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Monday Micro – killer viruses Siouxsie Wiles Feb 03

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Recent virus-related papers to get excited about:

1. Visualising HIV infection

A paper just out in the open access journal PLOS Pathogens describes using 3D electron microscopy to visualise the Human Immune Immunodeficiency Virus (HIV)-1 infecting gut immune cells (1). If you remember, HIV is the virus which causes acquired immunodeficiency syndrome (AIDS). It’s believed that 33 million people worldwide are infected with HIV.

Until reading this paper, I hadn’t realised that gut mucosal tissues were involved in HIV infection. According to the researchers, the gut contains large numbers of target cells which become depleted early on in HIV infection. Ladinsky and colleagues wanted to look at where the virus goes during an active infection so they needed to use some nifty tricks to make that possible. The first was to make mice which contain immune cells that HIV can infect. As the virus is pretty specialised for infecting human cells, it doesn’t normally infect mice. The researchers grafted mice with human immune cells, and then a few months later injected the mice with HIV. Mice were then euthanised and gut tissues removed and fixed for looking at using a fancy microscope. And here’s an example of a reconstructed image where the modelled virus particles are shown in blue. Pretty!

Tomographic slice of gut immune cells with modelled HIV virions (blue, membrane; purple, cores; average diameter = 99.3+/−4.7 nm). Adapted from ref 1

Tomographic slice of gut immune cells with modelled HIV virions (blue, membrane; purple, cores; average diameter = 99.3+/−4.7 nm). Adapted from ref 1

2. Hijacking the bacterial ‘immune system’ to make smart antibiotics

I’ve written before about the fact that bacteria can become infected with viruses, called phage. The bacteria have developed numerous forms of ‘immunity’ to protect themselves from attack, including the CRISPR system, which stands for Clustered Regularly Interspaced Short Palindromic Repeats. In this quite elegant system, foreign genetic material is chopped up and incorporated into the bacterial genome (as ‘spacers’) between CRISPR repeats. These spacers then serve as a sort of immune ‘memory’ of past potential invaders. Upon re-exposure, the CRISPR spacers recognise the foreign genetic material and target it for destruction.

In a paper just published in the open access journal mBIO, Gomaa and colleagues have shown that this CRISPR-Cas system can be hijacked to kill specific strains of bacteria (2). They designed and administered specific CRISPR spacers into mixed cultures of bacteria and showed that they could kill the particular bacterial strain they were targeting. This is exciting as one of the problems with current antibiotics is that they kill good and bad bacteria in one sweep. Now the researchers have to figure out CRISPR spacers could be delivered to target bacteria during an infection. Watch this space.

3. Exploiting viruses to target cancer cells for destruction.

And finally, a paper just published in the FASEB Journal describes using an engineered vaccinia virus to target breast cancer cells for destruction (3). Gholami and colleagues engineered vaccinia virus to carry the gene encoding the human sodium iodide symporter (hNIS). When the virus infected breast cancer cells, it made the cells produce hNIS. What’s cool about this is that hNIS is the protein that normally concentrates iodine in thyroid cells. By grafting the engineered tumour cells into mice, the researchers were able to treat the tumours by giving the mice radioactive iodine, a form of radiotherapy used to treat thyroid cancer in humans. Clever.

References:
1. Ladinsky MS, Kieffer C, Olson G, Deruaz M, Vrbanac V, et al. (2014) Electron Tomography of HIV-1 Infection in Gut-Associated Lymphoid Tissue. PLoS Pathog 10(1): e1003899. doi:10.1371/journal.ppat.1003899

2. A. A. Gomaa, H. E. Klumpe, M. L. Luo, K. Selle, R. Barrangou, C. L. Beisel. Programmable Removal of Bacterial Strains by Use of Genome-Targeting CRISPR-Cas Systems. mBio, 2014; 5 (1): e00928-13 DOI: 10.1128/mBio.00928-13

3. S. Gholami, C.-H. Chen, E. Lou, L. J. Belin, S. Fujisawa, V. A. Longo, N. G. Chen, M. Gonen, P. B. Zanzonico, A. A. Szalay, Y. Fong. Vaccinia virus GLV-1h153 in combination with 131I shows increased efficiency in treating triple-negative breast cancer. The FASEB Journal, 2013; 28 (2): 676 DOI: 10.1096/fj.13-237222

Monday Micro – sloths a source of new drugs?! Siouxsie Wiles Jan 20

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As a parent, I have watched the Ice Age movies more times than I care to admit. I quite like Sid the sloth but had no idea just how important his descendants could be in our fight against disease.

