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Wednesday
Sep212011

A few things I learned at Cold Spring Harbor Laboratories:

I spent the last week at the Cold Spring Harbor Laboratories on Long Island. This is a magical and beautiful place for science, and I had the pleasure and honor of being there talking about microbes amongst wonderful scientists.

Eight Nobel laureates including Barbara McClintock (who discovered transposons, or jumping genes), Alfred Hershey & Martha Chase (confirmed DNA as the genetic material) and Salvador Luria (who worked on phage, or bacterial viruses), all worked and played at Cold Spring Harbor Labs. A bonus was eating lunch next to James Watson (or Jim as I call him) from Watson and Crick, who won the Nobel Prize for determining the structure of DNA (it's a double-helix y'all).

1) Why ticks are successful ninjas.

Thanks to Joao Pedra, from University of California Riverside, and his talk “Inhibition of the Inflammasome by a tick salivary protein”, I learned why these teeny arachnids can bite mammals and live on their skin without being noticed for weeks at a time, and pass on horrible bacterial infections like Lyme disease.

It turns out that tick saliva has anti-inflammatory capabilities. Apparently, there are specific tick proteins (those of which will not be named – because I can’t find them in a publication, therefore this is TOP SECRET) that interact with human proteins to dampen the immune response so ticks can bury their little bodies into our cankels without our knowledge and infect us with the pathogenic bacteria they have been carrying around.

Generally when a foreign invader is detected by the immune system there are inflammatory pathways that signal with excitement so the cell can produce pro-inflammatory cytokines and chemokines (molecules secreted by host cells to communicate about invaders or irregular cellular growth) and possibly end in cell death – like apoptosis (planned cellular suicide) or pyroptosis (inflammatory cellular suicide).

HOWEVER, when the tick releases saliva onto the host cell a tick salivary protein interacts with these pathways and stops inflammation and allows the tick to stay within the host undetected and infect us with tick-borne bacteria. The pathways they interact with are currently under investigation, however I have my guesses.


I happened to ask him how he extracts the tick saliva in mass quantities and it involves collecting 2uL of tick saliva from tick bites on rabbits - until he got 500uL... that's a lot of tick bites.

An interesting side note, different species of ticks carry different pathogens; therefore the tick that carries the rickettsial pathogen Anaplasma phagocytophilum is different than a tick that carries Francisella tularensis – and this is very important in dampening the host immune response. The saliva isolated from a tick that carries Anaplasma phagocytophilum cannot prevent inflammation during a Francisella tularensis infection, and vice versa. This side note is intuitive, but interesting because it means that the bacterial pathogen carried by the tick has evolved to the tick species, as well as evolved to infect us!

2) Why lady bugs are more “highly evolved” than you and I.

The answer was right in front of us, they have been around longer and they replicate faster, therefore they’re more highly evolved. I also learned that lobsters can grow to be 30-50 years old; I hope you consider that next time you bite down into that juicy tail.

On a more serious note, Stephen Hedrick from University of California San Diego gave a brilliant talk entitled “Immunity: the cause of its own necessity”, that covered questions concerning the evolution of our adaptive immune system (that uses B cells or antibody-producing cells and T cells for long-term immunity) and why some pathogens are more successful than others. For example: why are some viruses around for hundreds of years (like flu) and why are some around for a brief period of time (like ebola)?

3) That we’re still discovering bacterial species in the small intestine.

The knowledge that microbes are present in our bodies reaches back almost 400 years ago when Leeuwenhoek visualized the first bacteria by examining samples from his… cavities... (Microbiology has always been a romantic science). Now it is everyday knowledge that there are more bacteria in our gut than cells in our bodies. However, these are not mere passive colonies of microbes, but these tiny hanger-oners form dynamic and interactive lifestyles with host cells – and they are absolutely necessary for normal host function (on a cellular level and on an organismal level). Bacteria synthesize important vitamins (pretty much all vitamin B’s – like biotin and folate), provide essential enzymes for digestion, metabolize all the delightful milk products you ingest, help salvage energy, and more recently help maintain overall host homeostasis.

It was shown a few years ago that T cell populations in the intestine, Th17 cells and Tregs, require signals from commensal bacteria (bacteria in the gut) to keep homeostasis in the intestines. Th17 cells are immune cells that play a very important role in clearance of infections, and loss of these cells results in an increased susceptibility to infections. Tregs, or suppressor T cells, are named appropriately – they suppress activation of the immune system to maintain homeostasis and promote tolerance to self-antigens (so your immune system does not attack your own cells, you need those).

Dan Littman’s group, from Skirball Institute in New York, showed the balance between these two cells types in the gut is crucial for maintaining homeostasis, and the balance is influenced by the intestinal microbiota.

