich medium, with almost all necessary nutrients provided, many metabolic genes were dispensable, aside from those necessary to effectively use the provided nutrients (cytosolic metabolism) or transport nutrients into the cell (cell membrane function). In contrast, a large proportion of genes involved in reading, expressing, replicating, and repairing DNA were maintained (after all, the presence of genes is of little use if there is no way to accurately read and maintain them). As the cell membrane is critical for a defined, intact cell, it’s unsurprising that the minimal genome also required many genes for cell membrane structure.

Of the 79 genes that could not be assigned to a functional category, 19 were essential and 36 were quasi-essential (necessary for rapid growth). Thirteen of the essential genes had completely unknown functions. Some were similar to genes of unknown function in other bacteria or even eukaryotes, suggesting these genes may encode proteins of novel but universal function. Those essential genes that were not similar to genes in any other organisms might encode novel, unique proteins or unusual sequences of genes with known function. Studying and identifying these genes could provide important insight into the core molecular functions of life.

One of the major advancements resulting from this study was the optimization of a semi-automated method for rapidly generating large, error-free DNA constructs. The technique used to generate the genome of JCVI-syn3.0 allows any small genome to be designed and built in yeast and then tested for viability under standard laboratory conditions in a process that takes about 3 weeks. This technique could be used in research to study the function of single genes or gene sets in a well-defined background. Additionally, genomes could be built to include pathways for the production of drugs or chemicals, or to enable cells to carry out industrially or environmentally important processes. The small, well-defined genome of a minimal cell that can be easily grown in laboratory culture would allow accurate modeling of the consequences of adding genes to the genome and lead to greater efficiency in the development of bacteria useful for research and industry.


plastic duck

A Newly Discovered Bacterium Finds Plastic Fantastic

 

By Elizabeth Ohneck, PhD

We produce over 300 million tons of plastic each year. One of the most abundant forms of plastic is polyethylene terephthalate, or PET, a polyester frequently used in fabrics and the primary component of plastic beverage bottles and other types of food packaging. In 2013, approximately 56 million tons of PET were produced worldwide, but only about 2.2 million tons were recycled. The high demand for PET drives increased production of its monomers, terephthalic acid and ethylene glycol, both of which are industrially derived from petroleum, leading to high consumption of oil. The ubiquitous presence of PET and its resistance to biodegradation – it takes 5 to 10 years to naturally degrade – has led to a massive accumulation of PET in the environment, leaving us searching for ways to clean up the mess.

Nature may have just offered us a helping hand. Researchers from Japan have identified a bacterial species, which they’ve named Ideonella sakaiensis 201-F6, capable of breaking down PET to use as a food source. Their findings were published this month in Science.

The research team collected 250 environmental samples from soil, wastewater, sediment and sludge outside a PET bottle recycling plant and cultured the samples with PET films. One sample contained a bacterium that, when isolated, was able to grow with PET as the sole carbon source and to completely degrade the PET film in 6 weeks at 30°C (86°F). Genome sequencing of Ideonella sakaiensis 201-F6 identified two enzymes, subsequently called PETase and MHETase, with weak homology to enzymes from fungi previously shown to have PET-degradation activity. Purified PETase and MHETase were able to break down PET films to produce terephthalic acid and ethylene glycol. Interestingly, PET has only been produced since the 1940s, meaning the evolutionary window for such a drastic metabolic adaptation is relatively short, particularly since PETase and MHETase bear little resemblance to even the most closely related enzymes known in other species. When and how PETase and MHETase arose thus remain a mystery.

These findings have several important implications. Ideonella sakaiensis 201-F6 is not only able to degrade PET, but can subsequently metabolize the resulting terephthalic acid and ethylene glycol, which, while far more environmentally friendly than PET, are toxic at high levels. By using terephthalic acid and ethylene glycol as a food source, Ideonella sakaiensis 201-F6 is able to remove PET and its breakdown products from the environment. An exciting application would be isolation of the terephthalic acid and ethylene glycol to use in the production of new plastic. Recovering and reusing the PET monomers would drastically reduce the amount of oil needed to produce plastic, and allow true recycling of PET into fresh plastic suitable for packaging, rather than the current recycling tactic of melting and reforming PET plastic into other products.

Obviously, more research remains to be done before Ideonella sakaiensis 201-F6 or its PET-degrading enzymes are useful on a large scale. Reducing the time of PET degradation from decades to weeks could be beneficial in contaminated ecosystems, but adaptations to further speed the process are necessary for practical use at the industrial level. Additionally, the ability of Ideonella sakaiensis 201-F6 to survive in varying habitats and disruptions it might cause to specific ecosystems need to be carefully considered before releasing this bacterium or an adapted version into other environments for PET cleanup.

Nevertheless, the discovery of a bacterium that can degrade PET is promising for our efforts to combat the havoc our plastic-dependent lifestyle is creating in the environment. The PET-metabolizing power of Ideonella sakaiensis 201-F6 is a testament to the adaptability and resiliency of nature. Hopefully this discovery sparks new ideas and research into healthier and more efficient means of plastic production and recycling.


How Can You Make Money and Help Others with Your Shit?

And other very important poop updates.

 

By Jesica Levingston Mac leod, PhD

First, you have to be a healthy pooper… Second, you have to live in the Boston area. Your stool can help a person suffering from recurrent C. difficile infections, which is a bacterium that affects 500,000 Americans every year.  Where antibiotic treatment has failed to help, a new treatment called “fecal microbiota transplantation” has shown a cure rate of 90%.  In this procedure, a fecal microbiota preparation using stool from a healthy donor is transplanted into the colon of the patient.  OpenBiome, the startup company based in Boston, helps facilitate this procedure by screening and processing fecal microbiota preparations for use in this treatment. After joining the registration you and your stool will be screened and if you are healthy and a good candidate you will became a donor. If you can succeed with all the tests and you can provide “supplies” quite often then you can exchange money for you poo.

Lately, the study of the human microbiota has been all over the news, specially related with weight control, pregnancy and the infant’s diet. In fact, it's estimated that the human gut contains 100 trillion bacteria, or 10 times as many bacteria as cells in the human body. Yes, I know what you are thinking: “More of them that my own cells, that cannot be right, right?”

These bacteria, or microbiota, influence your health in many ways, from helping to extract energy from food to building the body's immune system, to protecting against infection with harmful, disease-causing bacteria.

