Amy Proal, Microbiologist
Summary: Successful chronic pathogens exploit mechanisms that suppress the immune system. In so doing they make it easier for additional pathogens to thrive, creating a snowball effect. The resulting disease state may feature different pathogens from one person to another, yet the symptoms end up being similar due to commonalities in how they go about the business of immune system suppression.
This is a matter of interest to anyone suffering from chronic inflammatory disease such as Lyme, ME/CFS, fibromyalgia, etc. This is a presentation by microbiologist Amy Proal. She is employed by the Autoimmunity Research Foundation and specializes in the role of pathogens in chronic disease:
Here I talk about "successive infection" - a model I've published in several journal articles. The model helps explain how different pathogens and environmental exposures can "work together" to drive chronic inflammatory symptoms. I describe how pathogens can slow the human immune response in order to better survive. Any pathogen that slows the immune system allows other pathogens to better survive in the same immunocompromised person. This creates a snowball effect, where it becomes progressively easier for the person to acquire pathogens, or become susceptible to chemicals, as the strength of the immune response decreases. A person undergoing successive infection may eventually develop a chronic inflammatory condition. However, because so many microbes/viruses/fungi have the potential to cause disease, it is unlikely that any two patients will ever present with the exact same symptoms. It's important to understand that pathogens driving successive infection do not have to come from the external environment. If a person becomes immunocompromised, pathobionts already living in their own microbiome/virome communities can also drive persistent inflammation and symptoms.
I reference the following papers:
Inflammatory disease and the human microbiome
Microbe-Microbe and Host-Microbe Interactions Drive Microbiome Dysbiosis and Inflammatory Processes
Expression profile of nuclear receptors upon Epstein -- Barr virus induced B cell transformation
The effect of Aspergillus fumigatus infection on vitamin D receptor expression in cystic fibrosis
Altered Virome and Bacterial Microbiome in Human Immunodeficiency Virus-Associated Acquired Immunodeficiency Syndrome
Precision identification of diverse bloodstream pathogens in the gut microbiome
Transcript
[Emphases added]
Today I want to talk about successive infection. I've tweeted about that a couple times now and it actually forms a cornerstone of many of my papers. I want to better explain what I'm talking about. So first I'm going to begin with the original simple model of successive infection that I also actually developed with a colleague about ten years ago. So what happened is we were studying a receptor in the human body called the VDR nuclear receptor. That stands for vitamin D nuclear receptor. But don't worry about vitamin D now and food and Sun let's that's a different topic. This receptor the VDR nuclear receptor was of interest to us because it plays a very important role in controlling the human immune response. That's for two main reasons. The receptor which is like a protein complex that sits on part of a very important signaling pathway. It controls in a large part the activity of two important parts of the immune response. One are the activity of certain families of what are called antimicrobial peptides. Antimicrobial peptides in simple terms would be defined as natural antibiotics that the body creates in a range and in response to a range of viral, fungal, bacterial pathogens. These molecules can actually kind of be spliced differently depending on the nature of the infectious threat. They're a really important part of the ability of our immune system to respond to any infectious threat.
And also this same VDR nuclear receptor controlled expression of a protein called TLR-2 [Toll-like receptor 2]. TLR-2 is a protein that's found often on the exterior of cells that plays an important role in noticing in external like things like pathogens recognizing them and their proteins and alerting the immune system to their presence. So we have two key parts of how the immune system recognizes pathogens and deals with pathogens under control of this VDR nuclear receptor. So as we were studying the receptor we came across a paper which showed that Epstein Barr virus could infect, and when it did it would disable activity of this receptor. And that made so much sense. If you a serious pathogen and you wanted to survive and persist in the human body, slowing or disabling the ability of the VDR receptor to function, this would shut down or slow those important parts of the immune response that would otherwise try to target you if you were a pathogen. So it's an incredible survival mechanism.
In fact it was such a logical survival mechanism that we began to search the literature to see if we could find more examples of pathogens that may also survive by slowing activity of this important receptor. And we did. We found papers showing that Mycobacterium tuberculosis,a very common human pathogen, a persistent pathogen, often can slow activity of the VDR receptor to survive. We found that Borrelia burgdorferi can slow the VDR in order to survive. We found that Mycobacterium leprae slows the VDR receptor to better survive. We found that cytomegalovirus can disable and slow activity of this important receptor. We even found that HIV logically almost completely suppresses activity of the VDR receptor, which makes sense. Very potent immunosuppressive pathogen. And there's even a study that shows that the fungus Aspergillus fumigatus secretes a specific gliotoxin that significantly affects this receptor and also slows or down regulates its expression. So basically all these different pathogens have a same or similar survival mechanism. When they infect, they disable or slow activity of this same VDR nuclear receptor in order to slow activity of the host immune system and better survive and drive persistent chronic symptoms in that person.
