Spinach and siderophores: The bacterial battle for iron

Author: Ada Hagan

Editors: Alisha John, Irene Park

Many remember the boisterous, muscle-bound, tattooed sailor Popeye and the thin-as-a-rail Olive Oyl from Saturday morning cartoons. In times of need, such as when his rival Bluto stole Olive Oyl for the 50th time, Popeye would squeeze open a tin can of spinach. Eating the spinach, sometimes miraculously through his corn-cob pipe, gave Popeye that extra boost of energy needed to escape his bonds and rescue his lady-friend. What was so special about spinach that gave Popeye his superpower?


Or so I thought. It’s popularly believed that spinach was Popeye’s “super food” due to the high amounts of iron it supposedly contained, along with a later revelation of flawed calculations. Turns out, Popeye was actually after his vitamin A fix, but spinach is still a great source of dietary iron. So all’s well that ends well?

Regardless, iron is an essential nutrient for the human body. Iron deficiency in humans reduces the oxygen-carrying ability of red blood cells, leading to anemia. But iron isn’t only needed to help chauffer oxygen throughout the body, it’s also required by cells to aid proteins responsible for replicating DNA, generating energy, and protecting cells from damaging oxygen compounds.

While iron is so desperately needed to carry out everyday functions of the cell, an overabundance of iron can be toxic. Unchaperoned iron molecules (i.e. those not attached to a protein) can react with oxygen molecules, creating compounds that cause severe DNA damage (a process called the Fenton reaction). This double-edged sword requires a careful balance of iron uptake, transport, and disposal. To facilitate this, the human body has developed a sophisticated iron absorption system in the gut and has dedicated several proteins to iron’s careful storage within cells (inaccessible to invaders) and transport through the blood and plasma (accessible to invaders). While incredibly effective, there is still a tiny amount of iron left free in the blood, plasma, and bodily fluids.

But what does this have to do with invaders, such as bacteria? Well, nearly all bacterial species, including pathogens, need iron for the same or similar reasons that human cells do. But because of the stringent regulation of iron in the human hosts, very little is freely available for bacterial pathogens to access during an infection. As a result, strategies to gather iron in the blood are a near universal trait of bacterial virulence.

Bacteria have two general methods to gather iron when it is in low supply during an infection. First, they can use proteins on the surface of their cells to trap host proteins or molecules that bind iron, such as heme or transferrin. A second method is to make scavenger molecules called siderophores that leave the cell to poach iron from host proteins. Let’s focus on the second tactic.

Research shows that impairing the ability of a bacterial pathogen to use siderophores can starve the bacteria of iron, slowing down their growth. This hampers the infection enough to let the human immune system catch up. For example, Bacillus anthracis is a bacterial species responsible for causing anthrax in humans and other mammals. When researchers removed the genes coding for the proteins that produce (1, in the figure below), recognize (4), or import (5) its key siderophore, B. anthracis could no longer make mice sick.

Through a complex, multistep process, bacteria use siderophores to bind iron in the blood, even stealing it away from transferrin. Briefly, the bacteria first assemble the siderophore from several smaller components (1, in the figure below). Once assembled, they are sent out into the environment to search for iron (2). After collecting iron from host proteins in the environment (3), the siderophore must make it back into the bacterial cell, where specialized proteins then retrieve iron-bound siderophores, but not those without iron (4) and transfer it inside the protective surface of a bacterial cell (5). The final step is to remove the iron from the siderophore (6) so it can be incorporated into cellular proteins as needed.

A schematic of the “siderophore life cycle”. Image credit: Ada Hagan

Since there are many different steps in the bacterial hunt for iron in the human hosts, there are several ways to interfere with this process and stunt the growth of invading bacteria. While researchers are looking for ways to use our knowledge of siderophores against pathogens like Staphylococcus aureus or Mycobacterium tuberculosis, the human immune system has evolved a strategy of its own.

When a bacterial infection begins, white blood cells like neutrophils are some of the first responders. Their job is to kill the invading bacteria at all costs, sometimes even sacrificing themselves in the process. To accomplish this, neutrophils show up armed to the teeth with proteins specialized to target, to kill and maim the invaders. Siderocalin is one of those proteins targeting the invaders.

After a siderophore snatches iron away from accessible host proteins like transferrin, siderocalin helps the host fight back by binding to the iron-bound siderophore and stopping it from returning to the bacterial cell. This strategy works well against the siderophores produced by most bacteria since siderocalin recognizes the shape of an iron-bound siderophore like matching puzzle pieces.

There are some pathogens, however, that make “stealth” siderophores that siderocalin cannot bind.  The stealth siderophores bound to iron don’t match the shape of the siderophore-binding groove in siderocalin, so the pathogen still gets iron to continue growing.

This battle over iron between bacteria and humans is reminiscent of the competition between Bluto and Popeye and the arms race between predator and prey. Every time one seems to get ahead, the other comes up with a strategy to retrieve Olive Oyl. But in the end, our hero Popeye always comes through, which is what the ongoing iron research hopes to achieve for humans in the arms race against bacterial pathogens. How will humans evolve to counter the latest bacterial strategy and come out on top? Perhaps one day we’ll be able to use these siderophores against their makers. Stay tuned for a future post exploring how researchers plan to do just that.

