Monday, December 26, 2016

Break announcement- 4

Greetings

Fig 1: My Blog Statistics (Page hits) till date.
As has been the recent custom in this blog, am taking a official break from blogging. I would consider that I have successfully completed 5 years of blogging, and the end of this year has seen a steady rise in readership base. Including this post, I have posted a total of 54 posts for the year 2016. Thats not bad. That almost one post a week. I encourage you to go back and read my earlier posts that have been missed.

Wish all my readers, a happy festive time, vaccation and a happy new year in advance. I will see you back in 2017, with exciting new stories of microbiology.

Wednesday, December 21, 2016

Mycobacterium Tuberculosis CdnP hijacks Immune response

Greetings

M tuberculosis is a topic that has come up several times in this blog. Tuberculosis is rampant in many developing and underdeveloped countries. The lead problem with combating tuberculosis has been difficulty in laboratory diagnosis, which has been now addressed with new generation cheaper tests which are available worldwide. An equally enormous challenge is treatment, which is due to its long treatment time often ranging to several months. That makes vaccination and exceptionally important tool. Though a universal vaccination campaign is in working order (BCG vaccine), TB is something that has not been eradicated or even controlled.

TB-immunology is a deeply researched topic. As I have explained in multiple earlier blog posts, it is wrongly conveyed by many that TB doesn’t cause an immune response. TB infection does elicit a strong Type IV immune response. This is evident from tests such as Mantoux positivity and granulomatous histopathological findings. What is not achieved is, the immune response is not directed enough to induce pathogen clearance. There are several factors at an independent level which coordinates the immune resistant ability- Intracellular localisation being one among them.

So, give this question a deep thought. Does all intracellular pathogen (Keep the question limited to bacterial pathogens for simplicity) cause chronic infection via resistance to immune attack? The answer is definitely “No”. So mere sitting inside a cell doesn’t help, since intracellular location in itself isn’t a very good defence. Cytosolic surveillance pathway such cGAS-STING pathway can recognise intracellular pathogens and stimulate an innate immune response. These pathways have been well studied for viral infections, but not for bacterial infections. See my earlier post on STING response pathway (Link)

A simple explanation goes something like this. When M tuberculosis infects and internalises into a cell such as a macrophage, the bacterial DNA and c-di-AMP signal is captured in the human cell as the bacterial entry. In response, a molecule called cGAMP is made which signals innate response. In reality, Dey et al;2016 (Paper published in Nature chemical biology) have identified that this signalling never quite happens.
Fig 1: Graphical abstract of the study. Source
The findings of the study are schematically represented in Fig 1. Bacterial cyclic dinucleotide phosphodiesterase (CdnP) action reduces immune detection of bacterial derived c-di-AMP and c-di-GMP and host-derived 2′3′-cGAMP by degrading them into non immunogenic nucleotides. These molecules being danger signals, non detection of these signals leads to numbing of innate response pathways. Host cells possess a control system called ENPP1, which degrades the 2′3′-cGAMP thereby controlling the inflammation. The researchers show that ENPP1 can also degrade bacterial cyclic di-nucleotides. To further look into the evidence, researchers created TB mutants for CdnP and infected a mouse model through aerosol route.

Fig 2: PDEi tested for CdnP inhibitory activity. Source
They showed that indeed there was a significant difference in survival and lack of CdnP was associated with increased survival. This is an indication that CdnP is a possible drug target. So the group tested several phosphodiesterase inhibitors (PDEi) including some FDA approved drugs- Tadalafil, Sildenafil and Cilomilast and Cilostazol. Fig 2 shows commercially available PDEi tested for their ability to inhibit CdnP activity. FDA-approved drugs are marked as *. Though the study shows possible PDEi the authors caution that they are not optimal for development as drugs owing to potential membrane-permeation liability. Further, these PDEi may cross react with ENPP1 which may further impact the outcome.

Herman O Sintim, one of the authors in the paper comments, “The host cGAMP never gets to a high enough concentration to activate the immune response. This is a very effective strategy the bacteria have developed to suppress an immune response.”

  Dey R, Dey B, Zheng Y, Cheung L, Zhou J, Sayre D et al. Inhibition of innate immune cytosolic surveillance by an M. tuberculosis phosphodiesterase. Nature Chemical Biology. 2016. doi:10.1038/nchembio.2254

Wednesday, December 14, 2016

Microbiome and the Parkinson's

Photo 1: An essay on the shaking palsy.
Greetings

The concept of microbiome being involved with clinical conditions is now a heavily discussed concept. I have written several posts about this topic and readers are referred to my earlier posts for details. Most recently, a paper published in Cell has explored the connection between Microbiome and Parkinson's disease, which is making a lot of news. Certain findings of the paper have been hyped in the media and so I decided to write a detailed post about this paper.

