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The Schmallenberg Virus and Disease

January 21, 2013

This week in the online journal club #microtwjc we will be discussing this paper titled “Schmallenberg Virus Pathogenesis, Tropis and Interaction with the Innate Immune System of the Host” (Varela M, Schnettler E, Caporale M, Murgia C, Barry G, et al.  (2013) Schmallenberg Virus Pathogenesis, Tropism and Interaction with the Innate Immune System of the Host. PLoS Pathog 9(1):e1003133. doi:10.1371/journal.ppat.1003133).

I’ve written before about Schmallenberg here and here so I will only go into the background briefly before diving in to the paper.

Background

Correct as of November 2012. From FluTrackers.com

Correct as of November 2012. From FluTrackers.com

Schmallenberg virus was first discovered in November 2011 so it is still pretty new to scientists.  The virus infects ruminants and whilst it only causes mild disease in adult animals, if an animal is pregnant when she is infected then the baby can end up having both muscle and brain problems and can often be born dead.  The virus now seems to have spread across much of Europe (see the map from FluTrackers.com). The virus itself is in the Bunyaviridae family which means that the virus is surrounded by an envelope and has a genome made up of a single strand of RNA (for reference, our genome is made up of a double strand of DNA).  The virus’ genome is made of of 3 sections named (very imaginatively) small, (S), medium, (M), and large, (L).  The genome codes for 4 proteins that are important in making up the structure of the virus.  Schmallenberg virus is in a smaller subsection of the Bunyaviridae family called the Orthobunyavirus.  Orthobunyavirus members not only have the 4 structural proteins but they also have 2 extra proteins (the NS proteins).  This information will be useful for later…

So on to the paper…

Virus Growth

The first thing the authors wanted to do was to find out how Schmallenberg virus grows in various different cells – this is important because if researchers want to carry out experiments on the viruses they need to know what cells to use.  The researchers tested sheep, cow, human, dog and hamster cells lines from organs including the brain, the aorta and the kidney (all of these are cell lines that were grown in the lab – they are not being tested on live animals).  The virus grew in nearly all the cell lines but particularly well in sheep choroid plexus (part of the brain) cells so the researchers used this type of cell for all of the other experiments.

Virus growth in different cell types.  Taken from the paper.

Virus growth in different cell types. Taken from the paper.

‘Rescuing’ the Virus

The next thing the researchers did was design a system to make more copies of the virus.  (Very) basically they took the S, M and L sequences of the virus genome and put the complementary sequence  into plasmids (circular loops of DNA that are found ‘naturally’ in bacteria). (So if the virus sequence was CCG the plasmid sequence would be GGC.) They then put these plasmids into another cell line and these cells replicated the plasmid genetic sequence, so making more copies of the virus.

Looking for a good animal model

Another thing the authors did was investigate whether mice could be used as an experimental model for Schmallenber virus infection.  They inoculated the virus (or a negative control) into the brains of 2 day old mice.  Those mice that were infected with the virus died within 8 days whereas those that had the negative control survived.  They then looked at other ages, using 10 day old and 18 day old mice.  Infection with the virus also killed most of the animals at these ages.  When the scientists went on to look at the brains of these infected mice they found multiple abnormalities and evidence that the virus was in many of the cells.

The authors also looked at the brains of lambs and calves that had contracted the virus ‘out in the wild’ as it were.  They found the virus in places very similar to where they had seen evidence of the virus in the mice, suggesting that the mice might be a good model.

Which bit of the virus makes it harmful

Couple_of_BacteriaA good way to find out which proteins make a disease agent harmful is to stop the virus/bacteria from producing the protein you suspect.  You then infect this mutant back into your cell lines or animal model and look to see if disease still occurs.  If the disease is no longer seen then you know that protein is vital for the disease (although it is possibly not the only one involved).  If the disease proceeds exactly as it did before you know that you were wrong in your suspicion.

The scientists who wrote this paper did just that – they ‘knocked out’ one of the non-structural (NS) proteins and infected mice with the strain.  All the mice inoculated with the original strain died within 9 days (so very similar to the previous experiment), all the control animals survived.  Of the mice infected with the mutant strain, deaths that occurred happened later than they did in the original strain group and 40-60% survived until the end of the experiment.  These results suggest that the NS protein has an important role to play in the disease caused by the virus, although it is obviously not the only one involved.

