Dysentery is a GI disease with which not many in the
industrialized world are familiar, but which posed a severe problem only a
hundred years ago and still causes serious illness and death in the developing
world. The bacterium that causes dysentery is called Shigella flexneri, which infects the mucosal surfaces of the colon
and rectum. Shigella is a gram-negative,
intracellular bacterium. This means that it has a cell membrane but no cell
wall, and that when it infects a host it establishes itself and replicates
inside the cell rather than in the spaces and fluid between cells.
Intracellular bacteria can often be more difficult for the immune system to
find, especially if they have ways to make a cell look healthy instead of
showing the danger signs of infection.
The
innate immune system, or first responder to any infection of your body by a
foreign pathogen, is not specific to particular pathogens and relies generally
on compounds that are part of bacteria, viruses, or fungi, but are not present
in humans1. A distinguishing characteristic of gram-negative
bacteria like Shigella is a compound
called lipopolysaccharide, or LPS. LPS is a component of the bacterial cell
membrane, and is highly toxic when separated from the membrane2. LPS
is strongly recognized by the innate immune system as a danger signal, also
known as a pathogen-associated molecular pattern (PAMP)1. LPS is
made of a lipid called Lipid A, an oligosaccharide (a type of sugar polymer),
and the O-polysaccharide, another sugar located on the bacterial surface3.
Immune cells recognize the Lipid A part of bacterial LPS, and this causes the
release of certain small molecules called cytokines. The specific cytokines
released, particularly IL-1ß , TNF-alpha, IL-18, cause inflammation,
which helps alert the rest of the immune system to start combating the
infection, but also causes many of the symptoms associated with bacillary
dysentery3.
1. Diagram of bacterial LPS
One
would think that having undergone so much evolution, we wouldn’t need to worry
too much about these pathogens, as our bodies should be used to combating them
by now. Every day, however, all of that evolution is rubbed in our faces by the
tiny organisms that make us sick. This is because while the human immune system
evolves to fight pathogens and retains memories of them in special memory
cells, the microbes are also evolving, at a much faster rate than we are, to
avoid our bodies’ defenses. The Shigella bacterium has several ways to elude
our immune system, and new adaptations are being discovered all the time. Ida
Paciello and her team provide insight into one of the previously unknown ways
this bacterium escapes our immune system in their article “Intracellular
Shigella remodels its LPS to dampen the innate immune recognition and evade
inflammasome activation”.
The
basic argument of this paper is that the Lipid A portion of the LPS in the
bacterial cell membrane is very different when it infects a human cell than
when it is grown in a test tube in a lab. When grown with everything it needs
to live, the Lipid A has 6 acyl chains, or fatty acid chains that compose it.
Our immune cells recognize this number of chains, leading to the previously
described cytokine release and inflammation. The authors show in their research
that when infecting a human cell, the Lipid A is hypoacylated, meaning that it
has fewer than six chains. This makes it difficult for our immune cells to
recognize and combat, allowing the bacteria to infect many cells before an
immune response begins. Rather than giving a human bacillary dysentery, the
researchers infected HeLa cells, which are cancerous human cells that replicate
quickly and indefinitely, and are therefore used in research labs across the
globe. First, the team grew Shigella
both in HeLa cells and in nutrients outside of any cell. They found that the
acellularly grown LPS (aLPS) from these cells had six acyl tails as expected,
whereas the intracellularly grown LPS (iLPS) had far fewer, usually three or
four tails. Then, they tested the levels of NF-kB activated by phagocytic
immune cells called macrophages when exposed to aLPS or iLPS. NF-kB is a
protein complex that causes secretion of cytokines, and so is a good marker of
the level of immune response elicited by the two types of LPS. The iLPS caused
much less NF-kB activation, which is exactly what the researches hypothesized
would happen due to its lack of acyl tails. When the researches checked the
amount of inflammation-causing cytokines, particularly TNF-alpha, they found
that stimulation of the macrophage immune cells with iLPS caused significantly
lower levels of cytokine production than the six-tailed aLPS. All of these
factors support the hypothesis that the intracellular LPS can avoid detection
by the body’s immune system by having hypoacylated A lipids.
When
macrophages phagocytose (take up) bacteria, usually they chop then up and then
use their parts to activate more of an immune response. Shigella, however, is an intracellular bacterium, and prevents the
macrophage from killing it. Instead, Shigella
infects the macrophage, which undergoes a process called apoptosis (cell
suicide). Whether the researchers stimulated the cells with iLPS or aLPS, there
was the same amount of cell death. This means that it is not the LPS in
Shigella that stimulates apoptosis, but that it is caused by other signs of
infection. Finally, the researchers looked at the response of neutrophils
stimulated with iLPS or aLPS. Neutrophils are another type of phagocytic immune
cell that, unlike macrophages, are able to successfully take up and kill Shigella. These cells are very
interesting because although they can combat the bacterium, they cause the
inflammation that helps Shigella
colonize and brings about some disease symptoms. The researchers found that
iLPS stimulation caused much less of a reaction from the neutrophils than
aLPSs, which in turn would lead to less inflammation.
2. Macrophage Engulfing Bacteria
Ultimately,
these results show that Shigella flexneri
is capable of hypoacylating its LPS, allowing it to hide from the immune system
until it has colonized a massive amount of cells. At this point, the
proliferating cells fully acylate their LPS, allowing for the huge immune
response accompanied by a large amount of harmful inflammation. This mechanism
is not unique to Shigella; Y. pestis,
the bacterium that causes plague, uses a similar mechanism to change its number
of acyl tails in its vector (mode of transmission) the flea, and the human
host. This fact makes the researchers findings even more relevant in the
clinical realm.
Although
much of the so-called “Discussion” section was simply a restatement of various
portions of the Results section, this paper is definitely worth a read. It
sheds light on a development in the arms race between humans and their
pathogens, and in the future research into methods of recognizing the
intracellular Shigella before it is too late are promising. Furthermore, we can
learn more about ourselves by learning about our pathogens, because for many
evasion mechanisms developed by pathogens, our own cells have an equally ingenious
method of detection waiting to catch them. This type of research, then, is
doubly rewarding because it can help us understand both a foreign organism and
ourselves.
Sources
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.
Paciello, Ida et al. “Intracellular Shigella remodels its LPS to dampen the
innate immune recognition and evade inflammasome activation”. Proceedings of the National Academy of
Science 2013; published ahead of print October 28, 2013,
doi:10.1073/pnas.1303641110.
Image Sources
1.
http://hermes.mbl.edu/marine_org/images/animals/Limulus/blood/lpstyl01.gif
2.
http://www.relfe.com/Images/macrophage.jpg
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