Parkinson's disease (PD) is a chronic, progressive movement disorder (a subtype of motor system disorders) caused due to a loss of dopamine-producing brain cells. The condition was long known but gained its name and importance following a publication "An Essay on the Shaking Palsy" by a London doctor James Parkinson in 1817. PD is a type of Synucleniopathy (or rather called as α-Synucleinopathy). Synucleinopathies are neurodegenerative diseases characterised by the abnormal accumulation of aggregates of α-synuclein protein in neurons, nerve fibres or glial cells. In PD, it is postulated that the aggregates accumulate in dopaminergic neurons leading to death of the cells. However, there is no single explanation for the pathogenesis and biological pathway leading to PD.

The concept of gut microbiota and its link with Central nervous system is a theme I have talked about several times in this blog. Association of microbiome with neurodegenerative diseases is not a new publication, neither is the association with Parkinsons. A paper published in 2014 by Filip Scheperjans and colleagues, showed by fecal microbiome study from 72 patient vs 72 control subjects that there is a significant drop in abundance of Prevotellaceae in feces of PD patients by as much as 77.6%. In fact, Prevotella is also negatively assocaited with autism. Prevotella species is known to influence higher levels of neuroactive short chain fatty acids (SCFA) and a high capacity for biosynthesis of thiamine and folate, which is also in agreement with findings of lowered levels of short chain fatty acids in PD feces sample. Here is an interesting observation. Using intestinal biopsy of PD patients before onset, α-synuclein has been shown to be positive by immunostaining but negative for healthy controls. It has been shown that that newly diagnosed PD patients had increased intestinal permeability and abnormal accumulation of α-synuclein in enteric neurons. This also correlates with a significant number of papers showing that more than 70% of the PD patients on average have some gastrointestinal abnormalities, which precedes the appearance of motor symptoms.

In the latest paper in cell by Sampson et al; 2016, they looked into if microbiome can influence the Synucleinopathy. As stated by the senior author Mazmanian, "Because GI problems often precede the motor symptoms by many years, and because most PD cases are caused by environmental factors, we hypothesized that bacteria in the gut may contribute to PD."

Fig 1: Graphical abstact of the paper.
Source
The experiments were conducted using mice engineered to overexpress the protein α-synuclein. In the first experiment, 3 groups of mice was prepared- 2 groups had complex intestinal microbiome and one group was germ free (GF). Experiments measuring motor skills showed that germ-free performed much better. They also showed that GF mice treated with microbially produced SCFA activated microglia.

In the next set of experiment, GF mice were transplanted with fecal samples from human patients with and without Parkinson's disease. The germ-free mice who received transplants from PD patients showed a significant increase in PD symptoms. See Fig 1, for a summary.

Sarkis Mazmanian comments, "Our findings provide a completely new paradigm for how environmental factors may contribute to Parkinson's disease and possibly other neurodegenerative disorders. The notion that these diseases may be impacted by pathology in the gut and not only in the brain is a radical departure from conventional research in neuroscience. Parkinson's disease is complex and there are several genetic predispositions and environmental risks that play a role, but we believe our findings shed light on a previously unrecognized and potentially important part of this puzzle."

It must be noted that this study uses a mouse model overexpressing α-Synuclein. It is unilkely that human PD can be treated with fecal microbiome transfer or use of probiotics. But what is more likely is use of probiotc may alleivate the PD symptoms.

References

1. Scheperjans F, Aho V, Pereira P, Koskinen K, Paulin L, Pekkonen E et al. Gut microbiota are related to Parkinson's disease and clinical phenotype. Movement Disorders. 2014;30(3):350-358. 

2. Shannon K, Keshavarzian A, Dodiya H, Jakate S, Kordower J. Is alpha-synuclein in the colon a biomarker for premotor Parkinson's Disease? Evidence from 3 cases. Movement Disorders. 2012;27(6):716-719. 

3. Sampson T, Debelius J, Thron T, Janssen S, Shastri G, Ilhan Z et al. Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson’s Disease. Cell. 2016;167(6):1469-1480.e12.