To investigate this further the scientists first went back to previously published scientific literature – the NS proteins of other viruses in the same group have been shown to inhibit the making of host immune system proteins called interferon (IFN) alpha and beta.  The scientists speculated that this might also be true for the NS protein that they knocked out. To test this they first infected some cells that can produce IFN with the Schmallenberg virus (either the mutant or the original strain).  They then collected the supernatant (basically the fluid on top of the cells).  If their hypothesis was correct then the fluid from the original strain-infected cells would contain not contain any IFN (because the NS protein inhibits its production) but the fluid from the mutant-infected cells would.  They tested the fluid in a very clever way.  They got another cell line, this time one that could not make IFN.  They added the fluid from the first set of cells.  Then they infected these new cells with a 2nd virus.  This 2nd virus is susceptible to IFN so if the supernatant contained IFN the virus would not be able to properly infect the cells whereas if the supernatant did not contain IFN then the viruses would infect the new cell line.

The supernatant from the original strain-infected cells must not have had IFN because the 2nd set of cells got infected with the 2nd virus.  In contrast the supernatant from the mutant-infected cells must have had IFN because the cells did NOT get infected with the 2nd virus.  And so this tied in nicely with the scientists’ prediction.

Finally, to confirm this the scientists infected the 2 virus strains into mice that could not respond properly to IFN.  This time 80% of the original strain-infected mice died within 4 days and the rest died within the next 2 days.  ALL of the mutant-infected mice died within 4 days.  This further suggests that an IFN response is vital for protection against disease caused by Schmallenberg virus.

And that’s where this paper ends…

… having covered a lot.  We now know what type of cells we can grow the virus in, we have a proposed animal model of the disease and we know a little (tiny) bit about what the virus needs to cause disease and what can protect the host.  The paper also has the details of 2 different ways a synthetic virus can be produced (see the ‘rescuing’ section) which sounds like it will be of great help to researchers in the future.

I thought it was a very interesting paper and I am looking forward to discussing it with anyone and everyone who joins us at journal club on Tuesday 22nd January 8pm GMT (just follow the hashtag #microtwjc on Twitter).

Lambie!

Lambie!

Images

The map is kindly borrowed from FluTrackers.com

The ‘When germs go bad’ (one of my favourite microbe pictures) is by Gaspirtz (Own work) (made available under creative commons licence)

The lamb is by Evelyn Simak (made available under creative commons licence)

References

1.Varela, M., Schnettler, E., Caporale, M., Murgia, C., Barry, G., McFarlane, M., McGregor, E., Piras, I., Shaw, A., Lamm, C., Janowicz, A., Beer, M., Glass, M., Herder, V., Hahn, K., Baumgärtner, W., Kohl, A., & Palmarini, M. (2013). Schmallenberg Virus Pathogenesis, Tropism and Interaction with the Innate Immune System of the Host PLoS Pathogens, 9 (1) DOI: 10.1371/journal.ppat.1003133
ResearchBlogging.org

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My thoughts on the GRADschool course

November 7, 2012

Having just started the 3rd year of my (3 year) PhD I’ve been thinking recently about what I want to do when I finish.  There’s one job I’m very interested in doing but I think competition will be tight so I know I need to:

a)      Make sure I know what skills I will need for the job

b)      Make sure I actually have the skills for the job

c)      Just check that there are no other jobs I would be equally happy doing

I’ve been trying to work this out for some time but every time I sit down to have a think about it, whether at home or in the office, something interrupts me.  I wasn’t making any progress at all and was getting very frustrated.  Then I heard about a postgraduate course called GRADschool that was aimed at helping postgrads with their career choices and development.

I’ve decided to write my time on this course up as a blog post because well:

1)      I’ve been trying to tell people about it but I tend to get a wee bit over enthusiastic (start waving my arms about wildly etc.) and then people start to look at me a bit strangely…

2)      I’m very much a verbal type of person so writing it down/talking to myself is one of the ways I best take in information etc.  I’m basically using it to reflect on my experience.

But hopefully this post won’t just be useful for me but will be useful for any other postgrads out there considering whether or not to go on the course.

Read the rest of this entry »

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Zoonotic diseases – causing more problems than illnesses/deaths alone

July 26, 2012

ResearchBlogging.org 

@DiseaseMapper recently tweeted a link to a very interesting paper (which happily is also free to access so you can read it too – the link is here )

Why do I think this paper is so interesting?  Firstly, because it is a useful reminder that zoonotic infections (those that pass from animals to man and vice versa) do not just impact on our lives by causing us illness, and in the worst circumstance, death.  They have a massive economic impact as well.  In fact the paper reports that the estimated economic impact of zoonotic diseases from 1995-2008 was over 120 billion dollars.

