Let's start with skin. So, if you think about how is skin a good barrier? Well, first of all
it is a continuously sloughing keratin layer at the surface. That skin is turning over roughly
every 2-3 weeks and you are constantly shedding all that material. So, if you're a bug that
can only burrow through the first couple superficial layers of keratin, you're not going to
be very successful. So that's a good barrier function. It also has an endogenously low pH
and a very high fatty acid content that is not particularly pleasing to most microbes. So it
tends to restrict the growth of things in that setting. And then finally, there is a very diverse
commensal flora that's already there. Everyone knows you've got all kinds of bacteria in
your skin. Well in fact, most of those are not pathogenic, but they do prevent new microbes
from getting a foothold because there's no nutritional niche for them. So they kind of,
by having kind of a population explosion on your skin, they keep out other kinds of
microbial pathogens. So, if I'm going to be successful, if I am going to go through the route
of evading the skin barrier? What do I have to do? Well, I'm going to have to be very
adhesive because again things are sloughing up, I need to be able to get down into deeper
layers via say proteases but then also be able to stick there and avoid being just sloughed
off on a regular basis. I may take advantage of physical trauma, so a big burn or an insect
or animal bite to get through all those layers into the subcutaneous tissue where there
are vessels. And I can get a foothold if the normal flora are no longer there. So, those are
going to be the successful invaders through the skin. Let's look at the respiratory tract.
So what's being shown there in the little inset are the cilia that are constantly beating in
the epithelial layer of the upper respiratory tract. So there is mucus and ciliary beating
that's called the mucociliary ladder, it's going to be constantly capturing and clearing out
any microorganisms that might be inhaled. So that's going to be important barrier. It turns
out also that in the respiratory tract as well as the GI tract, secretory IgA is the most
common immunoglobulin that's made there and there is a very robust production of IgAs
that can capture and bind to invading microbes. Complement activation can elicit
phagocytosis. The secretory IgA is very important. And then, there are various proteins
that are secreted as part of the innate barrier function of the epithelium in the airways.
Those are defensins and cathelicidins and others like that that are also going to be very
important that are part of the normal barrier function. And then finally if you are able to
get inhaled all the way down to the alveolus, sitting in the alveolus waiting for you are a
bunch of pulmonary macrophages that are ready to gobble up anything from particulate
matter to microbes and happen to gotten all the way down in to the alveoli. So there are
multiple kind of barriers that are present. Okay now if I'm going to be successful as a
microbe getting through all that, what do I have to do? Well, so I've got to be reasonably
adhesive. I need to make enzymes or toxins that are going to defeat that mucociliary
clearance. So, if I make things that will break down the mucus, so if I have an enzyme that
will break down the mucus that will be very useful in gaining access. Some microorganisms
such as bordetella which is whooping cough, they are very clever. What they do is they
secrete a toxin that inhibits the movement of the cilia. So they basically paralyze the cilia
and then they aren't swept away, very clever. You can also take advantage of secondary
infection. So like I already mention, if you have a lytic infection of the upper airway, say
due to influenza, it's very easy now for bacteria to get in because there's no mucociliary
clearance and you've eliminated the epithelium. So that barrier has been defeated. It turns
out that smoking does something that can to that, so heavy smokers will get a metaplasia
from that pseudostratified ciliated columnar epithelium that lines the respiratory tract. And
it will be converted into a squamous epithelium that doesn't have the ciliary clearance.
So, if you are a smoker and your bug trying to get in, you actually have a bit of an
advantage because there's no mucociliary clearance. And, if you make it all the way down
to the alveolus, you can resist macrophage killing. And that's what happens with legionella.
You may remember Legionnaires disease, started in 1976, that's the first time we saw it.
But the bug is clever in that it can resist macrophage killing and that's its major success.
Okay, so that's the respiratory tract.