Wednesday, December 07, 2016

Blogger's Desk#10: Top 10 My Picks of Microbiology Blogs

Greetings

I have been busy recently and haven't been able to post regularly in the last couple of days. I have a couple of things that I wanted to write about and more recently I have been getting a lot of mail requests to write more basic stuff, that is useful fro grad students. The "Back to basics" and "Laboratory series" section is being especially liked by many. In future, I would sure look into it more in the future.

There are several microbiology blogs out there on the web and many have a great readership base. As 2016 is nearing to an end, I want to post my picks of microbiology blogs worth reading. Please be aware that this is my top 10 and I have my personal bias built into this list. If you think I should have included one (which is not on the list),  please add a comment.

Let us start with a reverse countdown of my choices.

10. The Genome factory

Tagline: Bioinformatics tips, tricks, tools and commentary with a microbial genomics bent.
Contributor: Torsten Seemann
http://thegenomefactory.blogspot.com

Microbiologists by default, have a problem in understanding computational biology though most of us are working on this concept. The blog has some really good posts, but posts are very rare. There are hardly 2-3 posts a year, since 2011. So if you want to know something about the Bioinformatics, have a look at this page once.

9. Aetiology

Tagline: Discussing causes, origins, evolution, and other implications of disease and other phenomena.
Contributor: Taca C. Smith
http://scienceblogs.com/aetiology/

She has been writing since around 2005, and posts appear once in a month (skipped once in a while). The posts are true to the tagline with a good explanation. There is a wide range of topics in this post, and worth the time spent reading.

8. Infectious thoughts:

Tagline: The blog of Dr. Siouxsie Wiles, a microbiologist who knows a lot about bacteria, viruses and infectious diseases.
Contributor: Siouxsie Wiles
http://sciblogs.co.nz/infectious-thoughts/

The page has a lot of science information and written so well, no wonder there is a big reader base for this blog. The blog is not specifically focussed on microbiology and there are a lot of posts on other scientifically important stuff.

7. Living in a microbial world

Tagline: -
Contributor: Nicola Fawcett
https://livinginamicrobialworld.wordpress.com/about/

A blog that focuses a lot on microbial stuff and antibiotics. The blog is up and running but the posts are not very frequent and appear approximately once in a month. This blog is up since around 2015 and its lucid style makes it something of an interesting approach.

6. Microbiology Info

Tagline: Online microbiology notes
Contributor: Sagar Aryal
http://www.microbiologyinfo.com

This page is all about teaching basics to the undergrads who are looking for some basic information. There is no particular periodicity of publication, but he writes when he wants to. The pages are pretty much up to date and most of the information that is being sought by a learner can be found here. The page also has many other interesting things, such as an app for bacterial identification.

5. Prophage

Tagline: The Blog for Bacteria, Phages, Computers, and Science
Contributor: Geoffrey Hannigan
http://prophage.blogspot.com

The blog has a very broad focus on Prophage, and there are quite a good number of important updates about research and other related, interesting topics. Active since 2013, has a good number of posts.

4. Pharmaceutical Microbiology

Tagline: Microbiology, pharmaceuticals, healthcare and contamination control news and discussion site
Contributor: Tim Sandle
http://www.pharmamicroresources.com

Almost everyone who reads microbiology news knows Tim. Just google his name and you will get a huge list of articles he contributed as a science communicator. I'm not sure if his web page should be called a blog, but it is updated regularly and has a lot of content that a microbiologist should be mandatory aware of.

3. Contagion

Tagline: Contagions is place to collect some thoughts on history, infectious disease and science in general
Contributor: Michelle Ziegler
https://contagions.wordpress.com

A biologist with interests in public health that's how the author defines himself. The tagline is well justified by his posts. The way things are written makes it a never boring read.

2. Virology blog

Tagline: -
Contributor: Vincent Racaniello
http://www.virology.ws

A great deal of global population listens to his microbiology podcasts and his blog is full of interesting stuff. If you haven't read his posts, well you really haven't read a good blog. A must in blog roll.

1. Small things considered

Tagline- http://schaechter.asmblog.org
Contributor- Multiple
http://schaechter.asmblog.org

This is a blog that I have never missed to read in years. I have read every post in it and what inspired me to start blogging. If I recall it right, this blog is up since about 2006 and clearly is the best, professionally maintained. Quoting from their website, "The purpose of this blog is to share our appreciation for the width and depth of the microbial activities on this planet. We will emphasize the unusual and the unexpected phenomena for which we have a special fascination". Needn't highlight that they are part of the ASM, with high quality of information.