Sidtree

Sloths are slow-moving tree-dwelling mammals found in the jungles of central and south America. They have unusual fur that under certain conditions plays home to photosynthetic bacteria (cyanobacteria) whose blue/green colour is thought to provide camouflage.

In a paper just published in the open access journal PLOS One, Sarah Higginbotham and colleagues from the Smithsonian Tropical Research Institute in Panama, have looked at the fungal communities associated with the coarse, outer hair of nine three-toed sloths of the species Bradypus variegatus living in Panama.

The researchers cultivated over 80 species of fungi and then screened extracts made from these fungi for the production of compounds that could kill bacteria, parasites and cancer cells. They found 2 extracts with activity against Plasmodium falciparum, the parasite that causes malaria, and eight extracts with activity against Trypanosoma cruzi, the parasite that causes Chagas disease. This is exciting as the current treatments for Chagas disease have serious side effects which can be so bad, patients stop taking their medicine. They also found three extracts with activity against a breast cancer cell line, and an extract with activity against Gram-negative bacteria such as E. coli and Pseudomonas aeruginosa. This is good news, as multi-drug resistant Gram-negative bacteria are fast-becoming untreatable using current antibiotics.

Fingers crossed some of these sloth-hair fungi compounds turn into new drugs. We certainly need them.

Reference:

Higginbotham S, Wong WR, Linington RG, Spadafora C, Iturrado L, et al. (2014) Sloth Hair as a Novel Source of Fungi with Potent Anti-Parasitic, Anti-Cancer and Anti-Bacterial Bioactivity. PLoS ONE 9(1): e84549. doi:10.1371/journal.pone.0084549

What Kiwis die of – Part II: The battle of the sexes Siouxsie Wiles Jan 31

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Two weeks ago, we asked Kiwis what they thought they would die of, and compared their responses to the primary causes of death recorded by the Ministry of Health for the 29,204 people who died in New Zealand in 2009. Mike Dickison produced a beautiful infographic* of the causes that were responsible for more than 1% of those deaths. Obviously this data reflects what was recorded on the death certificate which may not always be the immediate cause of death. In fact, there was some discussion afterwards about the reality of ‘old age’ being an unacceptable cause of death here!

This week we decided to take a look at differences for causes of death recorded for men and women. Mike has worked his magic again and produced the infographic below. This time the little coffins each represent 25 people.

Its striking that more men die of prostate cancer than women die of ovarian, and twice as many men than women die from cancer of the bladder and kidney. But lots more women die of cerebrovascular diseases, that is strokes and brain haemorrhages, and dementia. To see if people’s perceptions tallied up with reality, we took to social media and asked people whether they thought there were any differences between what men and women died of**. So what did the Kiwis we surveyed think? Results are summarised in the slideshare presentation below.



The first striking thing to come from our survey participants is that the majority thought that more men die than women, and that more men die of diabetes, cerebrovascular diseases, traffic accidents and suicide. But not skin cancer. In actual fact, the numbers of men and women who died in 2009 was very similar, 14,615 men and 14,589 women. As you can see from the infographic, more men died in traffic accidents and diabetes, or committed suicide. But our respondents were way off with cerebrovascular diseases. And with the fact that skin cancer killed more men than women. The other question we asked related to breast cancer deaths in men. 8.2% of our respondents thought that men couldn’t get breast cancer. In fact, in New Zealand in 2009, 1 in 100 breast cancer deaths were in men.

As several people pointed out with our first infographic, these differences between perception and reality could be dangerous if they mean resources are diverted away from where they are really needed.

*Head on over to Mike’s Pictures of Numbers blog to see how the infographic came about and for a downloadable version.

** We used Twitter, Facebook, and email to entice over 100 people to fill out our survey using the SurveyMonkey website. Like all online surveys, ours should not be considered representative of the population of New Zealand, but rather of people on social media who were happy to fill out our survey.

This post is the second in a series inspired by the Guardian newspaper’s infographic ‘What we die of’ and is a collaboration between myself, chief number cruncher Dr Paul Gardner and data visualisation extraordinaire Dr Mike Dickison. Dr Paul Gardner (@ppgardne) is a Royal Society of NZ Rutherford Discovery Fellow and Senior Lecturer in Bioinformatics at the University of Canterbury’s School of Biological Sciences. He gets very excited about RNA. Dr Mike Dickison (@adzebill) is a freelance information designer with a PhD on the evolution of giant flightless birds. He quite likes ukuleles too. Dr Siouxsie Wiles (@SiouxsieW) is a Health Research Council of NZ Hercus Fellow at the University of Auckland’s Faculty of Medical & Health Sciences. She is rather keen on nasty bacteria and anything that glows in the dark.

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