There are many reasons for the economic burden of these diseases being so high: impact on tourism; impact on international trade agreements; impact on consumer consumption and behaviour; loss of farmed animals.  In many outbreaks the local economy is negatively impacted in multiple ways and obviously in poorer areas this can also secondarily affect people’s health.

The paper also goes on to speculate about why there should be a resurgence of zoonotic infections.  The authors split it into ‘Factors associated with human behaviour’; ‘Factors associated with pathogen characteristics’ and ‘Climate change and zoonotic resurgence’.  So, pinching their titles…

Factors associated with human behaviour

Here the authors split it down further:

Individual human practices – the authors use the example of ecotourism.  “urban citizens of the developed world who visit developing countries or rural areas of the developed world and engage in activities such as forest camping, river rafting, or bat cave exploring, are prone to zoonotic infections such as vector-borne rickettsioses, leptospirosis, and haemorrhagic fevers or lyssavirus-related illness, respectively“.  The authors also talk about how pet ownership, especially the increase in ownership of ‘exotic’ pets like reptiles is increasing people’s exposure to infections that previously they would never have been exposed to.

Socio-economic alterations – with an ever increasing global population there is an ever increasing demand for food, including meat.  It also means that as urban populations are expanding people are moving into previously uninhabited areas and so are being exposed to disease-causing agents that they had never been previously.

Political alterations - the authors talk about some countries with poorer veterinary surveillance or that have focal areas of zoonotic infections that previously were not having a global impact because they had strictly state-controlled economies but are now having a global impact because they have transitioned to allowing free  trade.  They also discuss the role that political disruption and upheaval can have on increasing the spread of zoonotic infections.

Scientific impacts – Part of the reason that we are recognising so many zoonotic infections is that we have got better at detecting them.  Infectious agents that we couldn’t have characterised decades ago can now be identified and classified.  Another scientific impact the authors mention is one that you will recognise if you are a regular reader of this blog: there have been many advances in medicine that allow us to live to an older age, but that have a negative impact on our immune system (for example, chemotherapy drugs can make us immunosuppressed; if you have an organ transplant you have to take immunosuppressing drugs, etc.)  This leaves a section of the population at a much higher risk of contracting any disease and so gives rise to some human infections with agents that would otherwise not normally infect humans.

Factors Associated with Pathogen Characteristics

The authors talk about how pathogens (disease causing organisms) that have a high genetic mutation rate (like flu viruses) can help them become zoonotic infections: in the authors’ words ” their enormous mutation rate is essentially a factory producing the species that are most potently pathogenic for humans

The authors also talk about how biodiversity can impact zoonotic disease transmission in this section (although, personally I’m not sure why it came into this section).  They talk about how sometimes wide diversity can reduce the spread of zoonotic agents because (if I am parsing this correctly) if there are many host animals that a vector (like a mosquito) can feed off there is less chance of it coming into contact with an animal that harbours the zoonotic agent – this is called the ‘dilution effect’.

Climate Change and Zoonotic Infection Resurgence

To quote from the paper: “Global warming is an ecological emergency, but its implications for human disease caused by infectious agents remains understudied“.  We do know some of the effects it could have – increases in temperature in previously colder countries leads to the spread of insects like mosquitoes – and the diseases they carry –  into those countries.  Climate change may also affect bird migration patterns and so may affect the exposure of birds to pathogens and also the exposure of us to them via the birds.

Finally the paper finishes with Projections for the Future. The authors point to 4 issues that “need urgent clarification and further attention“.

1) Recognition of the need for pre-emptive studies on the effects of massive or smaller developmental projects on local animal fauna and local zoonotic reservoirs

2) Recognition and enhancement of the health literacy of special populations that are at increased risk for the development of zoonotic infections (meaning that those patients on immunosuppressant drugs or who are immunosuppressed for other reasons should get more information about where they might encounter zoonotic infections and hw to avoid them.

