Biology concepts – immune defense, antibiotic resistance
There
was a small Turkish weightlifter a few years back whose nickname was “Pocket
Hercules.” He won gold medals in three separate Olympics and was the one the
best examples of big things in little packages. Last week we talked about the
immune systems of vertebrates, invertebrates and plants, now let’s talk about
the defenses of the smallest organisms – bacteria are the Pocket Hercules of
biology.
Do bacteria have defense mechanisms? You bet – they get attacked
all the time. For bacteria that stray
into or purposefully target animal or plant hosts, the perils are many and
varied. Antimicrobial peptides try to burst them, antibodies try to bind them
up and point them out to killer cells. Macrophages and other phagocytic cells
try to eat them or wall them off from the other host cells. Organisms will even
sacrifice their own cells just to make sure they kill the bacteria. It’s a
jungle out there.
We don’t have the time nor the room to go into the thousands
of ways that bacteria protect themselves from plant, invertebrate, and vertebrate
immune attack, but we can give a few examples, like deception. Mimicry is when a bacterial antigen
looks much like one of our molecules, so that the body is either fooled into
not attacking, or tempers its attack.
Other bacteria change their clothes to remain hidden. Just when an immune
system sees it and starts the attack, Neisseria
gonorrhoeae changes its surface molecules and becomes invisible again. On the other hand, Yersinia pestis remains invisible by living inside macrophages.
Some bacteria stunt our antibody response. The best way to keep from being attacked is to not allow the host to recognize and identify you. The bacteria that cause TB inhibit our immune system from producing specific antibodies.
Some bacteria stunt our antibody response. The best way to keep from being attacked is to not allow the host to recognize and identify you. The bacteria that cause TB inhibit our immune system from producing specific antibodies.
The defense is a good offense, so some bacteria attack. Pseudomonas strains
kill the phagocytic cells that would try to eat them by releasing chemicals
called aggressins. Staphylococcus aureus just confuses the
phagocytes, producing toxins that stop their movement or make them move erratically.
These are but a few of the many bacterial defenses against our immune system. But they have evolved defenses against other threats as well, like our attempts to kill them with antibiotics.
These are but a few of the many bacterial defenses against our immune system. But they have evolved defenses against other threats as well, like our attempts to kill them with antibiotics.
We talked earlier about multidrug efflux pumps in bacteria that pump out the
antibiotics with which we try to kill them. This is related to the
stories in the media about antibiotic resistance in bacterial pathogens, but classic antibiotic resistance genes are often
plasmid based defenses,
as we have discussed. Recently, an additional defense against antibiotics has
been recognized.
It seems most bacteria produce hydrogen sulfide (H2S,
smells like rotten eggs), which was previously thought to be only a metabolic
byproduct. A late 2011 study
shows that H2S is part of an integrated defense system used by
almost all bacteria. The gas works to prevent oxidative damage. This is not
unheard of since a few bacteria produce nitric oxide to do the same thing, but
it is being recognized now that oxidative stress induction is a big part of how
many antibiotics work. When the H2S system was turned off in several
pathogens, they became much more sensitive to antibiotics. Maybe this a lesson
we can exploit in the future.
In addition to our attempts to kill them, the universe itself is a tough place to survive if you are a bacterium. They may end up in bright sunlight for long periods of time, or
hurtling through space on a rocket or meteor. Bacteria have ways to protect
themselves here as well. Ultraviolet radiation from the sun is a mutagen (causes mutations
in DNA), but it also can break down cellular molecules to release oxygen
radicals, like hydrogen peroxide or superoxide.
It has been known since the 1950’s that pyruvate and catalase,
as well as the newly discovered H2S discussed above, do some work in protecting the
cell against oxidative damage, but a 2009 study described a whole new mechanism. It seems that E. coli has two proteins that seek out,
identify, and repair oxygen radical-mediated damage to sulphur-containing
cysteine amino acids within proteins.
Cysteine is the
most reactive of the 20 common amino acids, which means that it are often
located in the functional site of enzymes (where the enzyme reacts with the
substrate). However, this reactivity also makes cysteine vulnerable to reaction
with radicals, especially oxygen radicals, after which it becomes modified and
non-functional.
To
prevent this radical-mediated damage, cysteines often occur in pairs, where
links between the sulphurs of the two cysteines help to prevent oxidation (called
disulfide bonds, they also serve to
link peptides together and give proteins their proper form). A 2008 study showed that this
mechanism provides unusual oxidative stability to a cysteine-containing enzyme
of the bacterium, Desulfovibrio africanus.
But there are exceptions; lone cysteines do occur, and these
are the cysteines most vulnerable to oxidative damage. The DsbG and DsbC
proteins of E. coli patrol the
cytoplasm looking for oxidized cysteines to fix.
