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This week’s #microtwjc coincides with the Society for General Microbiology’s (SGM’s) Autumn Conference. Sadly I can’t be there this time but I know many #microtwjc regulars are going so I shall be following the conference hashtag, #sgmsus, avidly.
The paper that we will be looking at this week is published in one of the SGM journals: in this journal club we only look at papers that everyone can access and so the SGM has very kindly made it free for everyone to access until 3rd September – thanks very much SGM!
Before I get onto the paper – if this is your first time learning about #microtwjc , welcome 🙂 ! We’re a very friendly bunch who enjoy getting together to discuss papers and we’d love you to join us (no experience necessary!). All you have to do is follow the hashtag #microtwjc from 8pm on Tues. You can do this simply using the search function on Twitter or you can use something like Tweetdeck or Twitterfall. If you’re new to Twitter then this LSE guide is great for getting your head around it.
Lurking silently is fine but we’d love people to contribute as well (even if it’s just to say “I didn’t really understand this bit…” – you won’t be the only one I promise! We’re a group with a wide range of experiences and so at least one of us will be unfamiliar with the topic being discussed.) If you do want to ask questions/make points etc. don’t forget to add the hashtag #microtwjc somewhere in your tweet so we all see it.
So on to this week’s paper:
Vartul Sangal, Peter C. Fineran and Paul A. Hoskisson (2013). Novel configurations of Type I and II CRISPR-Cas systems in Corynebacterium diphtheria
(It’s so hot off the press that it’s still in the prepublished pdf version!)
Clustered regularly interspaced short palindromic repeats (CRISPRs) are major barriers to recombination through recognition of invading nucleic acids, such as phage and plasmids, and promoting their degredation through the action of CRISPR associated (Cas) proteins. The genomic comparison of 17 Corynebacterium diphtheriae strains led to the identification of three novel CRISPR-Cas system variants, based on the Type II (Type II-C) or Type I-E systems. The Type II-C system was the most common (11/17 isolates) but it lacked the csn2 or cas4 genes that are involved in spacer acquisition. We also identified this variant Type II-C CRISPR-Cas system is also present in other bacteria, and the first system was recently characterised in Neiserria meningitidis. In the remaining isolates, the Type II-C system was replaced by a variant of Type I-E (I-E-a), where the repeat arrays are inserted between the cas3 and cse1 genes. Three isolates with the Type II-C system also possess an additional variant of Type I-E (I-E-b), elsewhere in the genome, that exhibits a novel divergent gene organization within the cas operon. The nucleotide sequences of the palindromic repeats and the cas1 gene were phylogenetically incongruent to the core genome. The G+C content of the systems is lower (46.0-49.5%) than the overall G+C content (53%), and they are flanked by mobile genetic elements, providing evidence they were acquired in three independent horizontal gene transfer events. The majority of spacers lack identity with known phage or plasmid sequences, indicating that there is an unexplored reservoir of corynebacteriophages and plasmids. These novel CRISPR-Cas systems may represent a unique mechanism for spacer acquisions and defence against invading DNA.
- What did you think of the paper? Was it easy to read? Did the results back up the conclusions drawn? etc.
- What do the results mean in the broader context of research on C. diphtheriae?
- What work would you like to see done next?
- On a broader note, where do you see CRISPR work in general heading?
As usual, if you do write a blog post about the paper please plug it below in the comments – it’s always very helpful when people do this.
I look forward to tweeting old and new members alike on Tues 3rd September, 8pm UK time.
If you want email reminders about the journal club (no emails about anything else I promise) – please contact me: zoonotica at hotmail dot co dot uk.
Image: Published under a Creative Commons 3.0 licence by Copacopac
I’ve been meaning to write about this paper for some time…
Viruses continue to cause extensive morbidity, mortality and not to mention economic stress, worldwide by infecting and causing disease in humans, animals and plants. Vaccines have been able to control many of the major viral diseases (smallpox, rinderpest, polio, measles…) but the development of vaccines against all viral pathogens is unrealistic and inefficient with current methods of R and D, testing and production.
When you consider the numbers of currently unknown, uncharacterised viruses replicating in reservoirs of animals or plants that have the potential to jump species (e.g MERS-CoV) and cause outbreaks (ebolavirus), epidemics (nipah) or even pandemics (influenza) then the thinking that generating vaccines against all these viruses becomes even more untenable. Even to generate specific antiviral drugs against them all becomes impossible.
This is why we have a back-up plan. This is why we broad-spectrum antivirals. Broad spectrum antivirals are drugs that will inhibit diverse viruses and are usually based upon targeting a common phenotype linking all the viruses (RNA dependant RNA polymerase, neuraminidase enzyme, RNA genome, RNA dependant DNA polymerase). These drugs tend to suffer from a number of problems 1) they aren’t all that broad spectrum, 2) resistance to antivirals can evolve rapidly and 3) we simply need more broad spectrum options.
This is why I have chosen the following paper for #microtwjc :
The paper describes an international collaboration between virologists and chemists that resulted in the development of a novel, highly effective, broad spectrum antiviral molecule that has little affect on the functioning of the host cell. The interesting thing is that the molecule inhibits virus – to – cell fusion of the viral envelope with the host cell plasma membrane, i.e one of the most important early steps in the virus (obligate intracellular parasite) lifecycle.
(the drug was originally described here: http://www.ncbi.nlm.nih.gov/pubmed/20133606)
Some points on the paper:
1) They know at what point the molecule inhibits (a late stage in virus-to-cell fusion).
2) They know that it leads to the oxidation of fatty acids in all membranes. (but only affects viral ones)
3) They know to do so it has to generate oxygen free radicals in the presence of light
4) Fatty acid oxidation changes membrane properties to prevent fusion of one membrane to another.
5) They can optimise the molecular to make it even more effective
6) It works to some degree in vivo, but cannot wholly prevent virus-induced disease and death.
And here are some discussion points:
A) do we really need broad-spectrum antivirals? Who is going to have access to these?
B) Is virus envelope fusion a good target? What about non enveloped viruses? What about viruses that can spread via cell-to-cell fusion with limited virus-to-cell?
C) Would these drugs induce viral resistance evolution?
D) Oxidisation of viral lipids sounds a good idea, how come evolution has not come up with this idea already? …Or has it?
E) In vivo it don’t look so good. How come? Can it be made better?