Researchers are only just beginning to understand how differences in the composition of gut bacteria may influence human health. From what we know so far, here are five ways gut flora can affect your wellness:

 

Weight Changes

Yes, your gut bacteria affect your eating disorders (or orders if you are lucky). For example the diversity of gut bacteria is higher in lean people compared to obese people. Also, some specific bacteria groups, the Firmicutes and the Bacteroidetes, are linked with obesity. The famous study were they transplanted gut bacteria from obese and lean people to mice, making the host of the first kind of poo gain more weigh that the mice who received the “lean fecal bacteria”, was a shocking confirmation of the importance of the gut bacteria in the body weight regulation. They discovered that the gut bacteria from obese people increase the production of some amino acids, while the material from lean people increases the metabolism of “burning” carbohydrates.

 

Preterm Labor

Realman and col. found that pregnant women with lower levels of bacteria Lactobacillus in their vagina had an increased risk of preterm labor, compared with women whose vaginal bacterial communities were rich in Lactobacillus. Apparently, the absence of Lactobacillus allows the grown of other species that would have different effects in the pregnancy.

 

Crying Babies

In a funny study on how diet may affect babies, Pertty and col. showed that giving probiotics to your baby does not change the daily crying time, around 173 minutes, compare to the placebo group (174 min), according to the parental diary. They enrolled 30 infants with colic during the first 6 weeks of life.  However, parents reported a decrease of 68% in daily crying in the probiotic and 49% in the placebo group.

 

Heart Attacks

Gut Bacteria produce compounds can even affect your heart. One of these compounds is the trimethylamine-N-oxide (TMAO), and the presence of it in the blood of the subjects of a recent research study, increased 2.5 times the probability of having a heart attack, stroke or to die over a three-year period compared with people with low levels of TMAO. They have also shown that the metabolism of the gut bacteria changes according of the host’s (your) diet. For example, the consumption of high cholesterol and fatty food can increase the bacterial production of TMAO.

 

The Immune System

A recent review published in Cell rang the alarm about the negative effect of the “rich countries” diet in the microbiota influencing the immune system. In ideal and normal conditions the immune system-microbiota association allows the induction of protective responses to pathogens and the maintenance of regulatory pathways involved in the maintenance of tolerance to innocuous antigens. In rich countries, overuse of antibiotics, changes in diet, and elimination of constitutive partners, such as nematodes, may have selected for a microbiota that lack the resilience and diversity required to establish balanced immune responses. This phenomenon is proposed to account for some of the dramatic rise in autoimmune and inflammatory disorders in parts of the world where our symbiotic relationship with the microbiota has been the most affected.

 

Lungs and Asthma

The gut bacteria can affect your lungs: The low levels of 4 gut bacteria strains (FaecalibacteriumLachnospiraVeillonella, and Rothia) in kids was been recently related to an increase in the risk for developing debilitating asthma. The introduction of these 4 bacteria in mice induced to suffered asthma shown protection as the mice’s lungs did not present inflammation.

The question is: how bacteria IN the guts can affect your other tissues and organs? One study that was just published shows  that these bacteria produce chemicals that may help the immune system to battle against other germs. Without this training, the immune system could fail and create inflammation in the lungs. As a follow up from the latest research it may be possible in the near future to predict asthma, and other diseases, as well as cure some illnesses with gut bacteria.

Be ready to give a shit about your shit.


Germs on the subway

Buggy Transportation

All the bugs in the metro, tube, subway, from NYC to Asia

By Jesica Levingston Mac leod, PhD

The New York City (NYC) subway is use for more than 5 million passengers per day. Passengers being humans, pets, bacteria, parasites, viruses and other unknown creatures. Consequently infectious diseases, like influenza can be easily transmitted in this transportation method. Other dangerous circumstances are the black carbon and particle matter concentrations, which In Manhattan are considerably higher than in the urban street level. If you have just ridden the subway, I recommend that you check you washed your hands before continue reading…because, literately, this article is about shit!

Last Month a great research team from Cornell published the studies on microorganisms from 466 subway stations where they found 76 known pathogens (aka “bad” bacteria), and, more interestingly, they found a lot of unknown organisms. This means that almost half of all DNA present on the subway’s surfaces matches no known organism. As they could identified some of the microorganisms, they described that these bacteria were originated in some metropolitan citizen food, pet, workplace… you can actually check which kind of bacteria was found in your favorite/closest subway station... just to be sure what to tell to your doctor next time that you have some infection….

During a year and a half, Dr. Mason, the leader of the group, took samples from materials like the metal handrails in order to collect DNA for the big data genetic metropolitan profile project, aka the Pathomap project. From the 15,152 types of life-forms, almost half of the DNA belonged to bacteria—most of them harmless; However, the scientists said the levels of bacteria they detected pose no public-health problem. The most prevalent bacterial species was Pseudomonas stutzeri, with enrichment in lower Manhattan (aka finance species ;)), followed by strains from Enterobacter and Stenotrophomonas. Notably, all of the most consistently abundant viruses (only 0.03%) were bacteriophages, which were detected concomitant with their bacterial hosts.

Other study done in 2013 in Norway, found that the airborne bacterial levels showed rapid temporal variation (up to 270-fold) on some occasions, both consistent and inconsistent with the diurnal profile. Airborne bacterium-containing particles were distributed between different sizes for particles of >1.1 μm, although ∼50% were between 1.1 and 3.3 μm. Anthropogenic activities (mainly human passengers) were the major sources of airborne bacteria and predominantly contributed 1.1- to 3.3-μm bacterium-containing particles. The peaks are at 8 am and 5 pm, following the rush hours.

Other great discovery was that the human allele frequencies in the subway mirrored US Census data. Within the neighborhoods they found African American and Yoruban alleles correlation for a mostly black area in Brooklyn, Hispanic/Amerindian alleles in the Bronx and they observed that Midtown Manhattan showed an increase in British, Tuscan, and European alleles.

In this globalized world, you won't be surprised that in the London's Tube a group of journalist and researchers found more than 3 million bacteria. These data suggested that the average train or bus seat could have more than 70 types of bacteria, plus cold and flu viruses. The North-South Victoria line was the only one that passed the hygiene test.

In a study at the Hong Kong subways system, researchers analyzed aerosol samples in order to find the taxonomic diversity of the "under" microbes. Each bacterial community within a line was dependent on architectural characteristics, nearby outdoor micro biomes, and distance to other lines, and were influenced by temperature and relative humidity.

Altogether these results sound really scary, but I hope that the reader won’t react panicking, but just being aware of the bad pathogens around him/her and carry a hand sanitizer/mask/cleaning aerosol/wipes or just wash your hands with soap! Actually, health officials from the FDA, believe washing hands with soap and water is the best method to get rid of germs.


