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Dec312012

Thinking outside of the box: How do complex organisms clear infections? 

by Brooke Napier

Sometimes when you have a big, hard, involved question you have to think outside of the box in order to answer it. Stepping outside of the box can be uncomfortable and brings a lot of uncertainty, but it can also be extremely interesting. 

Which brings me to my big, hard, involved question…This picture comes up when you google "Hard questions". I have a lot of questions about this picture, I'm not sure if they're "hard".

How do complex organisms, like us, clear infections?

Scientists generally go about this question by looking at very specific mechanisms used by the immune system and asking, how does such and such mechanism contribute to clearing infections?

An example of what I’m talking about would be:

Question: Does Peptide B contribute to clearance of a Listeria monocytogenes (causative agent of listeriosis) infection?

Method: Delete the peptide B gene in the mouse genome and infect that mouse with Listeria monocytogenes, conjointly infect a normal, non-mutated (wild-type) mouse with Listeria monocytogenes.

Results: Twenty-four hours post-infection the wild-type mouse has no detectable bacteria throughout its organs, however the Peptide B gene mutant mouse has large quantities of L. monocytogenes in its lung, spleen, and liver. Therefore, Peptide B is important in the clearance of L. monocytogenes in the lung, spleen, and liver.

This is a good way to start answering questions about clearing infections, and we are light-years ahead of what we knew only 10 years ago about this question… but perhaps we should step away from picking apart the specific immune system mechanisms, considering our immune system is an intricate network of mechanisms all striving to clear the infection together. Essentially, “each [immune] response does not exist in a vacuum”.

So what’s a different way? Well, you have to step outside of the box.I know, I feel it too.

David Schneider and his group at Stanford have done just that.

Moria Chambers, from this group, writes: “While it may be simplest to examine the effect of immune components individually, in order to effectively control immunity clinically we need a better understanding of the full immune network… [and that] patients normally do not have a single pathway or gene responsible for their entire pathology, and we need to develop the tools to deal with these levels of complexity.” 

How do you look at how complex immunological networks interact to contribute to clearance of pathogens?

It’s a similar technique, but instead of studying one immune function you study one multi-factorial immune component in the presence of a variety of pathogens.

Also, mutant flies aren't like mutant mice - something about hairless mice that makes me question if there is a God.David Schneider’s group decided they wanted to look at two specific immune system components within the model they study, Drosophila. As they elegantly put it, “Infected fruit flies get sick in ways that human patients would recognize; bacterial infections in Drosophila induce changes in feeding, metabolism and circadian rhythm…” – or as I like to put it: flies get sick too and it’s easier to manipulate their genetics than humans genetics.

They asked how do phagocytosis and melanization, two components of the Drosophila immune system, contribute to clearance of the infection and subsequent survival of the Drosophila?

First, wtf are phagocytosis and melanization?

They are the first-line response team during infection of Drosophila, equivalent to an innate immune response in humans, if they had that. Both of these immune components happen within seconds/minutes of infection.

Phagocytosis, from the view of a bacteria (dark purple).Phagocytosis – this comes from the Ancient Greek work phagein, meaning “to devour”, cytos (or kytos), meaning “cell”, and -osis, meaning “process”. OR… it’s the process by which a cell engulfs particles (FIGURE). This process was first revealed by one of my favorite microbiologists, Ilya Mechnikov in 1882. Basically, this mechanism is used to engulf foreign entities, like bacteria or viruses, and digest them. When you inhibit phagocytosis USUALLY this helps bacteria thrive and cause disease.

Melanization of a cuticle due to tramatization. Bring in the color (melanin), bring in the pain (ROS production).Melanization – this immune response is specific to invertebrates. The production of melanin, a derivative of tryosine, is triggered by the immune system and within minutes microbes (especially bacteria) can be encapsulated within the melanin – the really cool part is that the act of encapsulation of the microbe by melanin triggers the production of reactive oxygen species which can destroy the microbe. Again, when you inhibit melanization USUALLY this helps bacteria thrive and cause disease. 

Ok, so they have two immune components, and eureka! They have two Drosophila mutants that correspond to two different immune systems. Introducing: Mutant #1, which has increased phagocytosis and decreased melanization and Mutant #2, which has increased phagocytosis and increased melanization. Using these mutants they will try to understand the relationship of these two immune components in clearance of bacterial pathogens.

One more layer, they now have two bacterial pathogens. Bacterial pathogen #1: Listeria monocytogenes, which replicates within cells. Bacterial pathogen #2: Streptococcus pneumoniae, which replicates outside of cells. The differences in pathogen lifecycle will reveal the importance of each immune component during these two very different infections.

What they found was:

By using Mutant #1 they found the immune contribution of phagocytosis was dependent on the type of bacteria that was used for the infection.

If they infected flies with S. pneumoniae, or the bacteria that replicates outside of the cells, they found phagocytosis was the “death knell” for these bacteria. Therefore, if they amped up phagocytosis, they saw increased clearance of S. pneumoniae, or basically NO sick flies.

HOWEVER, if they infected flies with L. monocytogenes, or the bacteria that replicates within cells, phagocytosis HELPED this pathogen replicate and cause disease. This makes sense because L. monocytogenes can only replicate within cells, therefore it needs phagocytosis to be picked up from the environment so it has access to the intracellular environment.  In fact, they found that in both fly mutants (both have increased phagocytosis) you could increase the frequency of L. monocytogenes infection, tricky little bugs.

Let’s think about this in context. What’s the point of having a robust immune system if sneaky bugs like L. monocytogenes are just going to use it against you? There must be a very special amount of phagocytosis that is just enough to clear extracellular bacteria but not enough to help intracellular bacteria, but what is this amount?

They say thinking of it this way is a trap, and that it’s more complex than the perfect amount of phagocytosis…  by using their second mutant that has increased phagocytosis and increased melanization they found that little melanization (Mutant #1) increased killing flies by infection with L. monocytogenes (no environmental stress party!), and that increased melanization (Mutant #2) showed decreased amounts of killing flies by infection with L. monocytogenes – independent of level of phagocytosis. So things are more complicated than they seem!

I would love to tidy this post up with a nice bow, but the truth is this type of data opens more doors than it is closing… so the research continues…

Keep on fighting the fight.

How do all of our complex multi-factorial immune components combine to clear bacterial infections? How do they all relate, and what is the perfect balance of just enough immune function, but not too much?

Onward microbiologists and immunologists alike! 

 

Chambers MC, Lightfield KL, & Schneider DS (2012). How the fly balances its ability to combat different pathogens. PLoS pathogens, 8 (12) PMID: 23271964

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April 21, 2015 | Unregistered CommenterYatin

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