Here is how ingenious the system is – oxidizing a cysteine
may or may not unfold the protein, so DSbG is charged and can interact with the
still-folded proteins to correct the cysteine problem, but DsbC is uncharged,
so it works better with proteins that have been unfolded. Amazing - and bacteria developed it all on their own – well, with the help of the evolutionary
pressure of things trying to kill them.
I mentioned that radiation is also a DNA mutagen. The
mutagenic properties of radiation affect bacteria just like they affect us; it
is just that some bacteria can protect themselves better once their DNA is
damaged. Follow me closely here - by using protein repair and protection
systems, bacteria like E. coli, with
its DsbG and C enzymes, can keep protein functions going when other organisms
would break down and die. Some of these protein functions include DNA repair
after mutagenesis. So - some bacteria don’t survive radiation because they
protect their DNA better, they survive because they repair the damage better.
Other bacteria have a different mechanism to maintain
protein function. According to a 2010 study, a shield of manganese metal atoms and
phosphates was found in D. radiodurans.
It had been long known that manganese was present in very high levels in
bacteria that are most resistant to radiation, but its function was unknown.
The recent study shows that these manganese complexes work
together to protect proteins from radiation damage, but not DNA. The key for
this system is to keep proteins functioning, which can then repair any radiation damage to the DNA. This
mechanism allows D. radiodurans to withstand
prolonged radiation that is 1000x stronger than that which would kill a human.
So, bacteria have defenses against immune and environmental
attacks. Does anything else attack bacteria? How about other bacteria - it’s dog
eat dog out there, competition for resources is brutal. Many bacteria have
poisons (bacteriocins) that inhibit
or kill bacteria that are distantly related (because related types of bacteria
are likely to be in the same places looking for the same food).
One type of bacteriocin are the lantibiotics. These protein toxins contain a nonstandard amino
acid, called lanthionine. We
mentioned above that cysteines are very reactive; lanthionine is a modified
circular (polycylic) cysteine that gives the toxin its reactivity. And because
it is cyclic, it is much less vulnerable to oxidative damage itself – funny how
bacteria seem to cover their bases so well.
A recent discovery illustrates just how bacteriocins are
delivered to the target organism. It seems that bacteria can build a spike and a spike launching system anywhere on their cell membrane. The spike is spring loaded in a
tube just 80 atoms long, and is fired at the target cell. Then the bacteriocin is
released at the end of the spike to do its damage.
The release of toxin was already known, called a type IV
secretion system, but the CalTech study that identified the spring-loaded spike
as the delivery system is very new. Once fired, the whole system is broken down, ready to
be rebuilt somewhere else in the cell. Amazing. (click for video)
Of course, for every punch there is an evolutionary
counterpunch, so there are bacteriocin resistance mechanisms as well. Nisin, a bacteriocin active against
strains of listeria, is approved as a food preservative. But
listeria can spontaneously develop resistance to nisin. It appears that some
strains change their membrane chemistry in order to render nisin ineffective. Therefore resistance could be a problem if we pursue the use of bacteriocins as
antibiotics; we might end up back in the same situation that we're in now.
Regardless of this possible downside, scientists have found
a way to bring bacteriocins into the battle against antibiotic resistance. An E. coli has been engineered to contain the gene for pyocin, a bacteriocin that kills
strains of Pseudomonas bacteria. E.coli
and Pseudomonas are not closely
related, so E. coli would not
naturally possess this toxin, scientists added the gene to the E. coli.
When
the engineered bacteria encounters Pseudomonas,
it does two things; it produces the pyocin toxin to kill the target cell, and the
engineered E. coli commits suicide. No
release system has been engineered into the E.
coli, so the only way they get the pyocin to the target is to have the E. coli produce a lysin that destroys its
own cell membrane.
This suicide accomplishes two things, it releases the pyocin
to kill the target, and it prevents the engineered E. coli from hanging around forever, possibly trading genes with
other bacteria or causing havoc in some unforeseen way.
So it looks like bacteria have it made. They can resist immune
system attacks, some can resist environmental onslaughts, they even have ways
to protect themselves against competition and threats from other bacteria.
No wonder they have always been the predominate life form on Earth. But bacteria
do have foes of considerable power – veritable “Micro-Hercules” – we will meet
them after Thanksgiving.
Let’s take a couple weeks to talk about the biology of
turkeys and the so-called “tryptophan nap.”
For
more information or classroom activities, see:
Bacterial
defenses–
Bacteriocins
–
see Pubmed (http://www.ncbi.nlm.nih.gov/pubmed) for more information on these defenses.
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