Thursday, October 3, 2013

Friend or Foe? The Recognition of Microbiota vs. Pathogens

           The basic function of the human immune system is to detect and combat pathogens and harmful foreign bodies that we encounter on a daily basis. Bacteria, viruses, and fungi contain some very different proteins and nucleic acids than humans do, and it is job of the body’s immune cells to recognize when one of those components has penetrated our physical barriers, such as skin and the mucus in our digestive and urogenital tracts. Some things that trigger the immune system are peptidoglycan (a cell wall component of bacteria that is not present in humans), lipopolysaccharide (a bacterial cell membrane component also not present in humans), and double-stranded RNA (which encodes the genetic information of many viruses) (Mak & Saunders, 2010).
            The basic forms of an immune system are known as the innate immune system. Almost all forms of multicellular life exhibit some properties of an innate immune system, including microscopic organisms such as nematodes. Humans also have an innate branch of their immune system. The job of the innate immune system is to recognize the basic, general components of foreign bodies attacking the cell, such as those described previously. It seems simple, right? If it’s a human protein, leave it alone, and if it isn’t, get rid of it. Research within the past few decades, however, has revealed a gaping hole in this basic principle.
            It has been discovered relatively recently that microbes (aka foreign bodies) are absolutely vital to human life. There are thousands of types of microbes in the different tissues of our bodies, especially our gut, that help us with things like digestion and nutrient absorption (Slonczewski & Foster, 2010). It has been estimated that the number of microbial cells in our bodies is higher than the number of human cells! This estimation makes the hole in immune theory very obvious: if there are so many microbial cells colonizing our bodies, how do our immune cells know what to attack and what to leave alone? In their review article, Hiutung Chu and Sarkis K Mazmanian attempt to provide insight into this problem and perhaps fill in a few pieces of this gap in their 2013 paper “Innate Immune Recognition of the Microbiota Promotes Host-Microbical Symbiosis”.
            The basic argument of this article is that part of the innate immune system, a set of receptors called Pattern Recognition Receptors (PRR’s) evolved specifically to facilitate communication between symbiotic organisms and human cells. PRR’s have thus far been categorized as cell membrane receptors that recognize general features of many different pathogens (Pathogen-Associated Molecular Patterns, or PAMPs). Innate immune cells such as dendritic cells, which engulf and break down foreign bodies, express many PRR’s on their cell membranes. The authors suggest that the evolutionary purpose of PRR’s is not primarily to detect pathogenic cell components and spur phagocytosis of these foreign bodies, but to communicate with symbiotic bacteria and prevent activation of the immune response.

   The authors provide several convincing examples that add credibility to their argument, demonstrating that PRR’s function across the evolutionary board in preventing innate immune response to commensal bacteria. There are four in particular that stand out: Drosophilia, Hydra, Hawaiian Bobtail Squid, and humans.
            Drosophilia is an extremely common model organism, especially in genetic studies. It is a member of the genus of small flies, and much is known about its genes and systems. In the Drosophilia innate immune system, deleting the genes that encode proteins responsible for “detoxifying” bacterial peptidoglycan causes a tenfold increase in the production of antimicrobial compounds by the cell. This demonstrates the fact that the fly cells actually regulate the response to the microbes, disproving the idea that symbiotic microbes are simply ignored by the immune system or that they hide from it. A healthy immune system does not respond to all microbial components- we would be sick all the time! Even Hydra, a very simple member of an evolutionarily old phylum called Cnidaria, can recognize symbiotic organisms. Hydra relies almost solely on PRR’s to detect pathogens, as it does not have a highly developed immune system. Hydra has PRR’s called HyTRR-1 and HyTRR-2 that are responsible for triggering production of antimicrobial compounds, specifically a compound called periculin-1. When periculin-1 is artificially overexpressed in vivo, the microbiome of the Hydra polyp is extremely different than in naturally regulated polyps, and there is a much lower level of many types of symbiotic bacteria. This result suggests that Hydra PRR’s are also capable of recognizing beneficial microbes from those that are pathogenic.
            The most striking of the examples given in this paper is that of the Hawaiian Bobtail Squid. This animal has an extremely important mutualistic relationship with a bioluminescent bacterium called Vibrio fischeri, which colonizes the squid’s light organ. This allows the squid to escape predators by shining light in an orientation that makes it seem as if a predator is looking at the night sky rather than another layer of water containing prey (Chu & Mazmanian, 2013). When the squid is hatched, it promotes colonization via ciliated appendages on its light organ that secrete mucus when exposed to a specific fragment of peptidoglycan. This mucus helps the colonizing bacteria grow. Once colonized, the squid directs controlled apoptosis, or cell death, of the cells in the appendage to prevent colonization by other bacterium, essentially giving V. fischeri a monopoly on its light organ. The extent of this response is truly remarkable, as the proteins that cause the squid to create an extremely permissive environment for V. fischeri are very similar to those that would otherwise induce an immune response. This is also true of an adult squid, whose light organ is colonized by thousands of bacteria that constantly shed peptidoglycan without causing any inflammation or response. The mechanism by which the squid mediates this response is unknown, but its existence and regulation in some way by PRRs is a strong piece of evidence supporting the authors’ argument.

            Ultimately, this argument is also applied to the human immune system. There is a human commensal bacterium called Bacteroides fragilis that produces a compound called polysaccharide A, or PSA. This compound induces an anti-inflammatory immune response in the human intestine, and when tested in mice helped protect them against inflammatory bowel disease. It has also been shown that TLRs (Toll-Like Receptors), which were traditionally thought to upregulate the immune system, can also suppress inflammatory responses when given specific signals from bacteria. Finally, pattern recognition of symbionts by human B Cells, which are cells that have a higher immune function, results in less allergic inflammation. This is exciting because it represents the possibility of the human microbiota in some way aiding in the immune response rather than simply being ignored bystanders.
            This research is extremely important because it highlights a very confusing hole in immune function and extends a potential solution explaining that gap. The authors do not presume to understand how the host cells use PRRs to distinguish pathogenic bacteria from commensals and symbionts; they only assert that PRRs are involved and potentially have evolved for this specific reason. An obvious and wide avenue of future research is to understand exactly how this recognition happens. The bacterial proteins are extremely similar, and the fact that our cells can distinguish harmful from non-harmful with such specificity is yet another sign that there is no end to the elegance of nature, or to our efforts to understand it.

1.     Mak, Tak W. & Saunders, Mary E: Primer to the Immune Response: Academic Cell Update edition. Academic Cell (2010).

2.     Slonczewski, J. L., & Foster, J. W. Microbiology: An Evolving Science. WW Norton and Company. (2010)

3.     Chu, Hiutung & Mazmanian, Sarkis K. “Innate Immune Recognition of the Microbiota Promotes Host-Microbical Symbiosis.” Nature Immunology. 14 (7) 668-675 (2013).

Image Sources:

1.     http://www.sabiosciences.com/pathwaymagazine/pathways7/toll-like-receptors-and-innate-immunity.php
2.     http://www.nhmag.com/features/252011/tiny-conspiracies

No comments:

Post a Comment