You Can Help Cure Ebola!

 

By  Jesica Levingston Mac leod, PhD

Since the start of the outbreak last March, Ebola virus has already taken more than 8.000 lives and infected more than 21.200 people, according to the  Center for Disease Control (CDC). The panic raised from this situation rushed the testing of therapies to stop the outbreak and the research on the Ebola virus has seen a rebirth. Some research groups that have been working in this field for a long time can now openly ask for help. One of these groups is the one lead by Dr. Erica Ollman Shaphire at The Scripps Research Institute, California. In 2013 they published in Cell an analysis of the different conformations of Ebola VP40 (Viral Protein 40) aka the shape-shifting “transformer” protein. They reported 3 different conformations of this protein, and how this variety allows it to achieve multiple functions in the viral replication circle. This Ebola virus protein along with the glycoprotein would be used as target for anti viral research. In order to find new anti-virals, their approach is an in-silico scrutiny of thousands of compounds, using viral protein crystal structures in the in silico docking to find leads that may be tested in the lab as inhibitors. IBM is already helping them in this project, generating the World Community Grid to find drugs through the Outsmart Ebola Together project.  Here is where you can start helping, as this project involves a huge amount of data and computing time, they need volunteers that can donate their devices spare computing time (android, computer, kindle fire, etc) to generate a faster virtual supercomputer than can accelerate the discover of new potential drugs. This approach has been shown to be successful for other diseases like HIV and malaria, so you are welcome to join the fight against Ebola virus: https://secure.worldcommunitygrid.org/research/oet1/overview.do.

If you do not have any of these devices (I hope you are enjoying the public library free computers), you can still help Dr. Shapire quest to discover new therapies against Ebola. Her group is now “working to support the salary of a computer scientist to help process the data we are generating with the world community grid” as she describes it. To help identify the most promising drug leads for further testing you can donate money on: www.crowdrise.com/cureebola.

Other groups that were mostly working on other viruses, like Flu, also joined the race to discover efficient therapies. For example, last month, the Emerging Microbes and Infections journal of the Nature Publishing Group published the identification of 53 drugs that are potential inhibitors of the Ebola virus. One of the authors of this paper is Dr. Carles Martínez-Romero, from Dr. Adolfo García-Sastre’s lab in the Department of Microbiology at the Icahn School of Medicine at Mount Sinai. In the study, Dr. Martínez-Romero and collaborators described how they narrowed the search from 2.816 FDA approved compounds to 53 potential antiviral drugs. This high-throughput screening was possible thanks to the use of the Ebola viral-like particle (VLP) entry assay. This allows studying Ebola viral entry without using the ”real”, full replicative virus. These 53 compounds blocked the entry of Ebola VLPs into the cell. Understanding how these market-ready compounds can inhibit Ebola entry and its infectious cycle will pave the way for a new generation of treatments against Ebola virus-associated disease.

Dr. Martínez-Romero had an early interest in science; “Since I was a child, I showed great interest in biological sciences and a great desire to question and discover. This led me to pursue my studies in Biotechnology in order to become a successful researcher.”Viruses are very interesting to me because, although they are not strictly living organisms, they are as old as life itself. Even though they are the origin of many illnesses in mammals and other organisms alike, we are tightly interconnected with viruses and they will continue shaping our evolution throughout the years to come.

I also asked him about advice to his fellow researchers, and he answered: “There is a famous quote of Dr. Albert Einstein: “If we knew what we were doing, it wouldn’t be called Research”. As postdocs and researchers in general, we are constantly pursuing new hypotheses. It is a very arduous path with its ups and downs but full of rewards and new challenges ahead.” About the future of the antiviral research, he keeps a positive view: “Several antiviral therapies are being developed to combat the current Ebola outbreak, such as antibody cocktails (Zmapp), antiviral drugs, and specific Ebola vaccines. Together with re-purposing screens like the one we published, a combination of therapeutic drugs can be used to obtain better antiviral strategies against the Ebola virus.”


Teixobactin: Are We Jumping the Gun on a New Magic Bullet?

 

By Elizabeth Ohneck, PhD

The introduction of penicillin to the clinic in the 1940s ushered in an era of hope in our battle against bacterial disease. Penicillin, produced by a lowly mold, Penicillium notatum, was accidentally stumbled upon by Dr. Alexander Fleming in 1928, when he noticed areas of inhibited bacterial growth around the mold, which had contaminated a petri dish of Staphylococcus aureus. A team of researchers led by Dr. Howard Florey later purified the penicillin compound and developed a method for large-scale production. By 1944, penicillin was being mass-produced and commercial production methods refined. It was a powerful tool during WWII, drastically reducing deaths from infected wounds and surgical procedures. Finally made broadly available to the public in 1945, penicillin was heralded as a “magic bullet,” capable of curing a wide variety of bacterial diseases. For an excellent history of the discovery and development of penicillin, I recommend the book The Mold in Dr. Florey’s Coat: The Story of the Penicillin Miracle, by Eric Lax.

 

Just 4 years later, strains of bacteria resistant to penicillin began to appear, spurring a search for alternatives. Following the penicillin model, researchers turned to other microorganisms for potential antibiotic substances. Soil bacteria provided a rich reservoir for such compounds, leading to the discovery of antibiotics such as streptomycin, erythromycin, and cephalosporins. But carelessness, complacency, and overuse of antibiotics allowed the pathogens to fight back, developing ways to resist these new drugs and landing us in our current predicament, facing dangerous strains of bacteria resistant to almost all available antibiotics, such as MRSA (methicillin-resistant S. aureus), MDR-TB (multi-drug-resistant Mycobacterium tuberculosis), and Neisseria gonorrhoeae. Only a small percentage of soil bacteria – approximately 1% - are able to grow under normal laboratory conditions, and with this reservoir seemingly exhausted, biochemical laboratory synthesis efforts failing, and no new antibiotics in the pipeline, the need for new antibiotic candidates is obvious.

 

One team of researchers decided to go back to the soil. In an exciting paper published in Nature this month, Ling et al. describe the development of a novel method for growing previously uncultivable soil bacteria, leading to the discovery of a new antibiotic they have called teixobactin. To grow the finicky soil bacteria, a sample of soil was diluted and distributed into a multichannel device called an iChip so that each channel contained only one bacterium. The channels were covered with semipermeable membranes to keep the bacteria in but allow exchange of nutrients and growth factors between the channel and the environment. The iChip was then returned to the original soil from which the sample was taken, creating growth conditions highly similar to the bacteria’s native environment. This method increased the number of soil bacteria that could be cultured from 1% to nearly 50%. Even better, once a colony is established in the iChip, many of the bacteria can then be grown in a laboratory setting.

