Why and how can one amino acid cause Bubonic plague?

jackmell · Jul 4, 2015

What precisely is going on?

Ryan_m_b · Jul 4, 2015

What plague are you referring to?

jackmell · Jul 4, 2015

Ryan_m_b said: ↑

What plague are you referring to?

I'm sorry. Bubonic plague. I'm unable it seems, to change the title. May I ask you to change it for me to "Why and how can one amino acid cause Bubonic plague?"

Ygggdrasil · Jul 4, 2015

I'm not sure I understand the question either. Can you elaborate further? Is there some reference or source where you heard this claim that you could cite or reference?

jackmell · Jul 4, 2015

Well, I can't find it now. Just read it this morning along with a lot of other news and thought later to ask and now can't find it. What I recall, is that it's an enzyme, PSP or PSA or something like it which cleaves proteins (protease I think) and that enabled a lesser-form of the bacteria to mutate and become 100x more virulent by somehow being able to quickly enter the blood and travel through the body. I was just curious how the amino acid substitution enabled it biochemically, physiologically, structurally, enzymatically to do this. There was a technical reference which I did briefly look at but tough to read. I'll keep looking.

Also I thought weather had a lot to do with spreading the plague as we were in a little ice age at the time so people and rodents sought close-contact shelter for warmth. The article did not reference this factor however.

jackmell · Jul 4, 2015

Found it:

http://news.yahoo.com/plague-evolution-mild-stomach-bug-became-worldwide-killer-175828335.html

For example, a guess: did the substitution alter the conformation of the protein causing it to become more fat-soluble and thus more able to diffuse through the cell membrane, or something like this. The article gets you interested but lacks precise biochemical detail.

rootone · Jul 4, 2015

Influenza is well known for it's ability to rapidly mutate new variants which are viable and can be more damaging the original, 'vanilla' strain of the virus.
Other pathogens can behave be similarly but usually not as fast as influenza, (although I believe the common cold virus can produce successfully mutations even more rapidly).
The result of a mutation can be as little as a single amino acid change in some protein.
Whether or not that change is 'useful' (from the point of the pathogen), will be dependent on the usual natural selection pressure.

jackmell · Jul 4, 2015

I spent some time again reading the original Nature article:

http://www.nature.com/ncomms/2015/150630/ncomms8487/full/ncomms8487.html

and I need to remember it's not just an amino acid but rather one or more nucleotide substitutions really. And it looks like from what I can tell from the article, they do not know precisely what physiologically this protein change causes the bacteria to have become much more virulent although I may not just be understanding the article.

Also, in regards to rootone, I did delete my reference to influenze since I thought it was off-topic. Sorry about that rootone.

Ygggdrasil · Jul 4, 2015

Thanks for providing the links. I haven't had time to read through the articles in depth, but the article seems more focused on demonstrating that the mutation increases the virulence of the bacteria rather than determining the mechanism for how the mutation achieves this effect (though this is something that they are probably working on right now). They speculate that the mutation "optimizes" the protease activity of the enzyme, but the connection between the protease activity and the ability of the bacteria to spread is an issue that probably requires further study.

In general, however, single amino acid substitutions in proteins can sometimes have dramatic effects on the activities of the proteins and the organisms in which they reside. For example, a single amino acid substitution in hemoglobin is capable of changing the shape of red blood cells and causing sickle cell anemia.

It's also worth noting that the genetic sequence of Bubonic plague has not changed much since the middle ages (see Bos et al. 2011. A draft genome of Yersinia pestis from victims of the Black Death. Nature 478: 506. doi:10.1038/nature10549. or http://www.nytimes.com/2011/10/13/science/13plague.html), yet it does not cause as severe disease in modern times. Some of this is due to environmental factors (such as climate as jackmell alluded to in a previous post or modern sanitation), so changes to the genome of the bacteria may not tell the whole story with regard to historical plague outbreaks.

jackmell · Jul 4, 2015

Ok I have something:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3513919/

"Substrates of the Plasminogen Activator Protease of Yersinia pestis"

The plasminogen activator protease (Pla) of Yersinia pestis is a critical virulence determinant in the progression of both bubonic and pneumonic plague. A member of the omptin family of Gram-negative transmembrane proteases, Pla forms a conserved β-barrel fold in the bacterial outer membrane which permits the interaction of the protease with target substrates for cleavage. In vitro studies have identified numerous mammalian host targets, many of which comprise components of the coagulation and fibrinolytic cascades. Through the cleavage of host plasminogen, α2-antiplasmin, plasminogen activator inhibitor-1 (PAI-1), thrombin-activatable fibrinolysis inhibitor (TAFI), and tissue factor pathway inhibitor (TFPI), Pla is hypothesized to disrupt coagulation pathways that are initiated as a natural host response to infection and inflammation. The clearance of fibrin clots, enhanced by the activities of Pla, may alleviate physical barriers to bacterial dissemination and inhibit the recruitment of immune cells

As I interpret this, the protease Pla enzyme inhibits the body's response to infection by inhibiting the "coagulation and fibrinolytic cascades" which I assume means blood clotting but not sure. So possibly, the leucine substitution enhances the efficacy of the enzyme thereby even further inhibiting the body's response to the infection.

Basically, the mutation improves the ability of the bacteria to subvert the body from defending itself and in this way is becoming more virulent.

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Why and how can one amino acid cause Bubonic plague?

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