Staphylococcus aureus is probably the most important bacterial pathogen affecting the public health of Americans. Staph is the leading cause of pus-forming skin and soft tissue infections, the leading cause of infectious heart disease, the number one hospital-acquired infection, and one of the four leading causes of food-borne illness. MRSA, or methicillin-resistant Staph aureus, is a highly virulent form of the infection, and accounts for more deaths annually in the US than HIV/AIDS.
And of course the spread of MRSA and other antibiotic-resistant bacterial infections is becoming a major public health crisis in America. Joining us by phone on this edition of Focus in Sound, my guest, Dr. Eric Skaar, is fighting back. He was named an Investigator in the Pathogenesis of Infectious Disease by the Burroughs Wellcome Fund in 2006. Much of his lab’s research concentrates on Staph aureus, and he and his team have come up with some important new knowledge about Staph and the host-pathogen interface—findings that may lead to new approaches to treatment of Staph infections.
Transcription of “Interview with Eric Skaar”
00;00;07;18 – 00;00;39;06
Ernie Hood
Welcome to Focus In Sound, the podcast series from the Focus newsletter published by the Burroughs Wellcome Fund. I’m your host Science writer Ernie Hood. Staphylococcus aureus is probably the most important bacterial pathogen affecting the public health of Americans. Staph is a leading cause of pus forming skin and soft tissue infections. The leading cause of infectious heart disease, the number one hospital acquired infection and one of the four leading causes of foodborne illness.
00;00;39;21 – 00;01;05;06
Ernie Hood
Mersa or methicillin resistant staph aureus, is a highly virulent form of the infection and accounts for more deaths annually in the U.S. than HIV, AIDS and, of course, the spread of MERSA and other antibiotic resistant bacterial infections is becoming a major public health crisis in America. Joining us by phone on this edition of Focus In Sound, my guest, Dr. Eric Skaar, is fighting back.
00;01;05;20 – 00;01;35;01
Ernie Hood
He was named an investigator in the pathogenesis of infectious disease by the Burroughs Wellcome Fund in 2006. Much of his lab’s research concentrates on staph aureus, and he and his team have come up with some important new knowledge about staff and the host pathogen interface findings that may lead to new approaches to treatment of staph infections. Eric is an associate professor of microbiology and immunology at Vanderbilt University Medical School in Nashville.
00;01;35;16 – 00;01;53;07
Ernie Hood
He earned his B.S. in bacteriology at the University of Wisconsin, his Ph.D. in immunology and microbial pathogenesis from Northwestern University and his MPH in epidemiology and biostatistics, also from Northwestern. Eric, welcome to Focus In Sound.
00;01;53;16 – 00;01;54;18
Eric Skaar
Thanks for having me.
00;01;54;25 – 00;02;17;18
Ernie Hood
Your December 2010 publication in the journal Cell Host Microbe attracted worldwide attention as you offered solutions to some of the great mysteries about Staph aureus, including why it seems to prefer to infect humans over other animals and why some people seem to be susceptible to staph infections, while many others carry the bacteria but seem to be unaffected by it.
00;02;18;06 – 00;02;22;01
Ernie Hood
Can you elaborate on those issues and your related results?
00;02;22;27 – 00;02;47;25
Eric Skaar
Sure. So the interest in this work came about based on our observation that Staph aureus had a preference for hemoglobin as an iron source. The organism needs iron to live. The same reason that you and I need iron. And we take multivitamins. Many of the processes in the organism require that element and we’ve known for quite some time that it requires iron by binding to hemoglobin.
00;02;48;14 – 00;03;16;14
Eric Skaar
And in the process of learning about hemoglobin, we realized that much of the surface of the hemoglobin and protein is variable across different animals. So the region of the hemoglobin protein that staph aureus encounters is different depending on the organism that it’s colonizing. So just based on what we know about receptor ligand interactions, we reason that maybe the Staph aureus hemoglobin receptor would have a different ability to bind hemoglobin from one animal versus another.