About the author

IMG_20150821_180518_12Ada Hagan is a doctoral student here at the University of Michigan in the department of Microbiology and Immunology. She does recon on the sneaky ways bacteria find nutrients (like iron!) when they are invading our bodies. Originally hailing from the mountains of East Tennessee, Ada earned both her B.S. and M.S. in Microbiology from East Tennessee State University. In her spare time, Ada spends time with her pets, husband, and new baby, and tries to fit in cooking, fishing & the occasional Netflix binge. Follow her on Twitter (@adahagan) and see more of her posts onLinkedIn.

Read more posts by Ada here.

Regenerative medicine – Panacea or hype?

Author: Kaitlin Weskamp

Editors: Brittany Dixon, Zuleirys Santana Rodriguez, Scott Barolo

Zebrafish may not look impressive, but they can do something that no human can: regenerate large portions of organs that are damaged or lost. These fish, each about as long as your pinky finger, are able to regrow amputated fins, repair lesioned brains, and mend damaged eyes, spinal cords, and hearts. This remarkable ability to heal has fascinated scientists for some time, and in recent years, large strides have been made towards translating this regenerative ability to humans. Continue reading “Regenerative medicine – Panacea or hype?”

It’s all in the family! But how? The biology of inheritance Part 2

Author: Shweta Ramdas

Editors: Molly Kozminsky, Christina Vallianatos, Bryan Moyers

If you haven’t been living under a rock for the last five years, you have definitely come across headlines to the tune of “Researchers Find Gene for X”, where X can be anything from happiness, to political affiliation, to your preference for cilantro. There are quite a few people who respond to these studies with “but surely that’s not genetic!” I work on the genetics of psychiatric disorders and have fielded this question from most people with whom I discuss my research: “Isn’t something like depression just caused by things that happen to you or your upbringing? Why do we place the blame on genetics instead?”

Continue reading “It’s all in the family! But how? The biology of inheritance Part 2”

In silico biology: How math and computer science teach us about life

Author: Hayley Warsinske

Editors: Molly Kozminsky, Ellyn Schinke, Irene Park

We live in a world of science and technology. Biomedical research helps improve our lives everyday by providing us with vital information about everything from hygiene to Alzheimer’s disease. Computers provide us with access to wealth of information on any subject in an instant and expedite many of our daily activities. Often these two worlds overlap and computers are also used to provide scientists with information about our own health and survival to facilitate biomedical research.

Continue reading “In silico biology: How math and computer science teach us about life”

What the octopus genome can tell us

Author: Shweta Ramdas

Editors: Irene Park, Ada Hagan, Alisha John

The team at MiSciWriters certainly finds cephalopods fascinating, and we aren’t alone. Last year, the octopus (Octopus bimaculoides) was added to the growing list of organisms whose genome sequence is known.

Octopuses belong to a class of organisms called cephalopods, which literally means ‘head-feet’ (members of the cephalopod family have a head and tentacles or arms). These tentacles enable the creatures to do some very clever maneuvering, such as escaping their aquariums to eat crabs outside their tanks. It’s no surprise then that these are the most intelligent amongst invertebrates and now new information about the octopus genome can tell us more about these fascinating creatures.

Continue reading “What the octopus genome can tell us”

Superbugs and a new school year: How you can help slow antibiotic resistance

Author: Carrie Johnson

Editors: Ada Hagan, Irene Park

Whether you have heard about it or not, antibiotic resistance is a growing threat that affects us all.

For generations, we have benefited from antibiotics to fight bacterial infections that would otherwise threaten our lives.  Unfortunately, the effectiveness of antibiotics is increasingly at risk.  Bacterial infections resistant to antibiotics already have already taken a significant toll and the severity of the problem is only growing.  In the United States, it already costs us over 23,000 lives and an estimated $55 billion each year.

As we head into a new school year and the colder winter months when illness risks seem to rise, the timing couldn’t be better to remind you that everyone (yes, you!) plays a role in combating this growing problem of antibiotic resistance. But first we need to understand the basics of this problem, including the three major factors at play.

Continue reading “Superbugs and a new school year: How you can help slow antibiotic resistance”

Science behind the scenes: The costs and payoffs of science

By: Bryan Moyers

Edited by:  David Mertz, Shweta Ramdas, Scott Barolo, Kevin Boehnke

Why haven’t we cured cancer?  Physicians have known about cancer for over 5000 years, and the United States spends nearly $5 billion per year on cancer research.  But there’s still no cure.  Also, where is our clean, renewable energy?  We can’t even catch half the energy in sunlight, and solar panels don’t come cheap!  Why don’t we have a moon colony yet or a male birth control pill?

In the U.S., science funding comes from many sources, including the taxpayers.  As an example, half a percent of the federal budget goes to fund NASA, before considering all of the money that goes to the National Science Foundation (NSF) or the National Institutes of Health and other federal science organizations.  It is reasonable that publicly-funded science should provide some benefit for the public, but it seems like there’s a lot of scientific research out there that’s not giving us the technologies and discoveries we want and need.   So why do we throw money at projects that don’t seem to deliver?

Continue reading “Science behind the scenes: The costs and payoffs of science”