 

The researchers screened extracts from 10,000 isolates obtained by this method for antimicrobial activity against S. aureus and identified a new protein compound produced by the Gram-negative organism Eleftheria terrae, which they named teixobactin. Teixobactin showed potent activity against M. tuberculosis and Gram-positive pathogens such as Clostridium difficile (which causes intestinal infection sometimes referred to as “C. dif”), Bacillus antrhacis (which produces the causative agent of anthrax), and S. aureus, including drug-resistant strains. Unfortunately, it was not effective against Gram-negative bacteria. Teixobactin showed no toxicity against mammalian cells in culture, and effectively cleared S. aureus and Streptococcus pneumoniae infections in mice.

 

Through several biochemical investigations, the researchers determined that teixobactin inhibits production of the bacterial cell wall by binding to highly conserved cell wall building blocks. Without a cell wall, bacterial cells lyse, spilling their essential contents into the environment. Other antibiotics, including penicillin, that inhibit the cell wall target its protein components. One mechanism of antibiotic resistance, known as target modification, results when these protein components, encoded in the bacterial DNA, acquire changes from random DNA mutations that alter the antibiotic target site, preventing antibiotic recognition and action. But teixobactin recognizes a lipid (fat) molecule, suggesting it could be less likely that resistance will develop in this manner. Excitingly, growth of S. aureus and M. tuberculosis on low doses of the drug and passage of S. aureus in the presence of subinhibitory concentrations for 27 days did not result in resistant isolates. In contrast, resistance to the antibiotic ofloxacin began emerging after only 3 days of serial passaging. (Research note: Oflaxacin targets DNA gyrase, an important enzyme in DNA replication and transcription. It would have been nice to see the serial passaging experiment done with penicillin and vancomycin, the antibiotic the researchers compare teixobactin to throughout the paper, as this would have provided control data related to other cell wall targeting antibiotics.) The potent effectiveness, lack of observed toxicity, and failure of immediate resistance development make teixobactin a good candidate for a new antibiotic.

 

These findings have been well celebrated in the media, with the suggestion that teixobactin might be a new “magic bullet”, its “resistance to resistance” finally giving us the upper hand in the battle against antibiotic resistance. It is important to keep in mind, however, that this drug is not effective against Gram-negative bacteria, which have a second membrane that protects the cell wall components which teixobactin targets. Thus, multi-drug resistant strains of pathogens such as E. coli, Pseudomonas aeruginosa, and N. gonorrhoeae are left to wreak havoc in the clinic. More importantly, claims of teixobactin’s “resistance to resistance” are a bit premature. Target modification is only one mechanism by which bacteria can gain antibiotic resistance. Other mechanisms include the acquisition of an enzyme that destroys or modifies the antibiotic, alteration of cell metabolism to avoid use of the product or pathway that the antibiotic targets, changes in cell wall composition or structure that keep the drug out of the cell, or use of an efflux pump, a cellular machine that can recognize and pump out antimicrobial compounds. While some of these mechanisms are more complex and may require exchange of DNA with other bacteria to acquire, all are possible. Development of resistance by serial passaging of a single strain in the lab is much different than within a human patient, where interactions with other pathogens and the normal flora (the bacteria normally found on and in the human body) are plentiful, and the presence of other antimicrobial compounds and alternative nutrient sources create a complex environment that could have significant effects on the development of resistance. There is evidence that genes for antibiotic resistance can be transferred among bacterial species, including those of our normal flora, in vivo.

 

The authors do acknowledge that resistance may develop, but assert that it would likely take several decades, citing the 30 years it took for development of resistance to vancomycin, which works by a mechanism similar to teixobactin, as an example. The comparison of the development of vancomycin resistance to that of other antibiotics, however, isn’t entirely fair. When vancomycin was first introduced, its relatively high toxicity and low efficacy kept it as an antibiotic reserved only for patients with allergies to β-lactams (such as penicillin) or resistant infections. In the early 1980s, as resistance to other antibiotics became more prevalent, vancomycin use spiked, and was followed by the development of resistant strains by 1986. Thus, the case of vancomycin resistance should actually serve as a warning: should teixobactin prove a viable antibiotic, careless overuse will quickly relegate it to the ever-growing pile of ineffective antibiotics.

 

Still, the significance of these findings should not be overlooked or understated. Ling et al. have provided us with the first truly promising antibiotic candidate in many years. Perhaps more importantly, they have developed a method for growing bacteria previously uncultivable in the lab, not only expanding the pool of available antibiotic candidates, but also creating a tool that could prove revolutionary in microbiology, ecology, and environmental research. We should be hopeful that teixobactin is safe and effective in human trials, and that either it can be modified to be effective against Gram-negative pathogens or that the iChip method reveals another compound as potent as teixobactin for their treatment. But we must also be responsible and cautious, so as not to squander these precious new drugs and hasten an era of untreatable bacterial diseases.

 


MRSA vaccine

The Hunt for the Holy Grail: A Potential Vaccine against MRSA

 

By Elizabeth Ohneck, PhD

Vaccines represent the “holy grail” in prevention and treatment of infectious diseases. Effective vaccines have allowed the eradication of small pox and contributed to drastic declines in cases of diseases such as polio, measles, and pertussis (whooping cough). As bacterial pathogens become more resistant to a broader spectrum of antibiotics, the desire to develop vaccines against these offenders to prevent disease altogether heightens.

 

Staphylococcus aureus is a common cause of skin and skin structure infections (SSSIs), as well as post-surgical and wound infections. SSSIs, which frequently present as abscesses in the upper layers of skin tissue, can serve as sources of more serious infections with high mortality rates, such as pneumonia, endocarditis, and bloodstream infections, when the bacteria break through the upper layer of tissue and invade other sites of the body. With the high prevalence of methicillin-resistant S. aureus (MRSA) depleting our antibiotic arsenal, S. aureus infections have become difficult to treat, spurring intense investigation into vaccine development.

 

A group from UCLA recently developed a potential vaccine, NDV-3. This vaccine is actually based on a protein from the fungal pathogen Candida albicans, which causes diseases such as thrush and yeast infections. The C. albicans protein is similar in structure to S. aureus adhesins, proteins on the bacterial surface that allow the bacterial cell to stick to host cells. In preliminary studies, the NDV-3 vaccine was shown to be protective against both C. albicans and S. aureus. In a recent paper in PNAS, Yeaman et al. examine in detail the efficacy of this vaccine in MRSA SSSI and invasive infection.