00;03;16;14 – 00;03;42;01
Eric Skaar
And that was the initial hypothesis that we set out to test. We knew the Staph aureus hemoglobin receptor called the highest, the B. Using that knowledge, we grabbed hemoglobin from a bunch of different animal species and tested whether or not staph could bind to the hemoglobin. So the differential affinity and we found that it did in fact bind hemoglobin differently and it seemed to bind nonhuman primates and human hemoglobin the best.
00;03;42;27 – 00;04;09;18
Eric Skaar
So that was kind of the key result for us that let us down this path to test whether or not human hemoglobin was a preferred hemoglobin source for staph aureus. That was all in test tubes or in vitro. So we next wanted to determine if that had relevance to the host pathogen interaction using an animal model. So we obtained mice that express human hemoglobin, and mice are notoriously difficult to infect with staph aureus.
00;04;09;19 – 00;04;32;19
Eric Skaar
The animal model, it’s effective, but it takes a very large dose of bacteria to infect a mouse, presumably much more staff than you would ever need to infect a person. And what we found was when we took a mouse that had human hemoglobin coursing through its blood, that mouse was much more susceptible to staph infection. And we can, in fact, infect the animal with less death and get a similar results.
00;04;32;19 – 00;04;41;08
Eric Skaar
Based on that, we concluded that human hemoglobin is a preferred iron source for staph aureus in a way that impacts the ability of staff to grow inside its host.
00;04;42;06 – 00;04;50;03
Ernie Hood
I see. And Eric, does this phenomenon seem to hold true of other pathogens as well, or is this unique to staph aureus?
00;04;50;13 – 00;05;08;27
Eric Skaar
We’ve only begun to touch on that subject. And all of the experiments that we’ve done so far have been in a test tube. But with that caveat, it does appear as if organisms that have evolved to live in humans, these are bacterial pathogens that are called obligate human pathogens, organisms that don’t really grow anywhere else but inside people.
00;05;08;27 – 00;05;36;28
Eric Skaar
Those organisms seem to have a similar preference where they don’t grow and utilize nonhuman animal hemoglobin nearly as well as they utilize human hemoglobin. One of the strongest examples we have is Corynebacterium Diphtheriae, the causative agent of the theory that organism can’t grow on any hemoglobin besides human hemoglobin. So I don’t have data for it, but I would predict that this would be generalizable across many pathogens that have evolved to grow inside humans.
00;05;38;08 – 00;05;54;20
Ernie Hood
I’d like to return briefly, Eric, to the mouse model. I understand, as you mentioned, that it’s been difficult to model staph infections in mice previous to this work. So what will this new model that you’ve developed allow that hasn’t been possible before?
00;05;55;06 – 00;06;26;06
Eric Skaar
Well, I think from the standpoint of the animal model, what this potentially allows is it just provides increased resolution within the model, meaning that maybe smaller differences that would previously been difficult to identify or unable to be identified, those differences might now be visible or identifiable within this animal model. So the hope would be that small, subtle virulence factors that have a small but important effect on the pathogenesis of staff, those through those factors now might be uncovered, whereas they otherwise wouldn’t be.
00;06;26;19 – 00;06;49;05
Eric Skaar
We can also learn a lot more about how staph eats or requires its nutrient iron during infection, because now we have the nutrient iron source that the organism presumably has evolved to use. So from the standpoint of studying how nutrient acquisition occurs in the animal, I think there’s a lot of potential there. The other thing that we haven’t tapped into yet is there are other animal models of staph infection.
00;06;49;05 – 00;07;13;22
Eric Skaar
I mean, as you mentioned in your introduction, staph is the leading cause of a number of different types of disease. And the take home point there is that the organism can infect almost any site in the body. So we know that human hemoglobin makes the mouse more susceptible to bloodstream staph infections. It would be interesting to see what happens with heart infections like endocarditis or pneumonia or bone infections, osteomyelitis.