3) Recognition of the major long-term burden induced by certain of these diseases with a chronic phase. There are some diseases that take a long time for any symptoms to show.  If a person has migrated from an area where the disease is relatively common to one where the disease is rare, the clinicians may be less likely to recognise the disease (or may recognise it at a later stage than if they were practicing in a country where the disease is common).  The authors recommend that clinicians “should be prepared to recognize the long history evolving in such patients and the extreme costs, mentioned in the introductory section, that will be passed on to the host countries”

4) Planning any intervention is difficult, for financial and scientific reasons. The burden of many of these diseases remains unrecognized… any zoonosis imposes a threat to the family as a unit—exposure is likely to be common for members of a household, particularly in agricultural settings, and animal loss (owing to the disease or state regulations for sick animals) may have a significant impact on the economy of the household, which is further worsened by the often observed inadequate access to appropriate medical treatment for the human patients themselves (imagine the scenario in any impoverished or conflict-active region of Africa or Asia). … ambitious eradication campaigns are not always feasible when all of the aforementioned issues have not been taken into account, and neither are successful elimination campaigns, as these may have temporary positive results but subsequent surveillance degeneration, leading to zoonotic resurgences, usually with some twists. (So basically we don’t really fully know the burden of most zoonotic diseases and rushing in there with eradication campaigns without considering all the other factors is not necessarily the best move.)

I think sometimes it can be really easy to think of zoonotic diseases as something one human gets from one animal, but this paper was a good reminder that these diseases can have a much broader impact.  It also had a useful discussion about why the number of zoonotic infections seemed to be increasing, but as it said (and as all papers say) there is still more work to be done in this area.

Image credit

All images were released under a creative commons licence (see links for details).  Thanks to Rugby471 for the dollar sign, to Wegmann for the tourist shot and to DROUET for the virus

Reference

 
Cascio A, Bosilkovski M, Rodriguez-Morales AJ, & Pappas G (2011). The socio-ecology of zoonotic infections. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases, 17 (3), 336-42 PMID: 21175957

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Fish Pedicures and Zoonotic Diseases

July 10, 2012

ResearchBlogging.org
As you can see the blog hiatus is over – it’s not that things have got a lot quieter (they haven’t), I’ve just missed blogging!  And what better way to get back into things than with a random anecdote…

When a friend asked if I would like a fish pedicure for my birthday my initial response was “Ewwww!”  It wasn’t at the thought of fish biting me per se (I’ve snorkelled and had wild fish do that – it’s not bad but it wasn’t something I found brilliantly therapeutic either). It was the thought that those fish had been nibbling on someone else’s feet before they nibbled on mine – surely that meant they could spread diseases to me?

Well having now had a look at what information is out there it turns out there aren’t many reported problems from these fish.   The Health Protection Agency in the UK produced a report called “Guidance on the management of the public health risks from fish pedicures”(PDF) that states:

On the basis of the evidence identified and the consensus view of experts, the risk of infection as a result of a fish pedicure is likely to be very low, but cannot be completely excluded.

The report also has a list of recommendations it says should further reduce the risk of disease transmission.

So maybe the pedicures are not such a bad idea then…

What I hadn’t considered, (and I really should have done), was that some of these fish could be being imported into the country already infected.

That’s what the scientists behind this letter in Emerging infectious Diseases found.

Large numbers of the toothless carp used in fish pedicures are imported weekly into the UK (generally from Indonesia and other countries in Asia) via Heathrow Airport.

In April last year there had been a disease outbreak among some imported fish and it turned out the bacteria killing them was most likely one called Streptococcus agalactiae.

To get an idea of how common it is for bacteria to be carried into the country by these fish, scientists from the Fish Health Inspectorate of the Centre for Environment, Fisheries & Aquaculture Science (that’s a mouthful and a half!) visited Heathrow Airport 5 times and sampled the fish being imported.

They found quite a range of bacteria on these fish and in their water, some of which did have the potential to infect people too. (Nice!)

The researchers say that these fish or the water they travel in could potentially be harmful to people, particularly those people with previously existing medical conditions like diabetes or who are immunosuppressed for some reason.  They do say however that if fish identified as disease-free were reared in controlled facilities this risk would probably be reduced so perhaps this is the way to go?

Another thing the researchers mention is that these controlled facilities should have “high standards of husbandry and welfare”.  I’m not aware of any studies looking at the welfare of these fish (please let me know if you know of one).  What we do know is that if the welfare of fish is bad then this can lead to poor fish health.  If the fish are unhealthy they are less able to fight off a pathogen (e.g. bacteria) so something that might ordinarily have caused no problems can instead go on to infect many fish and so multiply to really high numbers in the water, increasing the risk to anyone who puts their skin in the water.  (Not that protecting our own health is the only argument for making sure the welfare of these fish is good.)