 

To determine the efficacy of the NDV-3 vaccine in prevention of S. aureus SSSIs, the researchers vaccinated mice with NDV-3, and administered a “booster shot” 21 days later. Two weeks after the booster, the mice were infected with S. aureus by subcutaneous injection, or injection just under the skin, to induce abscess formation. Abscess progression and disease outcomes were then monitored for 2 weeks.

 

Abscess formation was slower and the final size and volume of abscesses were smaller in vaccinated mice compared to control mice. In addition, mice vaccinated with NDV-3 were able to clear S. aureus abscesses by 14 days after infection, whereas abscesses in control mice were not resolved. Using a S. aureus strain expressing luciferase, a protein that emits light, the researchers were able to watch proliferation of the bacteria within the abscesses by measuring the strength of the luciferase signal. Vaccination with NDV-3 resulted in a significantly weaker luciferase signal than in unvaccinated mice, indicating NDV-3 vaccination prevents growth of the bacterial population. This finding was supported by a decrease in the number of CFUs (colony-forming units), an estimate of the number of viable bacteria, isolated from abscesses of vaccinated versus unvaccinated mice. Importantly, the researchers conducted these experiments with 3 distinct MRSA strains and observed similar results for each. Together, these findings demonstrate that while the NDV-3 vaccine does not completely prevent SSSIs under these conditions, vaccination can significantly reduce severity.

 

As skin infections can often serve as a source for more serious disseminated infections, the researchers also examined the effect of NDV-3 on the spread of S. aureus from the original site of infection. While control mice developed small abscesses in deeper tissue layers, vaccinated mice showed little to no invasion of infection. Additionally, significantly fewer bacteria were found in the kidneys of vaccinated mice compared to control mice, indicating NDV-3 can prevent the spread of S. aureus from skin infection to more invasive sites.

 

To examine how NDV-3 was stimulating a protective effect against MRSA, the researchers measured the amount of molecules and cells important for immune response to MRSA in vaccinated and unvaccinated mice. Abscesses of vaccinated mice showed a higher density of CD3+ T-cells and neutrophils, as well increased amounts of the cytokines, or immune cell signaling molecules, IL-17A and IL-22. Vaccinated mice also showed higher amounts of antibodies against NDV-3, as well as increased production of antimicrobial peptides, small proteins with antibiotic activity produced by host cells. Thus, the NDV-3 vaccine helps encourage a strong immune response against MRSA.

 

The NDV-3 vaccine was recently tested in a phase I clinical trial and found to be safe and immunogenic (i.e., stimulates an immune response) in healthy human volunteers. While the vaccine in it’s current form doesn’t prevent S. aureus infections altogether, it could help make infections easier to treat by slowing bacterial growth, preventing spread to other tissues, and boosting the host immune defenses. Further research on this vaccine may also lead to a form that is more protective and can better prevent infections.

 


Crafty Pathogens Share the Cost of Resistance

 

By Elizabeth Ohneck, PhD

 

Bacteria have been evolving with us humans since we first came into being. Some of these microorganisms have become our indispensable partners, aiding our digestion, helping the development of our immune systems, and protecting us from less friendly bacteria. Others, in this less-friendly category, cause a vast number of illnesses and diseases, and have evolved to more insidious organisms, developing ways to outsmart our immune systems and resist antibiotics to survive within us and spread to new hosts. Pathogens like Neisseria gonorrhoeae, Staphylococcus aureus, and other multi-drug resistant “superbugs” have been continuously acquiring clever adaptations to protect themselves from our immune and antibiotic arsenals, leaving few options for patient treatment.

 

Many of the mutations that protect pathogenic bacteria from antimicrobial factors, however, come at a cost. Most antibiotics target cellular parts and processes essential to bacterial survival. To block antibiotic recognition of or action on these targets, bacteria must mutate critical cell components, which can reduce fitness, or the ability to grow and reproduce efficiently. Such fitness costs cause these mutants to grow more slowly than their wild-type, or “normal,” counterparts and other microorganisms present in the environment; thus, it is possible these mutants may not persist, as they might lose the battle for space and resources to their more fit opponents. In addition, some of these mutations decrease the ability of bacteria to produce virulence factors, which are critical in causing disease. Yet bacteria with mutations in important cell components are frequently recovered from patients with serious illness. How are these mutants able to successfully survive within the human host and cause severe disease?

 

A team from Vanderbilt University sought to answer this question with research published in Cell Host and Microbe in October. Hammer et al. examined Staphylococcus aureus small colony varients (SCVs), which are often isolated from patients with chronic disease and are resistant to multiple antibiotics. SCVs contain mutations in important biosynthetic pathways, resulting in slow growth and limited virulence factor production. Hammer et al. chose two primary mutants for their study: one unable to produce heme, and one unable to produce menaquinone, both of which are essential metabolites for bacterial respiration. Both mutants showed reduced growth rate and decreased ability to cause bone destruction in a mouse model of osteomyelitis. These defects were overcome by providing the metabolites during growth, demonstrating it is the inability of these mutants to produce the metabolites that causes their reduced fitness.

 

Interestingly, growing these two mutants together restored their growth and ability to cause bone destruction, suggesting the mutants could use the missing metabolite produced by the other mutant for normal growth and efficient virulence factor production. Surprisingly, growth of the mutant unable to produce menaquinone with another human pathogen, Enterococcus faecalis, also restored growth of the mutant, demonstrating that SCVs can use metabolites not only from other S. aureus, but from other bacterial species. Most importantly, the researchers demonstrated that these interactions can occur in patients during infection. The team isolated bacteria from the upper respiratory tract of patients with cystic fibrosis and found several bacterial species, including Staphylococcus epidermidis and Streptococcal species, that enhanced growth of the SCV mutants unable to produce heme, menaquinone, or both. In addition, they found many distinct SCVs that could rescue the growth of the heme and menaquinone mutants, as well as one another. These findings provide evidence that antibiotic resistant mutants can survive and cause disease despite fitness defects by borrowing factors important for growth from the surrounding microbial community, including the “friendly” bacteria that normally reside with in us, turning friends into foes.

 

It’s important to note that slow growth is an important factor in the antibiotic resistance of SCVs. When the heme or menaquinone synthesis mutants were rescued by growth with other strains, they became more sensitive to the antibiotic gentamicin, clearly demonstrating the trade-off between fitness and resistance. It’s plausible that wild-type S. aureus and SCVs work together for efficient, resistant infection. Wild-type strains can establish infection and increase the overall population, while the development of SCVs ensures population survival in the face of antibiotic treatment. The ability to use metabolites from other microorganisms is a clever evolutionary adaptation to compensate for the sacrifice in fitness made for the gain of antibiotic resistance, and an important consideration in the treatment of patients with bacterial infections and the development of new drugs.