But to stay on track with my new revelation – A few years ago Littman’s group found a new bacterial species in the gut of mice, segmented filamentous bacteria (SFB) (pic left), that are required for inducing Th17 cells in the gut, therefore maintaining T cell homeostasis. They found these bugs by looking at mice without Th17 cells and mice with Th17 cells. The gut microbes found in each mouse colony were very different, including many species that have never been identified, SFB being among these. In Th17-containing mice SFB was abundant, but completely absent in Th17-deficient mice. SFB most closely resembles Clostridia species, but not a lot of research has been done on SFB because no one has discovered how to grow them in broth.

To prove SFB was responsible for the presence of Th17 cells, they infected germ-free (GF) mice with SFB. GF mice are not colonized by any bacteria; therefore they’re the perfect blank canvas. After infection with SFB there was a large induction of Th17 cells, and this induction was specific to Th17 cells. This is good for the mouse because the presence of more Th17 cells means there is an increase in microbe-fighting cells and it increases the ability of the host to fight off infections. But! If you have too many Th17 cells you would constantly have inflammation, therefore you need Treg cells to calm the system down, so there is an increase of Treg cell recruitment - creating a perfect balance between the two populations.

This was the very first example of gut microbes inducing T cell populations, therefore influencing T cell balance and affecting the total immune fitness of the mouse.


The composition of the intestinal microbiota participates in the regulation of immune homeostasis.

Left panel - different microbes signal to different parts of the immune system, regulating T cell response in a particular pattern.

Right panel - Changes in the composition of gut microbes (ex: adding SFB), shift the immune system in a different direction. In the case above, there is an increase in Th17 cell signals (IL-17). There is an increase in anti-microbial peptides (blue circles) which increases the hosts ability to fight off infections.

Dan Littman’s talk “Role of the intestinal microbiota in systemic Th17 cell-mediated disease” elaborated on the communication between SFB and Th17 cells and their effect on the status of T cell balance and gut homeostasis. I was blown away by the novelty of discovering new microbial species that play such a large role in immune regulation. I will note this was all done in mice, and he hasn’t found SFB in humans – however it makes you wonder what human microbes are doing down there while we’re at work updating our blogs.

ResearchBlogging.org

Ivanov, I., Atarashi, K., Manel, N., Brodie, E., Shima, T., Karaoz, U., Wei, D., Goldfarb, K., Santee, C., Lynch, S., Tanoue, T., Imaoka, A., Itoh, K., Takeda, K., Umesaki, Y., Honda, K., & Littman, D. (2009). Induction of Intestinal Th17 Cells by Segmented Filamentous Bacteria Cell, 139 (3), 485-498 DOI: 10.1016/j.cell.2009.09.033

Ivanov II, & Littman DR (2010). Segmented filamentous bacteria take the stage. Mucosal immunology, 3 (3), 209-12 PMID: 20147894

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Reader Comments (7)

This sounds like an extremely informative conference.

Do you know if the pulling of ticks (not leaving their heads!) causes inflammation? Or, rather, why? I pulled some out of my skin a few months ago, and they swelled a bit like a mosquito bite and were irritated for several days.

September 21, 2011 | Unregistered CommenterSarah Scoles

I'm guessing without constant production of tick saliva there wouldn't be constant suppression of inflammation, so it would swell up like you saw.

September 21, 2011 | Unregistered CommenterBrooke N.

Nice post B! Some really interesting tidbits. Gut microbiota is one of my favorite topics, and it influences so many things (our metabolism, immune response, etc).

September 22, 2011 | Unregistered CommenterBrigid

PS- your white text on black background hurts its precious, more specifically my eyes... I am seeing stripes now

September 22, 2011 | Unregistered CommenterBrigid

Hahaha, oddly enough I read a study that people pay more attention to saturated backgrounds and light text.... they didn't mention the stripe-effect afterward...

September 23, 2011 | Unregistered CommenterBrooke N.

I think the tick saliva component you're looking at in Lyme disease is called Salp 15.

I looked at PubMed using "Salp 15" and "proteins" as keywords, and one of the 23 papers there might contain some clues for you as to composition, but they may be behind pay walls. Hopefully you have an Athens account or access in general.

See: http://www.ncbi.nlm.nih.gov/pubmed?term=Salp15%20proteins&itool=QuerySuggestion" rel="nofollow">http://www.ncbi.nlm.nih.gov/pubmed?term=Salp15%20proteins&itool=QuerySuggestion

September 26, 2011 | Unregistered CommenterCamp Other

Incredible discoveries and revelations. I would say, that ticks are the worst to learn about.

February 1, 2012 | Unregistered CommenterAjlounyinjurylaw

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