00;07;13;22 – 00;07;31;14
Eric Skaar
So those are the places that we’d like to move in the future, is to take the animal and move it through a series of different infection models to see if we can find infection models that benefit from this even more. But I think the real value is what it potentially might mean to human infections.
00;07;31;29 – 00;07;44;12
Ernie Hood
I did want to get you to talk a little bit about the differential susceptibility to Staph aureus infection. And I understand that you’ve been able to elucidate some of why that may be occurring.
00;07;44;21 – 00;08;11;16
Eric Skaar
I think it’s a little bit of a leap to say that we’ve figured out why that’s occurring, but we now have a hypothesis. It’s definitely worth testing. And the idea is fairly simple. Based on the paper that you mentioned, we very clearly have shown that staff will differentially bind hemoglobin depending on the animal that comes from, and the differential recognition is due to the fact that hemoglobin varies across animals in a surface exposed portion of the protein.
00;08;12;01 – 00;08;37;08
Eric Skaar
So the exciting thing about that is that hemoglobin varies in the surface portion of the protein across individual people as well. It’s a highly polymorphic protein and it’s particularly polymorphic in the surface of the protein. So this is not the portion of the protein that complexes heme on the inside, which is what the protein does. It moves oxygen around our body by having oxygen bound to the heme that’s inside it.
00;08;37;16 – 00;09;04;09
Eric Skaar
But the surface part of the protein is fairly variable. So if we extrapolate what we know in animals to human hemoglobin, this suggests that maybe the differences in human hemoglobin across the population might also impact the ability of staph aureus to bind hemoglobin. And if that’s true, we might be able to predict people that are at risk for more severe staph aureus infections than others based on their human hemoglobin sequence.
00;09;04;15 – 00;09;16;18
Ernie Hood
And I understand that you’re going to be actually using some gene bank data that Vanderbilt actually has DNA from thousands of patients. To take a look at those questions.
00;09;16;28 – 00;09;42;05
Eric Skaar
That’s right. There’s a excellent resource at Vanderbilt called bio View. Bio view. And if you have been a patient of Vanderbilt University Medical Center within the last 10 to 15 years, your blood has been taken. Assuming you signed the consent form, your blood has been taken and your DNA banked and now what is available is the DNA for all of the patients that have been through the medical center over this period of time.
00;09;42;17 – 00;10;16;19
Eric Skaar
And in addition to that, you can access the medical records or the reason for why the patient was admitted or was a patient at the hospital. So, of course, all of this is de-identified. We don’t need that information. But the information we can get is why any particular person was a patient at Vanderbilt. And what we’re doing now in collaboration with Buddy Creech, who’s a pediatric infectious disease physician here who specializes in staph infections, is buddies helping us find the ICD nine codes, which are the code for why all the patients were admitted to identify people that were admitted with systemic staph infections.
00;10;17;00 – 00;10;32;02
Eric Skaar
And then we’re sequencing their hemoglobin genes to see if there’s any conserved polymorphisms that are conserved amino acid residues in that particular population of patients as compared to otherwise healthy people or people that did not suffer from systemic staph infections.
00;10;32;25 – 00;10;59;08
Ernie Hood
Well, that’s a tremendous resource of data you have available to you. And and that’s going to be very exciting to see where where those experiments take you. Eric, if you’re able to, you know, eventually suss out the differences in hemoglobin ultimately between, you know, patients who’ve had infections and the seemingly resistant people. What will that mean in terms of potential translation into practice?