Ancient virus can infected after being defrosted.

Ancient Viruses - New Concerns

 

By Robert Thorn

Recently scientists have discovered a new type of virus in the Siberian permafrost. The virus discovered is about 30,000 years old, and amazingly after all that time the virus was still able to infect cells after being defrosted. Specifically, the scientists who discovered the virus have shown that it can infect amoebas, which are single celled organisms. They also found that this virus poses no risk to humans or animals but the real worry behind this discovery is that there could be more virulent microorganisms lying dormant under the ice.

 

In recent years there has been growing concerns over global warming but much of the focus has been on changing weather patterns, the melting of the polar ice caps and rising sea levels. The scientists who discovered this new virus have raised the concern that more, unidentified viruses could be released with the melting of ice and permafrost around the globe and that these pathogens may pose a risk to humans, plants or animals. Climate change is not the only way that these potentially harmful viruses could be released. Drilling, mining, or anything other human intervention that might disrupt the permafrost could be an avenue for these dormant viruses to be awakened. With increasing pressure on the oil industry to find new stores of fuel to power our modern world, these dormant viruses may add an extra layer of concern to drilling for oil in areas covered by permafrost.

 

With all of the uncertainty that is lying under these sheets of ice and frozen soil, there is a pressing need for a discussion on how to deal with an ever thawing permafrost due to climate change, and increased pressure or taking advantages of untapped resources. The paper mentions that in the 20th century alone there was a 7% decrease in the permafrost. Based on the author’s research this decrease in permafrost has very likely coincided with a revival of dormant organisms that could be altering the ecosystems of the world in unknown ways. It is clear that these findings need to be added to the conversations about global climate change that are being had across the world.

 

While this may all seem scary, there is a silver lining. Despite the potential risk that is posed by these ancient microorganisms, the methods the authors used to revive and analyze this new virus can be used as an inexpensive and safe way to assess the viruses that are dormant in the permafrost. By documenting these pathogens in the permafrost, we can be more prepared to contain the potentially harmful organisms, or to fend them off if they do get reactivated.

 

 


One Flu Over the Cuckoo’s Nest: Has the New Avian Influenza Virus Achieved Human-to-Human Transmission?

 

By Asu Erden

Human cases of H7N9 – a new avian influenza A virus – were first reported in China between February and March 2013. It is believed that infection with this virus requires exposure to poultry but when and how the virus crossed the species barrier remains elusive. The Centers for Disease Control (CDC) originally estimated that up to 20% of the people that become infected with this virus die. There are currently no vaccines available against this avian flu virus, although clinical trials are under way with the help of the World Health Organization (WHO). The disease caused is severe and mainly affects the respiratory tract. Li et al. recently published a study in the New England Journal of Medicine that sheds light on the epidemiology of the disease caused by H7N9 and suggests that the virus might have achieved human-to-human transmission.

 

In their study, Li et al. investigated 139 confirmed cases of H7N9 from 12 different areas in China (including Shanghai and Beijing). Their aim was to better understand the epidemiology of the lower respiratory illness caused by this avian flu virus newly infecting humans. They were able to identify cases thanks to the Chinese surveillance system for pneumonia of unknown origin, which was put in place in 2004 at the time of the H5N1 avian influenza outbreak. The study confirmed that infection with H7N9 is most likely caused by exposure to live animals (poultry, birds, or swine). Most of the studied cases (77%) occurred in older individuals with the median age of patients being 61. Despite an older age distribution, the H7N9 virus seems to infect people from a broader age range than H5N1 did a decade ago.

 

This emerging zoonosis seems to be particularly virulent. After an incubation period of 7 days, H7N9 caused an acute illness characterized by severe lower respiratory symptoms – including pneumonia and respiratory failure – in all studied patients. The case fatality rate was also high, with 34% of patients dying. This rate is significantly higher than originally estimated by the WHO but remains lower than for H5N1. Further studies are required to establish the true case fatality rate of the disease caused by H7N9 in the overall population.

 

Li’s group also carried out family cluster analyses based on four families in which two or more individuals had confirmed cases of H7N9. In each cluster, one of the individuals became infected due to close contact with poultry (e.g. visits at poultry markets) but the other infected individuals never came in close contact with live animals. This suggests that the virus might have evolved to achieve human-to-human transmission. On the other hand, Li et al. also followed over 2500 close contacts of their 139 confirmed cases and only 1% developed respiratory symptoms, none of which tested positive for H7N9. Of note, however, is that these individuals were only followed for 7 days after contact and only single swabs were collected from them. This likely decreased the likeliness of detecting H7N9 cases among close contacts.

 

The most significant finding from this study also happens to be the only negative data that were presented:  Li et al. were unable to discard the possibility that H7N9 can transmit from human to human. Given the virulence, case fatality rate, and ongoing outbreak of the H7N9 avian influenza virus, the possibility of human-to-human transmission is cause for concern. The establishment of a putative human reservoir would allow for fast spread of the virus worldwide and should be scrutinized by public health officials.


Stopping the Unstoppable: New Drug Candidates Against MRSA

By Elizabeth Ohneck

Rapidly spreading antibiotic resistance is threatening our arsenal of treatment options against bacterial pathogens. One microorganism of particular concern is methicillin-resistant Staphylococcus aureus, or MRSA, which causes diseases ranging from mild skin infections to pneumonia and sepsis. While originally primarily found in immunocompromised patients in hospital settings, MRSA is now being acquired by otherwise healthy individuals in the community. The development of effective new antibiotics requires identification of drug targets essential to bacterial survival, resistant to the development of mutations, and not found in humans. Recently, the MRSA pyruvate kinase (PK) was identified as one such target, as it is an important player multiple metabolic pathways in MRSA. While humans and other mammals also have PK, the MRSA and mammalian PK enzymes significantly differ in structure, allowing specific targeting of MRSA PK. Additionally, because this enzyme is critical in metabolism, it is expected that PK will be less tolerant to the development of mutations, reducing the risk of acquiring resistance to drugs targeting PK.

 

Previous chemical screens identified several indole-based compounds that were able to selectively inhibit MRSA PK and kill a panel of other Gram-positive bacteria. The road from discovery to drug is long, and in a recent paper in Bioorganic and Medicinal Chemistry, Kumar et al. detail their efforts to optimize these compounds for drug development. Using a chemical scaffold based on a compound previously crystallized bound to PK, the researchers created a panel of bis-indole compounds varying slightly in size, shape, charge, or chemical group content, and examined their antibiotic potential. The ideal optimized drug candidates should both inhibit MRSA PK and kill MRSA at low concentrations, and lack both activity against mammalian PK and toxic effects on human cells.

