Friday, March 26, 2010

Help me Win a MiniGrant!

Francisella tularensis is a ninja: silently attacking our cells, undetected by our immune system is sponsoring a mini-grant competition. The winner(s) receive $500 towards the pursuit of their particular project.

Proposals have 100 words or less to convince readers (including non-microbiologists) to vote for the project. You can vote for mine through Facebook at this link.

I've included my proposal here to catch your interest:

Bacterial Super-Ninjas: Staying in the Shadows:
Like a ninja on a mission, Francisella tularensis is a silent, deadly bacterial pathogen. Despite being weaponized and a recognized bioterrorism agent, little is known about how Francisella escapes immune detection. We have isolated a Francisella protein that blocks the immune system’s ability to sound alarms during infection. Preliminary evidence suggests that it is used as a projectile weapon, directly attacking immune communication lines. This grant will allow us to examine how this protein is fired from Francisella into our immune cells, rendering them mute. Importantly, this represents a novel target for vaccine development against this bacterial assassin.

Here is the voting link again: Bacterial Super-Ninjas: Staying in the Shadows

If you have any more questions, such as specifics to what I will do with the funds if I win or a more technical outline of my project, feel free to e-mail me!

You can vote once per day, so feel free to continue voting until the contest ends in May!

Thank you so much!

Monday, March 8, 2010

A Role for the Host-Microbe Interface in Obesity

by Tim

This post was chosen as an Editor's Selection for ResearchBlogging.orgOur bodies are home to 10 times more bacterial cells than human cells. With such sheer numbers, we have developed an intricate balance with the mutualists living on our skin and in our guts. Their mere presence is vital for protection from pathogenic species; but at the same time, our immune system must keep their numbers in check to prevent overgrowth.

Those bacteria within our guts perform important roles in fermenting carbohydrates and producing essential nutrients like vitamin K and biotin. As such, it is not too difficult for us to realize the importance of our gut flora in our health. I do not even need to mention the countless mainstream (and not so mainstream) probiotic supplements available in grocery stores.

Over the last few years, there have been a number of studies demonstrating the importance of gut flora in proper metabolic function, where dysfunction yields obesity. One article published in Nature in 2006, described a microbiome sequence comparison of obese vs. lean mice, finding the ratios of different phyla between the two mice strains. A few complementary studies have been performed since with the same result: the metabolism of the microbes in the gut is directly linked to the host's metabolic health.

This raises the question, how is gut flora composition determined? While studying up on some innate immunology literature for my qualifying exam, I came across this fantastic article set for publication in Science describing the role of the innate immune system in regulating those microbes necessary for proper metabolic function.

The authors describe the metabolic dysfunction of Toll-like Receptor 5 knockout mice. TLR5 is a receptor present on innate immune cells and intestinal epithelium and is responsible for sensing bacterial flagellin, subsequently priming cells for an immune response. Interestingly, mice deficient in TLR5 show drastic metabolic dysfunction; the authors go to a great extent characterizing this phenotype. Everything from fat pad size, to blood glucose, insulin, cholesterol and triglyceride levels are significantly increased in the mutants.

Furthermore, when the gut flora of the TLR5 knockout mice are depleted by antibiotics, the metabolic dysfunction clears and the mice's metabolism returns to wild-type levels. To top it off, the gut flora of TLR5 knockout mice were removed and introduced to wild-type germ-free mice. The introduced gut flora induced metabolic dysfunction in these wild-type mice identical to that of the TLR5 knockouts.

Unlike previous studies which saw different ratios of bacterial populations between obese and lean mice (ie. %Firmicutes vs %Bacteroidetes), this study found that instead specific species were present or absent in the TLR5 knockouts, indicating a role for TLR5 in maintaining specific characteristics in population of gut microbes.

This is the first study, to my knowledge, which equates mucosal immune surveillance with a metabolic phenotype. Furthermore, it strengthens the argument that the complex interactions we have with our bacterial symbiotes are vital to our physiology. The microbes around us do more than just cause disease or ferment our cheese, but are also key in allowing us as an organism to function.

Vijay-Kumar, M., Aitken, J., Carvalho, F., Cullender, T., Mwangi, S., Srinivasan, S., Sitaraman, S., Knight, R., Ley, R., & Gewirtz, A. (2010). Metabolic Syndrome and Altered Gut Microbiota in Mice Lacking Toll-Like Receptor 5 Science DOI: 10.1126/science.1179721

Other Articles of Interest:
How Helicobacter Gets Around
A Home for the Bugs in Our Appendix
A MAP to Crohn's Disease: Revisiting Koch's Postulates
Altruism in Bacteria: Allowing Yourself to Die for the Good of the Species

Friday, March 5, 2010

Noisy and Bistable Gene Expression: Hedging Your Bets

by Tim

ResearchBlogging.orgThis is Part 2 of a two part series. Part 1 can be found here.

Often times resistance to antibiotics has a genetic basis. That is, a bacteria encodes a protein that functions to export, degrade, or otherwise block the function of a given antibiotic compound. However in the last few years, the observation of non inherited antibiotic resistance has come into view. One of my favorite articles describing the phenomenon is one by Nathalie Balaban et al, in Science back in 2004, particularly due to her super cool use of microfluidics and single cell imaging.
Following treatment with ampicillin, cells in a persistant state are readily identified
Following treatment with an antibiotic, a bacterial population doesn't completely die off, but instead shows at first a drastic decrease in viable counts followed by a much slower rate of death. Those cells isolated at later time points are not resistant to the antibiotic, and when grown to full populations show the same sensitive phenotype. These cells are termed "persistors" and are a form of non-genetic resistance to antibiotic treatment.

Many of us know that some antibiotics require actively growing bacteria to be effective. Particularly, the use of the beta-lactams which are only effective when a cell is growing it's peptidoglycan, such as during replication. However, Balaban shows us that even in an actively growing population of identical cells in identical environments (microfluidic chambers), there is a very small subset of cells which are not growing. These cells aren't defective, but rather are in a paused growth cycle, allowing them to be resistant to ampicillin at that moment in time. When these cells restart their growth, their progeny are still sensitive. Again, a key point in demonstrating that this formTwo ways to hedge your bets; but don't try this in Vegas of resistance is non heritable.

Very likely, genetic noise, as described previously, plays a role in determining the cell's fate. However, the more important point here (in my humble opinion) is that this is a beautiful example of a population that is "hedging its bets."

By having two sub populations: a majority that is actively growing, and a small percentage that is paused, that identical set of genes in both populations is capable of either 1) exploiting the current resources at the risk of antibiotic death or 2) taking a short pause in growth allowing antibiotic resistance at that time, at the risk of losing out on some resources. A risk, but with large rewards.

Each has their consequences, but together allow for a dynamic population without changes in genetic content (hence the non inherited resistance). Other great examples of bet-hedging include: sporulation and cannibalism in Bacillus, and the induction of inflammation by Salmonella.

Nathalie Q. Balaban, Jack Merrin, Remy Chait, Lukasz Kowalik, Stanislas Leibler (2004). Bacterial Persistence as a Phenotypic Switch Science, 305 (5690), 1622-1625 :

Other Articles of Interest:
Noisy and Bistable Gene Expression: Why Genes and Environment Aren't Everything
Altruism in Bacteria: Allowing Yourself to Die for the Good of the Species
Antibiotic Treatment: Increasing the Rate of Genetic Exchange

Personal Note:
Due to my ever-looming qualifying examination (April 30th), updates to The Times Microbial may be rarer than usual this semester. I hope to get back to full swing, perhaps with some surprises, this Spring.