Bacteriophages, Asthma, Airway Inflammation and Infection

To understand Bacteriophages and their role in airway inflammation, chronic infection and Asthma, World Asthma Foundation reached out to Dr. Bollyky, immunologist and infectious disease specialist at Stanford Medical Center for an introduction to these topics.

Allergic disorders pose a growing challenge to medicine and our society. Therefore, novel approaches to prevention and therapy are needed. Recent progress in studies on bacterial viruses (phages) has provided new data indicating that they have significant immunomodulating activities. We show how those activities could be translated into beneficial effects in allergic disorders and present initial clinical data that support this hope.” – Society for Experimental Biology and Medicine

Introduction to Bacteriophages

World Asthma Foundation: Dr. Bollyky, can you introduce us to bacteriophages, their impact on chronic bacterial infections, airway inflammation and asthma?  

Video: Introducing Asthma and Bacteriophages – Airway Inflammation and Infection Interview with Dr. Bollyky, immunologist and infectious disease specialist at Stanford Medical Center

Dr. Bollyky: Yes, sure. First, just a little bit about the background of the lab and what we do. Then I’ll tell you about the bacteriophage we’re working on, and how we think it may relate to immune regulation, and airway inflammation in general.

We’re immunologists, as well as being infectious disease docs, and so my lab has worked now for a number of years trying to study immune regulation in the lung, and how populations of different regulatory cells sense allergens, and how they keep healthy folks from developing hypersensitivity to those allergens, and really where they go wrong in asthma. We’ve been doing that work about as long as I’ve been a professor at Stanford, which is about seven years. And a lot of that is funded by the NIH.

The other hat that I wear is as an infectious disease doc, and obviously anyone who has asthma will tell you that infections are among the triggers that seem to precipitate flares. 

There’s a lot of literature about asthma being related to flora, and to both episodic as well as long-term exposures to the microbial world. My lab studies a particular type of microorganism called the bacteriophage. These are viruses that are made by bacteria, and they are very abundant in your body as well as in your lungs, and really anywhere where bacteria tend to live. In the same way that you and I have viruses, your bacteria do too, and they produce these things in incredible amounts.

A fairly good rule of thumb is that you’re going to find somewhere in the neighborhood of 10 bacteriophages for every bacteria that you have at a site of chronic infection. The number is higher than that in sea water, but in most of the studies that have been done of the gut, or the oral tract, or the vagina, in spaces like this the numbers hold true. 

There’s less data in the lung, but I think you can be fairly confident that, again, anywhere where you’ve got long-term bacteria setting up shop, you have these phages. What we’ve been looking at recently is how your immune system sees these phages, and how they alter both the immune response to bacteria, but then sort of immune homeostasis in general.

One of the things that we found is that these phages tend to dampen responses to infection by bacteria, and they do that basically by being perceived as viruses, as you might expect, because that’s really what they are.

Phages and Asthma

World Asthma Foundation: How do  phages relate to asthma?

Dr. Bollyky: In two ways.

The first is, it may alter the microbiome of the lung and allow bacterial infections to persist, ironically longer than they might otherwise, because they keep immune clearance from happening. This may be counter-intuitive because most of us think of viruses as being bad for the host organisms, in this case bacteria, but both are probably true, meaning, bacteriophages are parasitized bacteria, but vis-a-vis the immune system they probably may also contribute to their persistence.

The other part about it, which is what we’ve been looking at recently, is how bacteriophages modulate the immune environment of the lung in general. There, it seems that, not unlike other viruses, that you see some interesting polarizing effects on immunity.

In all of this, there’s some very particular aspects of this that I think are relevant to the microbiome of the lung, and again, particularly to phages, but all of this highlights the complicated and, I think, fascinating immune and microbial environment of the lung in asthma, and how much we have to learn about that environment, and conversely, how many opportunities there would be to intervene in that system, if we only knew more.

Key Findings

World Asthma Foundation: What are the key findings?

Dr. Bollyky: A couple of things that folks who follow the literature will relate to. The first is there’s just been a lot more attention that’s being paid to the microbiology of the lung, and the idea – when I did my medical training, it’s getting close to 20 years now, what I learned at that time was that the lung was sterile, for example.

We know that that’s by far an oversimplification, and that there’s actually a lot of stuff going on there. Most of the past decade has been about characterizing the bacteria, and the fungi, and what have you, that are in the lung. Now, I think people are becoming alert, or attentive to the possibility, or to the fact that there are also endogenous viruses in these places, and that your lung has an ecology to it, where maybe not unlike, well, really any other ecology, the African Savanna, or your favorite fishing hole down the street.

There’s a lot of organisms that exist in competition, and in equilibrium at some points, and those are dynamic and living systems that we need to think about. That’s one trend, it’s just the attention to the microbiome and then the attention in particular to components of the microbiome.

I would put fungi in this, but also these bacteriophages that were relatively ignored until fairly recently, and then we’ve become kind of cognizant of what they do.

The other trend that I think is arising, that’s part and parcel of that in terms of asthma, is realizing that these different organisms, like fungi, like viruses and bacteria, exert opposing and, I think, important effects on the immune response, and that these things, the endogenous viruses you have, much like the endogenous bacteria, or the endogenous fungi can influence the ways that your immune system sees the rest of the world, and the ways in which it’s regulated.

Bacteriophages and Gut-Lung Interaction

World Asthma Foundation: We’ve been reporting on the Gut-Lung axis. Do you see that connection playing a role?

Dr. Bollyky: Yes, it’s a particularly interesting one too, because again, I think we tend to think of the lung in isolation, but the reality is that, both from above, in the form of your sinuses and secretions from there, but then also from below, meaning your gut.

Every time you sleep we know these secretions do go down. If you look at the microbiome of the lung, a lot of it tends to be oral flora, and a lot of it tends to be fairly transient, meaning, the studies that have been done would suggest that the bugs, the bacteria, and assuming it will probably be the case for the phages as well, but certainly the bacteria and the fungi that you have in your lung are fairly representative of the same organisms that you have in your sinus tract and in your gut. Your upper GI tract.

This ends up populating to a large extent your lungs. This big debate about whether your lungs are sterile or not really comes down to whether you think that these microbial interlopers are a part of a stable population or what their relationship is. As you are clearly aware, a lot of these same antibiotic resistance patterns, a lot of the same metabolites that your gut bacteria produces or that your sinus bacteria produce is going to end up in your lungs. Then, that’s going to influence the local immune response and ultimately asthma.

New Phage Research

World Asthma Foundation: Thank you Dr. Bollyky. What’s next?

Dr. Bollyky: We’re looking at phages and asthma models, and we’ve been studying a lot of infections, both human diseases like cystic fibrosis and in mouse models. Hopefully, I’ll be able to tell you more soon about phages and the allergens and regulatory T cell populations and that sort of stuff, and I’d love to come back.

World Asthma Foundation: We look forward to that. Thank you very much.

Dr. Bollyky: You got it.

See also Dr. Dietert’s interview about the Gut and Lung connection.

Find more information about Dr. Bollyky here.

Dr. Bollyky introduces bacteriophages, impact on chronic bacterial infections, airway inflammation and asthma