So, thinking about that we began to think, okay, each pathogen that could slow activity of the VDR would actually facilitate survival of another pathogen. So think about it. Let's say you are infected with Epstein Barr virus and it's slowed activity of the VDR. You become more and more immunocompromised. Now because you're immunocompromised you're more likely to acquire another pathogen. Let's say that pathogen is Mycobacterium tuberculosis. Well it can also slow the VDR to better survive in the body so now by doing that the immune response drops even more making that same patient even more immunocompromised. Now, maybe it's easier for that person to acquire Borrelia, which now joins into the mix of pathogens affecting the patient and also slows activity of the VDR nuclear receptor to better survive. Now all of a sudden there's a snowball effect in which each infecting pathogen is slowing the immune response in a way that makes it easier for the next infected pathogen to better survive and also slow the immune response.
Literally when I when I picture this successive infection I picture a snowball rolling down a hill. An initial infection that then slows the immune response making it easier to acquire another infection, and as these different infections all affect the patient and sort of join into a mix, the snowball of what becomes possibly a chronic inflammatory condition for that patient, grows as it rolls down the hill. Okay. Now a couple things. The VDR is sort of an example. It's not sort of it is an example of how pathogens can slow the immune response. There are actually many other ways that infecting pathogens slow the immune response to survive. One we're very familiar with - they can simply persist inside white blood cells often like macrophages. Where they actually are alive inside the very cells of the immune system that's supposed to kill them. So even a pathogen that infects and doesn't dysregulate the VDR receptor could still contribute to the success of infectious process. As long as it either disables the human immune response in some way or even begins to disable the body's metabolic pathways, anything that begins to compromise the host in a way that makes that person less likely to be able to fight off yet another infectious agent.
Now, add to that into this snowball model, that successive infection doesn't just have to involve pathogens. A chemical exposure or a stressful event could also jump start the successive infection process. Let's say you were exposed to a chemical in a way that almost inevitably lowers immune function. Most chemical exposures or mold exposures drop the immune response as the immune system struggles to deal with that chemical of the exposure. So that may be an immunocompromising event that can begin the successive infection process. The pathogens may be incorporated at a later point. Maybe the chemical knocks down the immune response, making it easier now for a person to acquire Epstein Barr virus and other pathogens as the snowball rolls down the hill. Or let's say someone sustained a car accident, a really serious car accident and they were under a lot of stress. There are studies that show that stress serious stress does deplete the immune response substantially. So maybe this stressful event can jump-start the success of infectious process compromising the immune system again then allowing the person to pick up pathogens that also further slow the immune response. Now imagine also that chemical exposures are stressful events or other things that feed into a disease process can also happen in intermediate steps of this process. So let's say you have a condition like ME/CFS and your condition started with mono. You got sick with a bad case of mono and persistent EBV is now affecting you. Certainly slowing activity of the VDR but also persisting inside immune cells driving a lot of dysregulation but slowing the immune response to survive.
Now, let's say there's a chemical in your environment. Maybe you weren't that sensitive to it before, but now that your immune system is compromised you may be more susceptible to exposure from that chemical. That chemical may affect you dropping the immune response. Now you sustain a stressful event. Now that stressful event may feed into the process also. So what we're looking at is a model in which no two patients have to have the exact same mix of pathogens or chemical exposures or stressful problems, but they can still develop a chronic inflammatory disease state. That's somewhat similar, that may result in similar diagnosis. Let's say for example in ME/CFS diagnosis. CFS is a great example of this is - an illness in which we've been searching for a single pathogen for a long time. And if research teams don't find the pathogen or the single pathogen that drives ME/CFS they tend to contend that this is not an infectious chronic inflammatory condition. That no longer makes sense where we realize that pathogens can facilitate the survival of each other. In fact they just do. So that may be happening is that in patients who end up with an ME/CFS diagnosis, which of course is a spectrum disorder. There's a range of symptoms associated with ME/CFS. There may be differences in the exposure and the pathogens and the order of the pathogens and exposures that a patient has, but the end symptoms may be somewhat similar. And you know that really accounts for the fact that no two patients with the same condition ever have the same exact symptom presentation. And in fact it even helps explain why there's similarities between the conditions like ME/CFS and other conditions like MS or fibromyalgia or gulf war syndrome, because these same trends likely feed into a lot of these different conditions.