 

Using a photometric assay for purified MRSA PK activity, Kumar et al. were able to identify several potent inhibitors of MRSA PK. Surprisingly, some of the most effective PK inhibitors were ineffective as antibiotics against S. aureus, as determined by minimum inhibitory concentration (MIC) assays. For a few of these compounds, improving solubility lowered the MIC to an acceptable level, likely by improving the ability of these compounds to enter the bacterial cells. For many others, altering the solubility had little to no effect. The research team wondered if the inability of these compounds to kill S. aureus despite their potent PK inhibitory activity was due to removal from the bacterial cell by efflux pumps, molecular machines in the bacterial cell wall that recognize toxic compounds and actively export them from the cell interior. Efflux pumps are major contributors to the multidrug resistance phenotypes of many bacterial pathogens. By administering the efflux pump inhibitor verapamil with the indole compounds, the researchers were able to drastically reduce the MIC of several compounds, demonstrating some of these molecules can be recognized by MRSA efflux pumps, which creates concern for the development of resistance to these particular compounds and places further constraints on the specific bis-indoles that can be pursued as drug candidates.

 

Several compounds from the panel were found to be both effective PK inhibitors and antibiotics, and Kumar et al. demonstrated that the 3 most effective compounds were active against both a laboratory strain of S. aureus and the MRSA strain MW2. Additionally, they determined that the ability of these compounds to kill S. aureus is dependent on PK activity, as these compounds were unable to kill a strain in which PK had been removed. As the ability of S. aureus to survive without PK requires special growth conditions extremely unlikely to be found in a host during infection, the inability of these compounds to kill a PK mutant is not particularly concerning for drug development. Finally, the research team found that even at high concentrations, the indole compounds were both unable to inhibit mammalian PK and not significantly cytotoxic toward HEK 293 cells, a cell line derived from human embryonic kidney cells.

 

In summary, Kumar et al. have identified several indole-based compounds that are able to efficiently inhibit MRSA PK and kill S. aureus without detrimental effects on mammalian PK or human cells. The lead compounds will be further tested for effectiveness in animal infection models. MRSA PK inhibitors may provide a novel drug treatment against this highly multidrug resistant pathogen.


The Art of Manipulation

 

By Sophia David

Parasitism is the most common way of life on Earth. It occurs when two species live in close proximity to one another and while one species (the “parasite”) benefits from the relationship, the other species (the “host”) suffers. Humans are only too familiar with parasites - the common flu virus, the tapeworm and the malaria parasite are just a few examples of organisms that parasitize our own species. While these organisms benefit from us by gaining shelter and food, we, of course, gain nothing but illness.

Through thousands of years of evolving together with their host (a process known as co-evolution), parasites have learned to manipulate their hosts in remarkable ways. The most unique example I have come across is that of a bacterium called Wolbachia. This is thought to be one of the world’s most common parasites. The hosts of Wolbachia are wide-ranging; they can infect numerous species of insects, spiders and worms. Sometimes, the relationship can be beneficial to the host, in which case the relationship is one of mutualism, where both species derive benefit, rather than parasitism. More often than not, however, the relationship is parasitism.

The defining feature of these bacteria is that they are transmitted to the offspring of an infected female host through the female's eggs. Crucial to this story is that it is only female hosts that transmit Wolbachia, and not males. Instead, males are a dead-end host; once in a male host, the bacteria have nowhere to go. So, to enhance their transmission, Wolbachia would rather be in a female host than a male host. And they evolved the most fascinating mechanisms to achieve this. Like many parasites, they manipulate their host’s biology, but rather uniquely, they are able to alter their host’s reproduction in a way to favor their spread. In a paper by John Werren and colleagues from the US, the authors outline four fascinating ways in which Wolbachia can alter the reproduction of its hosts to its own advantage.

Cytoplasmic incompatibility

This sounds complicated but “cytoplasmic incompatibility” is just a way of saying that sperm from Wolbachia-infected male hosts is incompatible with eggs from females that do not harbour Wolbachia. This kind of match would produce offspring that are not infected with Wolbachia, since the bacteria can only be transmitted from the female. So Wolbachia has developed a way of manipulating the sperm of infected males so that they are only compatible with eggs that are also infected. It’s clever! The molecular mechanisms of how Wolbachia achieves this are still not properly understood though.

Parthenogenesis

Parthenogenesis is a type of asexual reproduction whereby embryos develop from eggs that have not been fertilized by sperm. While insects and other hosts of Wolbachia usually undergo sexual reproduction, parthenogenesis can also occur. Wolbachia makes use of this by ensuring only daughter progeny can be produced through parthenogenesis.

Male killing

Just as it sounds, Wolbachia are able to kill the male offspring of its hosts, usually when the embryos are developing. This gives the surviving, Wolbachia-infected females an advantage as more food and resources will be left for them.

Feminization

Even when Wolbachia is not able to kill the male embryos, it has another trick up its sleeve. By interfering with the sex-determining pathways of its host, it can cause genetic males to instead develop as females through a process known as feminization.

 

Different species and strains of Wolbachia use different combinations of these strategies to spread efficiently through host populations. Going to such extreme lengths, it is no surprise that they are among the most abundant parasites in the world.

Another characteristic of Wolbachia is that it inhibits the growth of many other microbes in its hosts. This feature, along with its remarkable ability to spread in host populations, has led to its use as a biological tool for preventing the spread of disease. One such disease is dengue fever, caused by dengue virus and transmitted by mosquitoes. The dengue virus is not able to survive inside a Wolbachia-infected mosquito. Therefore, scientists have created a strain of Wolbachia-infected mosquitoes which, when released into the environment, rapidly replace the non-infected population and prevent transmission of dengue fever. Small, pilot trials of this have worked well in Australia and larger trials are currently now taking place. In the coming years, Wolbachia could become a major, albeit slightly unusual, tool for combatting insect-borne diseases.

This post originally appeared on thetripletcode.wordpress.com


Sizzling Papers of the Week - Nov 22

 

The Scizzle Team

Guys, Stop Fighting Over Me!

