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Immunity in Bacteria
“They say that the best weapon is the one you never have to fire. I respectfully disagree. I prefer the weapon you only have to fire once.”
Robert Downey Jr., Iron Man. Marvel Studios.
Many of you are probably familiar with several aspects of your immune system. If it’s all new to you or you need a refresher, you can always take a look at our Basic Immunology page. But, were you aware that even prokaryotic organisms like bacteria have their own versions of innate and adaptive immunity? Bacteria can come under attack from things like bacteriophages, which literally translates to “bacteria eaters”. To combat this, bacteria have come up with an assortment of defense mechanisms to get rid of these unwanted intruders.
The first type of mechanism bacteria can use is essentially self vs. non-self discrimination. The most well-characterized mechanism involves the restriction-modification. Bacteria will methylate certain DNA sequences and consider this to be self1. Any DNA that doesn’t bear those methylation points will be considered foreign and be targeted for cleavage with restriction enzymes. A similar mechanism called phosphorothioation modifies the bacterial DNA, where dnd gene clusters incorporate sulfur into the DNA backbone2. DNA lacking this modification are targeted for cleavage. This is similar to TLR9 in mammals, where unmethylated and phosphorothioated CpG rich oligonucleotides are identified as foreign and trigger an immune response.
The second method bacteria can use gets a little more complex and mimics what we might call adaptive immunity. CRISPR (clustered regularly interspaced short palindromic repeats) were initially discovered in 1987 in E. coli, but their role as a defensive mechanism wasn’t suggested until 2005. CRISPR (which can also be utilized by archaea) are made of repeat sequences and spacer sequences. This spacer sequence is actually created with foreign genetic elements that are obtained from bacteriophage DNA or plasmids. Cas proteins will take portions of this foreign DNA and incorporate it as a spacer region.

The CRISPR mechanism. Image from Universitat Düsseldorf.
The CRISPR loci is then transcribed into “crRNA”. If the bacteria should encounter foreign DNA in the future that closely resembles one of its CRISPR space regions, the crRNA can act on its own or as part of a complex to direct enzymes toward this foreign sequence, targeting it for destruction. This is why this mechanism is compared to adaptive immunity, as the bacteria can “remember” the previous encounter with a virus. Of course, in an evolutionary arms race, viruses are always competing and can introduce mutations into these sequences, protecting them from being assaulted by bacterial enzymes.
No, not that kind of crisper. Image from Gorenje.
The CRISPR/Cas mechanism shows some similarities to eukarytoic defense mechanisms involving RNA interference. Eukaryotic cells use microRNA and small interfering RNA to help destroy certain mRNA molecules to prevent protein expression (e.g. from viruses). To this point, however, no homology has been found between proteins of the CRISPR/Cas pathway and the RNA interference pathways of eukaryotic cells.

Scientists are looking to adapt CRISPR to benefit mankind, as Editas Medicine wants to use this mechanism to repair single base pair mutations in defective genes of stem cells in diseases like cystic fibrosis and sickle-cell anemia3. Astra Zeneca is attempting to use CRISPR, drug treatments, and the human genome project to snip out portions of disease-related genes4. This, of course, is all still being investigated, but it’s intriguing that a prokaryotic defense mechanism could be cultivated to fight a variety of diseases affecting us “higher” life-forms.

It’s certainly interesting to study the defensive abilities of other life-forms, and we’ll continue to examine this topic in the future with a look at plant immunity. Until then, let us know if you have any thoughts on bacterial immunity at tech@biolegend.com.
References:
  1. Comparative genomics of defense systems in archaea and bacteria.
  2. Phosphorothioation of DNA in bacteria by dnd genes.
  3. New genome-editing method could make gene therapy more precise and effective.
  4. Astra Zeneca drive to develop drugs from genome project.
  5. CRISPR in bacteria and archaea.

Just when I thought I got the hang of science.
Iron Man, Marvel Studios.
Contributed by Ken Lau, PhD.
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