00;10;59;24 – 00;11;35;11
Eric Skaar
I think one of the biggest problems that we face in a field of staph aureus is that patients who check into hospitals for a variety of reasons tend to acquire staph infections when they’re in the hospital. So these are patients that are otherwise uninfected that then get admitted to a hospital and acquire a hospital acquired infection. If we could identify the patients that were at risk for the most severe cases of staph infection when they check into the emergency room or the intensive care unit or if they’re about to have surgery, if we could potentially design a test where we could take blood samples from these people, determine if they had a hemoglobin sequence that
00;11;35;11 – 00;12;06;00
Eric Skaar
is consistent with a highly aggressive systemic staph infection, We could then prophylactically treat these people aggressively with antimicrobials therapy in an effort to prevent these hospital acquired infections. The idea would be that we don’t have the resources available to treat every person that enters the hospital with antimicrobial therapy to prevent infection. However, if we could identify a very small subset of highly susceptible people, we could potentially protect them from infection by treating them with antibiotics.
00;12;06;25 – 00;12;28;25
Ernie Hood
Well, Eric, in the context of the comments you’ve already made, I’d like to get your take on a couple of interrelated concepts that you’ve already kind of partially delineated. And one is a quote I saw on your website that I found intriguing where you talked about the battle for metals between bacterial pathogens and their hosts.
00;12;29;29 – 00;12;50;27
Eric Skaar
Yeah, the umbrella program for my research lab is basically that sentence. And it goes back to a comment that I made earlier, which is that all bacterial pathogens, all bacteria need to acquire nutrient metals when they’re inside of the host. They need them for the same reason that we need them. There’s no such thing as an organism that can’t live without manganese or zinc.
00;12;51;08 – 00;13;16;09
Eric Skaar
Iron is required by almost all organisms on earth, so they just need to get this these metals. And the thing about metals that makes them so important to the host pathogen interaction is that metals have coordination, chemistry that allows them to be held on to very tightly by proteins. And because of that, the human body has evolved to bind and hold on to metals exceptionally tightly to prevent bacterial growth.
00;13;16;20 – 00;13;48;12
Eric Skaar
So this is the simplest way that we prevent bacteria from making us sick, is we just keep the food away from in high affinity metal binding proteins. And that process was called or termed nutritional immunity by Eugene Weinberg in the seventies. And I love that term. And we use it a lot. So this is just a very simple idea, exceptionally important and I think often underappreciated component of host defense against infection is that the active process of keeping food away from bacteria and if you can’t eat, you obviously can’t grow.
00;13;48;12 – 00;14;06;26
Eric Skaar
And if you can’t grow from for the most part, you can’t infect the host. We think that this is an exceptional target for the development of new therapeutics. Just very simple idea of if you can make it so bacteria can’t eat anymore, they’re not going to be able to make people sick. So that’s something that we’re focused on.
00;14;06;27 – 00;14;11;22
Eric Skaar
I’m trying to learn more about these processes and with the long term goal being it’s targeting them.
00;14;12;07 – 00;14;19;23
Ernie Hood
So what might that targeting? What form might that take down the line as you characterize these processes further?
00;14;20;23 – 00;14;50;10
Eric Skaar
Well, from a translational standpoint, I think we have a lot of potential avenues we could go down and we just discussed one. So we’ve exploited some host and metal binding properties that we might be able to exploit that for a diagnostic test for highly susceptible patients. A very different than a therapeutic, of course, but yet translational potential from a therapeutic standpoint, what is needed is some sort of small molecule modifier of the bacterial processes that are required for metal uptake.
00;14;50;21 – 00;15;14;07
Eric Skaar
But the key is that it has to be a modification strategy that does not globally disrupt the metal homeostasis in the person, because as I mentioned, for the same reasons that the bacteria need the metals, we need the metals. So you can’t just completely kill all the metals or disrupt metal trafficking throughout the body. You have to specifically target the bacterial metal uptake systems for this to be effective, I think.
00;15;14;07 – 00;15;17;21
Eric Skaar
And and that’s where the real innovation is going to have to come in.
00;15;18;02 – 00;15;25;03
Ernie Hood
Sure. Well, again, that that looks very promising and it will certainly be keeping you busy for a while.
00;15;25;13 – 00;15;38;12
Eric Skaar
Yeah, I think so. One thing that’s great about metals is that metals are required for something like 40% of all proteins in nature. So it gives us a lot of targets. There’s a lot of area that we can cover and a lot of different things that we can look at.