So if the offer was made again for my next birthday (it’s in autumn – I am obviously not getting over-excited about it already…) would I take it up this year?

I don’t think so.  Not yet.  Not when so many of these fish are imported and we don’t fully know what they are carrying.  Just knowing there was a slight risk would mean I wasn’t very relaxed during my pedicure! :S

Image:

Released under a creative commons licence by jenny8lee

Letter:

Verner-Jeffreys DW, Baker-Austin C, Pond MJ, Rimmer GSE, Kerr R, Stone D, Griffin R, White P, Stinton N, Denham K, Leigh J, Jones N, Longshaw M, & Feist SW (2012). Zoonotic Disease Pathogens in Fish Used for Pedicure Emerging Infectious Diseases DOI: 10.3201/eid1806.111782

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More on Schmallenberg virus…

May 30, 2012

The Society for General Microbiology has released a nice, easy-to-read briefing on Schmallenberg virus which can be found here (pdf).  Plus they have also made available the Schmallenberg lecture I mentioned in this post

 

 

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Short blogging hiatus

May 2, 2012

That’s me up there – or at least it feels like it!

Given how busy I am at the moment, with my PhD, some public engagementy stuff and setting up the new Microbiology Twitter Journal Club (check it out here) I’m going to reduce how much blogging I am doing for a bit (hopefully no longer than 2 months).

I will still be posting links to interesting content from other blogs (like this excellent piece from Contagion on tracking live plague bacteria with bioluminescence and this fascinating post by Maryn McKenna on the long-term effects of food poisoning) but my research blogging will slow possibly to a complete stop.

However, come July when I am hopefully like this:

I shall be back!

In the meantime check out the Microbiology Twitter journal club (#microtwjc).  Even if you are not a microbiologist you can still join in (the papers will all be open access) – if you get stuck on something, just ask.  Chances are you are not the only one!

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Twitter Microbiology Journal Club #microtwjc

April 23, 2012

At the Society for General Microbiology’s Spring Conference in Dublin I attended a talk given by Natalie Silvey on Twitter Journal Club.

The Twitter Journal club (@twitjournalclub) was started in June 2011 and runs as a traditional journal club that discusses medically-related papers with the twist being it is all done by the medium of Twitter.

Having lurked at @twitjournalclub’s meetings a few times and listened to the talk at the SGM I thought it would be great if there was a microbiology journal club and I think others at the meeting thought so too. 

One month after the conference and there is no sign of one being set up so I figured I would get the ball rolling and give it a try…

Details will follow but what I really need are some willing volunteers to help me choose papers, run and moderate it.  It would also be good if people could help out putting transcripts together (I guess storify might be the easiest way of doing this?)

My plan is that we will run twice a month (edited for clarity!) as @twitjournalclub do (schedule to be decided depending on when volunteers can make it but will likely have a UK bias as that is where I am based) and ideally we would have at least a couple of moderators each time.  If there are enough people to help out it would mean that moderators would only have to be around once a month or perhaps less so it shouldn’t take over too much of our lives!  (My aim is for this to be fun and not just another work-related thing to occupy our precious time!)

If you are reading this and thinking it sounds like a good idea but you don’t have enough experience to volunteer – YOU DO!  I did barely any microbiology in my undergrad degree and I’m a second year PhD student – to be honest I feel like a bit of a fraud setting this up!  But my hope is that the volunteers are just there to steer the conversation/ask questions if it all goes a bit quiet.  Hopefully other, more experienced researchers will take part and they can help us out if we get stuck.  Hey – the worst that will happen is that we don’t understand something and so we will go away and find it out and learn something new.  Please don’t be put off helping out because of your level of experience.  ANYONE is welcome.

If you are interested and would like to help out please can you comment here/email me (link in the side bar)/talk to me on Twitter (@_zoonotica_).  It would also help if you could let me know what type of microbes you work with so I can try to make sure we have all areas covered.

For everyone else who can’t help out but would like to take part… watch this space and watch twitter #microtwjc

Images:

E Coli picture – Released into the public domain by Mattosaurus
http://commons.wikimedia.org/wiki/File:Diverse_e_Coli.png

Desk picture – Original picture by MZMcBride. Derivative work by Train2104.  Available at: http://commons.wikimedia.org/wiki/File:Less_busy_desk_red.svg?uselang=en-gb