Male-male aggression is part of sexual selection in many species, and is affected by environment, experience, and the animal’s state - but how?  Researchers found that while male fruit flies will usually be at each others’ throats when an eligible [fly] bachelorette is around, this fighting is reduced in males who’ve had prior exposure to the ladies.  Turns out the male flies can sense females via a special pheromone-sensing  ion channel, triggering activity in a pathway mediated by the inhibitory neurotransmitter GABA which quells male aggression.  Thus, this new found circuit represents a key means for experience to modulate aggression.

 

Female contact modulates male aggression via sexually dimorphic gABAergic circuit in Drosophila, Yuan Q. et al., Nature Neuroscience, November 17, 2013

Create a feed for gABAergic circuit to keep up with all the fighting.

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Another Reason to Love Germs

You know how when you tell distant family members you’re a scientist, there’s always someone who asks whether you’re curing cancer?  Well it turns out the millions of microbiota living in your gut can answer that question with a resounding “yes.”  These little guys can have a big effect on inflammation, which in turn plays an important role in cancer.  Investigators found that when mice lack a robust host of microorganisms, they responded less well to cancer therapies.  Way to go bacteria!

 

Commensal Bacteria Control Cancer Response to Therapy by Modulating the Tumor Microenvironment, Iida, N. et al., Science, November 21 2013

Create a feed for bacteria, microenviroment and cancer. 

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If Only We Could Remember What This Paper Was About...

With the medical use of marijuana on the rise, it’s more important than even to understand the mechanisms of unwanted side effects.  Researchers made important strides in clarifying how marijuana effects memory when they discovered that ∆9-THC, the active component in the plant, induces the activity of the enzyme COX-2 via CB1 receptors.  Blocking COX-2 reduces the negative impacts of ∆9-THC on memory, while permitting the medicinal effects such as reducing neurodegeneration in Alzheimer’s disease.

 

9-THC-Caused Synaptic and Memory Impairments Are Mediated through COX-2 Signalling, Chen, R. et al., Cell, November 17 2013.

Fascinated by marijuana? Create a feed for marijuana, COX-2 and memory.

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Taking a Closer Look at Chromosomes

We know that mitotic chromosomes are critical to cell division, but there remains a lot of doubt about precisely how these structures organize.  Now investigators have used chromosome conformation capture methods to shed more light on the issue.  They demonstrated that the way nonsynchronous cell were believed to organize is actually only true in interphase, while a more homogenous, consistent organization occurs during metaphase.  Simulations went on to show that classical models don’t correctly explain the organization of chromosomes during mitosis.

 

Organization of the Mitotic Chromosome, Naumova, N., et al., Science, November 21 2013

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Are You Cold?

Apparently, the mandated temperatures in which lab mice are kept are too cold for them and suppress their anti-tumor immune response. A new study published in PNAS shows that when mice were kept in thermoneutral temperatures, there were fewer immunosuppressive cells with significantly enhanced CD8+ T cell-dependent control of tumor growth. This study highlights the importance of the environmental temperature conditions and show how it may lead to a misunderstanding of anti-tumor immune response and its effect when studying potential anti-cancer therapies.

Baseline tumor growth and immune control in laboratory mice are significantly influenced by subthermoneutral housing temperature. Kokolus KM et al., PNAS, November 2013.

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Don't Touch That! You'll Get Germs

 

Robert Thorn

Everybody can relate to a parent saying “Don’t touch that, you’ll get germs.” For most of our lives we have been told to avoid ‘germs’, an ambiguous mix of all things that might get you sick. The truth is that not all germs are created equal. Scientists have been trying to decode the human “microbiome,” or the bacteria that live within our digestive system, to determine how these bacteria come to inhabit our digestive tract and how they relate to human health and disease. Good bacteria in the intestines can help us digest food and keep out bad bacteria, but bad bacteria in the intestine can have harmful effects such as obesity, allergies, and short-term sicknesses like food poisoning.

A recent paper in Nature suggests a method by which bacteria can initially colonize our digestive system. It is well known that newborns have a weaker immune response to infection but this has generally been attributed to an immature immune system. These researchers suggest a different reason, that newborns have a system to actively suppress the immune system. They have found an enrichment of CD71 positive immune cells in newborn mice compared to adults. In addition they have shown that these CD71 positive immune cells secrete factors that repress immune function, even in mature adult immune cells. Newborn mice that were depleted of these CD71 cells could fight infection better than those that still had an enrichment of the CD71 positive cells. The obvious question is why? The researches went on to answer this question by looking at the effects of bacteria in the intestine and the amount of CD71 cells. They showed that there was a positive correlation between the amount of CD71 cells and the amount of bacteria in the intestine. This means that evolution has made it so that newborns are more susceptible to possibly harmful infections in an attempt to protect the potentially helpful bacteria that colonize the intestines.

In contrast to the shutting down of the immune system by gut bacteria, a new study published in eLife has suggested a role for certain kinds of gut bacteria in rheumatoid arthritis. Rheumatoid arthritis is an autoimmune disorder, meaning it is one in which the immune system attacks the body. In this case, joints are being attacked, and the resulting inflammation causes the arthritis. Based on a screen done of human fecal samples (which shows a representation of gut bacteria) of people with and without rheumatoid arthritis, the researchers correlated a single strain of bacteria, P. copri, to patients newly diagnosed with rheumatoid arthritis. Since rheumatoid arthritis is a multifaceted disease, it is possible that the P. copri bacteria either thrives in an environment that also causes rheumatoid arthritis or that P. copri pushes an already compromised over the edge and is an early factor in rheumatoid arthritis. The researchers also showed that mice infected with P. copri had an increased occurrence of colitis, which is inflammation of the colon. This could show a link between P. copri and general inflammation in the host, strengthening the correlation between P. copri and rheumatoid arthritis.

Whether we are talking about good gut bacteria or bad gut bacteria, new areas of medicine are focused on how to maintain a healthy microbiome. Generally, good bacteria can be maintained by proper diet but upsetting the balance with a bad diet, or by taking too many antibiotics, can give opportunistic bad bacteria a chance to over-colonize the digestive system. In many cases of intestinal disease that result from microbiome imbalance, fecal transplants have been used to treat patients. Fecal transplants involve the use of a fecal sample from an individual with a healthy mix of bacteria and transplanting it into a sick person, generally by enema. This allows a healthy mix of bacteria to recolonize the sick person’s gut. This may seem like a barbaric or gross treatment, but it has been shown to be effective in treating cases of inflammatory intestinal disease. As research on gut microbiomes progresses, we may discover more sophisticated ways to treat these diseases, but currently fecal transplant can be the best option.

As our understanding of the microbiome increases, we may discover a more complicated relationship between human health and gut bacteria. Finding more links will help advance medicine by taking advantage of this relationship to more easily detect and cure diseases.