00;15;38;21 – 00;16;04;16
Ernie Hood
Well, Eric, what are the implications of this work for the overall problem of antibiotic resistance, which is such a huge issue right now? I’ve seen you quoted as saying that complete and total antibiotic resistance of staph aureus seems inevitable at that at this point. Now, that’s kind of a scary and alarming conclusion. Where do you think we stand and how might your work help that situation.
00;16;04;29 – 00;16;25;14
Eric Skaar
From the standpoint of antibiotic resistance in the long term? I think we potentially are in a lot of trouble. It’s not just staph aureus. In fact, there’s other organisms that are probably a much bigger threat right now that gram negative rods come to mind. Pseudomonas aeruginosa Acinetobacter baumannii. These are organisms that are developing resistance at an exceptionally alarming rate.
00;16;25;27 – 00;16;53;26
Eric Skaar
And to the best of my knowledge, there are no new antimicrobials in the development pipeline that are focused on targeting these diseases with these infections. So it doesn’t take much to realize the potential and maybe even likelihood that there will be a day in the not too distant future when we’ll have infections that are virtually untreatable. I think the solution is to ramp up hugely in the area of anti-infective research and how that happens.
00;16;53;26 – 00;17;17;05
Eric Skaar
I’m not exactly sure, but that that’s something that desperately needs to happen, not just for Staph aureus, but for all of these organisms. And that’s one of the reasons why I study. What I study is because metal uptake is important for all of these organisms, not just staph aureus. So if we could find a globalized or a general targeting strategy to inhibit bacterial metal uptake, we might have a new antimicrobial family against a number of different pathogens.
00;17;17;09 – 00;17;28;08
Ernie Hood
So the drugs you talk about developing would not be new antibiotics. They would be a completely different novel class to address this metal uptake issue.
00;17;28;14 – 00;17;43;17
Eric Skaar
That’s right. There are no. To the best of my knowledge, there are not clinically relevant antimicrobials that target bacterial pathogens based on nutrient metal uptake targeting detrimental uptake systems.
00;17;44;16 – 00;17;52;03
Ernie Hood
I see. Well, it’s certainly wonderful in another, you are well supported in your work because it sounds like there’s a tremendous need for it.
00;17;52;07 – 00;18;19;12
Eric Skaar
Yeah. Thank you. Yeah, I think so. I think this is a really important problem and unfortunately, I think it’s underappreciated because today we have antibiotics that most of the time work. So it’s very difficult to imagine the future because today we’re okay. But I think the reality is that the future does not look very bright. And if we’re not aggressive about it and proactive about it, it could be it could be very bad indeed.
00;18;19;22 – 00;18;28;11
Ernie Hood
Well, Eric, how did you happen to pursue this particular line of research? What attracted you to studying the pathogenic source of infectious disease?
00;18;29;11 – 00;18;54;21
Eric Skaar
I was very fortunate that I went to a public high school with a microbiology class. So when I was maybe 15, I took a class and essentially a bacteriology class, and I loved it at that point. And so I focused my decisions for college on schools that emphasized bacteriology. I went to the University of Wisconsin in Madison, which has one of the few bacteriology bachelor’s of science degrees in the country.
00;18;55;08 – 00;19;21;23
Eric Skaar
I’ve always been fascinated with the process of infection and how these tiny little organisms can take over a seemingly insurmountable host and wipe them out in rapid order. So that was something that I wanted to learn more about, and I decided to focus on researching bacterial pathogens when I was in college. And I was fortunate, as I think was the most people that are in science as a career are fortunate to have excellent mentors.
00;19;21;23 – 00;19;45;20
Eric Skaar
Everything from my high school biology teacher to my college research advisor to my graduate thesis mentor to my postdoctoral research advisor. All of them gave me excellent advice and helped me along the path I got in the pathogens In graduate school. I did my thesis work on Neisseria Gonorrhea and Hank Cipher laboratory studying DNA recombination, and that was my introduction into pathogens.
