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From soil to human: evolution of bacterial immune evasion mechanisms

by Brooke Napier, dedicated to Christian Raetz

This post was chosen as an Editor's Selection for ResearchBlogging.org

Most, if not all, pathogenic bacteria did not get their start infecting humans. No, most of them started off as meager soil or water bacteria, just hoping to catch a rock to colonize. A lot of biologists have dedicated their lives to understanding the genetics or mechanisms behind harmless soil/water bacteria evolving into lean, mean, human-killing machines.

This month in PNAS, Li et al. took a closer look into one of the mechanisms pathogenic and antibiotic-resistant bacteria use to evade the immune system and antibiotics, LPS remodeling, and how this mechanism has evolved from non-pathogenic soil bacteria.


First off, WTF is LPS remodeling?


Gram-negative bacteria (depicted below in yellow) have an inner and outer lipid membrane (in blue) separated by the periplasm (this is distinct from Gram-positive bacteria that only have one membrane and a thick periplasm on the outer surface). The outer-leaflet of the outer membrane (in orange below) is the LPS, or lipopolysacchride (lipids and sugars, y'all). The LPS it the first thing the host immune system can see, since it's the outer most surface of the bacteria (unless there is a capsule, which is an entirely different post).

Not surprisingly, the mammalian host has developed a quick response to LPS by the cellular receptor TLR4. Stimulation of TLR4 leads to inflammation in the host, which can lead to destruction of the invading bacteria; therefore, it is intuitive that the bacteria have evolved mechanisms to escape detection of the host immune system by remodeling the LPS, or the outer surface of the bacteria.



Remodeling of the LPS can occur in many forms, you can modify the sugars or the lipids of the LPS Lipid A (pictured bottom left, bottom yellow structure), the biologically active portion of the LPS, to evade host detection.

Many books and hundreds of papers have been devoted to understanding modification of Lipid A sugars and the adjoining phosphates; however, Li et al. describe a specific modification of the lipids in the LPS Lipid A that can be turned on when the bacteria senses that is within a human host.

How are these bacteria sensing the environment? 


It's briliant, really: the temperature. The temperature of the environment (like water or soil) is generally 15°C, whereas the human body is 37°C, and bacteria can sense this temperature difference and regulate Lipid A modifications accordingly. Yersinia pestis, the causative agent of the plague, can colonize rodents and is transmitted by fleas. In response to these different environments, Y. pestis can synthesize alternative Lipid A structures in different growth temperatures - one for the temperature of a flea (21°C) and another for the temperature of a mammalian host (37°C). 

The flea-specific LPS has a hexaacylated Lipid A, or contains 6 fatty-acid chains (as pictured in the Lipid A to the left), to protect the bacteria from conditions in the flea digestive tract or external environment, whereas the tetraacylated Lipid A contains 4 fatty-acid chains found within the mammalian host allows bacteria to evade detection by TLR4.


What about bacteria that are soil bacterium and now pathogenic?


To answer this question, Li. et al looked at Francisella tularensis, the causative agent of tularemia, that is been identified in a wide array of environments and hosts (soil, water, fresh water protozoans, arthropods, and mammals), indicating its need for adaptation among various conditions. Since Lipid A remodeling has been identified as temperature-sensitive, in this study they looked at Francisella Lipid A modifications in response to temperature changes. 

What is the role of temperature in modulating Francisella membrane remodeling?


The Francisella tetraacylated Lipid A is depicted to the right, with a characteristic galactosamine (GalN - green) addition on the 1 phosphate and 4 acyl (or fatty acid) chains (black). As noted at the bottom, the acyl chains are 14-18 carbons in length. This is important because these are the carbons affected by temperature.

As shown below, when subjected to different temperatures, Francisella Lipid A acyl chains vary in length. In the figure below, A) shows at 37°C, mammalian host temperature, the acyl chains are 16, 18, 18, and 18 carbons in length, B) at 25°C, insect temperature, the acyl chains are 16, 18, 18, and 16 carbons in length, and C) at 15°C, environmental or soil/water temperature, the acyl chains are 16, 16, 18, 16 carbons in length. These data indicate that Francisella Lipid A is modified by number of carbons of the 4 acyl chains in response to environmental vs. host temperatures.

Additionally, they identified two different acyltransferases, LpxD1 and LpxD2, that are responsible for Lipid A acyl chain modifications. LpxD1 adds longer acyl chains upon transmission to mammalian host temperatures and LpxD2 adds shorter acyl chains to Lipid A, allowing growth and adaptability in cold-blooded hosts or soil/water. Both genes encoding LpxD1 and LpxD2 are temperature-regulated, allowing for "exquiste control over this process and suggesting the process is critical for survival". 

Ok, so what does this mean for the bacteria?


As I mentioned before, Lipid A modifications are important for bacteria to survive in the host in order to evade TLR4 recognition, subsequent inflammation and bacterial destruction. However, Francisella is not detected by TLR4 - so why is this modification important? 

Their last figure shows that a lpxD1 deletion mutant cannot survive in a mouse, which means the gene responsible for acyl chain modifications in mammalian host temperatures is required for survival in the host. Therefore, this acyl chain modification is an adaptation required for Francisella to causes disease in humans.

In this paper they did not take this idea any further, but it would be interesting to understand why there is protection of Francisella in the host with this acyl chain modification. If TLR4 does not recognize Francisella, does TLR4 recognize Francisella without modified acyl chains (in the lpxD1 deletion mutant)? Or is it another host receptor?

Anyone want to do this as a post-doc project in my lab? I should have one going by the 2090 ;)


ResearchBlogging.org Li Y, Powell DA, Shaffer SA, Rasko DA, Pelletier MR, Leszyk JD, Scott AJ, Masoudi A, Goodlett DR, Wang X, Raetz CR, & Ernst RK (2012). LPS remodeling is an evolved survival strategy for bacteria. Proceedings of the National Academy of Sciences of the United States of America PMID: 22586119

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Reader Comments (3)

Or you could make it YOUR postdoc project ;)

May 22, 2012 | Unregistered CommenterSarah

Also, what do we know about soil bacteria evolving from water bacteria?

May 22, 2012 | Unregistered CommenterSarah

Just off the top of my head, I know that water bacteria generally produce capsules (sticky sugar coatings) or biofilms (a sticky coating that is community influenced) so that when they reach a surface like a pebble or a tree stump they can stick onto it and start a colony... however I'm not sure if that is a water bacteria evolving from a soil bacteria, but I do know that that is a difference.

May 22, 2012 | Unregistered CommenterBrooke

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