Here’s a defense against bacterial infection that you might not have heard of: “nutritional immunity”. It’s been known for a long time that bacterial and protozoans have easier access to some vital nutrients than they do to others, and that one particular bottleneck is iron. Iron is a vital component for some key enzymes, and the problem is that bioavailable iron is relatively hard to come by. Its two common oxidation states (+2 and +3) have behaviors that don’t help much: iron (II) is very susceptible to oxidation, not least with plain ol’ atmospheric oxygen, and the iron (III) compounds tend to have terrible solubility. Iron (III) oxide, known as rust, is one of the most ridiculously insoluble substances you’ll ever come across, and that’s where a lot of iron tends to end up.
Iron and oxygen share another quality: they’re simultaneously essential and toxic. Iron species can be a great way to generate oxygen radicals, which are not what you want running around in your cells under ordinary conditions. You see it used biologically for that purpose in enzymes like the CYPs where it’s hidden down in an active site, but free iron can be dangerous stuff. At the same time, it’s such a biologically crucial element that living creatures have come up with all sorts of ways to scavenge it wherever it can be found. Siderophores are an example of this, proteins used by microorganisms (and higher plants) that have extreme avidity for iron ions. You can see this particularly clearly with plankton populations in the ocean. As the references in that paper will show you, all you need to do to get a phytoplankton bloom in many parts of the ocean (the “high nutrient, low chlorophyll” regions) is to dump some soluble, bioavailable iron over the side of the boat. Iron in general moves through a pretty complex cycle involving atmospheric dust from mineral weathering, interaction with the oceans, emissions from volcanos, and more. Microorganisms are waiting to snag it as it goes past.
That goes for inside our own bodies during a bacterial infection, too. One of the strategies to limit bacteria growth is to stop absorbing and transporting iron from the intestines – during an active infection, available iron drops dramatically (as do zinc and manganese). That’s a really effective broad-spectrum defense – as far as I know, the only human bacterial pathogen that doesn’t actually seem to need iron is the Lyme disease spirochete Borellia burgdorferi, and it makes up for that by requiring manganese instead. That metal-hoarding is done through a number of mechanisms (detailed in that link at the beginning of this paragraph), but a new one has just been discovered.
It turns out that when an infection is detected, macrophages start releasing extracellular vesicles that have numerous receptors for iron-containing proteins. These go around vacuuming such species up and making them unavailable for bacteria. The authors show that with Salmonella infection in a mouse model, macrophage ER stress in response to infection seems to set off a program in their lysosomes that causes them to start producing and releasing the vesicles. It’s known that some bacteria lyse erythrocytes in order to grab iron from their hemoglobin supplies, and this new mechanisms suggests that there’s another layer of defense waiting to pick up that species and others before the bacterial can take advantage. And there are surely others that we haven’t discovered yet. . .