00;19;45;20 – 00;20;07;02
Eric Skaar
I had read about them before, but only worked on environmental microbes. So that was really exciting for me. And after that experience, I wanted to focus on one of the most significant public health problems that I could identify in an organism that was genetically tractable and had an animal model. Because for me, I’m very interested at the interface between the host and the pathogen.
00;20;07;02 – 00;20;27;20
Eric Skaar
And I like to study both the host and the causative agent of infection. So I wanted an organism that had an animal model and staff satisfied that Bill and I was fortunate to get a postdoctoral training position in all of Stephen’s lab, who is one of the foremost researchers in staff staph aureus, and he sort of set me on my path to study this organism.
00;20;27;20 – 00;20;37;26
Eric Skaar
And while I was in his lab, I made some collaborations with some chemists who got me interested in metals. So that was sort of how it worked. Really just had great people helping me along the way. I think.
00;20;39;22 – 00;20;46;26
Ernie Hood
As you said, that is so often true of of, you know, well-established scientists that they stand on those shoulders.
00;20;46;28 – 00;20;58;08
Eric Skaar
Yeah, there’s no no question about that. All along the way, too, from when I was 15 to postdoc, it was somebody there was some critical person at each step which helped me get to the next one.
00;20;59;07 – 00;21;06;23
Ernie Hood
Eric You’ve already touched on it a little bit, but I want to kind of focus you in on the question of where your research is headed from here.
00;21;06;26 – 00;21;39;10
Eric Skaar
The research that we’re talking about is for hemoglobin. I think that yeah, I touched on it a bit. We want to identify human hemoglobin sequences that are recognized more efficiently by Staph aureus. So what hemoglobin might make people more susceptible to staph aureus infection? And we’re going to do that in a laboratory by making recombinant versions of hemoglobin with different sequences and seeing how they bind to staff and and then making mice that have different versions of human hemoglobin and see how those might change susceptibility to staff.
00;21;39;20 – 00;22;02;12
Eric Skaar
But also we’ll do it in a clinical, epidemiological sense by taking patient DNA from Vanderbilt Hospital and and seeing if we can make correlations between hemoglobin sequences and susceptibility to infection. In addition, the wonderful thing about hemoglobin is it’s one of the most well-studied proteins in nature, and hemoglobin is sort of a paradigm for genetic susceptibility to infectious diseases.
00;22;02;12 – 00;22;27;01
Eric Skaar
You might be familiar with the sickle cell trait and how a sickle hemoglobin is believed to have evolved to protect against malaria. This is an interesting observation and we want to now look at the pathologic hemoglobin. So this would be thalassemia and sickle cell and see if there’s any difference in the ability of Staph aureus to recognize the pathologic hemoglobin that I just mentioned.
00;22;27;12 – 00;22;48;15
Eric Skaar
And then finally, there’s other versions of hemoglobin. There’s neonatal or fetal hemoglobin, and we have a different hemoglobin in our body when we’re first born, and it switches to another kind of adult hemoglobin as we age. And how these different hemoglobin forms impacts the host pathogen interaction are not known. So these are all different areas that we’re thinking about investigating.
00;22;48;24 – 00;22;59;29
Eric Skaar
Just trying to get a sense for when during a person’s life and what kind of genetic sequences, human genetic sequences, staph aureus has evolved to most efficiently colonize.
00;23;01;09 – 00;23;10;25
Ernie Hood
Eric, your work is just as fascinating as it is important, and we certainly wish you the best of luck for continued success. Thanks so much for joining us today on Focus In Sound.
00;23;10;27 – 00;23;14;04
Eric Skaar
All right. Well, thanks. I appreciate the opportunity.
00;23;14;04 – 00;23;29;16
Ernie Hood
We hope you’ve enjoyed this edition of the Focus In Sound podcast. Until next time, this is Ernie Hood. Thanks for listening.