So what that means is that we would actually expect variability in the symptoms of these conditions. We not only may not have to break patients into subsets so rigorously, instead we may want to study these larger more common mechanisms in these more similar pathways, like the VDR pathway that pathogens can impact and chemicals can impact in order to drive a disease process. Because for example if cytomegalovirus and M tuberculosis and Mycobacterium leprae and you know, HIV, all affect the immune system by disabling the same receptor, what it that means is if that receptors dysregulated, no two people have to have the same pathogen for that same pathway to be a problem and that that is a key thing to understand when it comes to chronic disease. There's redundancy in the way that pathogens act and disable human pathways, and that redundancy means that patients with similar symptoms don't always have to harbor the same pathogen or the same exact mix of pathogens.
Another way I used to describe the successive infectious process, was picture a bowl of alphabet soup. So the letters in the soup and the broth that's different pathogens different chemical exposures different stuff that can contribute to a chronic inflammatory condition. Now you take a spoon, you dip that spoon into the soup and you come up with certain mix of letters on your spoon. That may be the unique mix of pathogens and exposures and events that have fed into your particular inflammatory diagnosis. But if another person with even the same diagnosis dips their own spoon into that same alphabet soup, they're going to come up with a different mix of letters on that spoon. And it doesn't really matter that it's not the same exact letters. What matters is that the general soup and the general noodles that made the letters are all derived from similar processes, similar immunosuppressive events, similar dysfunction of the human immune response by pathogens and by environmental exposures.
So, moving on from that I want to explain a consideration that then began to better inform my impression of the way I regarded this model over time. And it's actually part of the reason that I became really interested in studying the human microbiome and the human virome. Because in all of us as I think you know i've explained there are these vast microbial ecosystems and almost all tissue and blood that contain viruses, bacteria, fungi, archaea and other organisms. And so in patients, well in all of us, who have these microbiome communities the most important thing I can stress is that in any person these communities harbor what are called pathobionts. Pathobionts are microbes or viruses that don't appear to drive disease in someone who's healthy. So in a person who's healthy the immune system has these microbes in check. And they are kept in a way that the person functions fine they're going about their life they don't have symptoms. They harbor these pathobionts but they're okay. But these same pathobionts from microbes or viruses, if the a person becomes immunocompromised, or if the body becomes imbalanced in other ways the cause the body to suffer, they can change their gene expression and they can change their activity so that they begin to act as pathogens. Essentially they evolve the way they act to act as pathogens under conditions of immunosuppression and dysfunction. So what can happen is part of the successive infectious process that is key, is that it doesn't just have to be external infections that begin to contribute to a chronic inflammatory condition as it develops. You may have external infections, but what happens is if any of those infections or exposures drop the immune response causing a person to be more immunocompromised, pathobionts already present in many of these persons microbiome ecosystems may begin to change their gene expression and act as pathogens themselves adding into the disease process themselves and contributing to the unique mix of imbalance and dysbiosis that can drive chronic symptoms in this patient.
So, for example, let me give you a study an example of a study that shows this well. There was a research team that looked at patients with HIV infection and they found of course that HIV has a profoundly immunosuppressive effect on the body. It affects the VDR receptor, that's not in that particular study, I just know it does. But this study looked at its ability to lower what's called CD4 T-cell count so when HIV infects it has a very negative effect on CD4 T-cell function and count. So CD4 T-cells basically drop down so low in these patients and of course T-cells are very important part of the immune response. So patients with HIV become very immunocompromised. What this research team did that was really important was that they looked at the flow-on effects of that infection and that immunocompromised state. And what they did is they sequenced the microbes using computer-based tools. They looked at the bacterial gut microbiome and the DNA gut virome, or viral communities, in patients in these HIV infected patients. And what they found was that because the patient was immunocompromised pathobionts in those microbiome communities were much more likely to act as pathogens. So for example in this virome in the gut, there was an expansion of adenovirus which are a perfect example of pathobionts. Adenoviruses persist in healthy people, but in patients who move towards immunosuppression and illness they can begin to cause all kind of infections - from cardiac infections and cardiac symptoms to ear infections, nose infections, all kinds of different issues. So these patients had an expansion of these adenovirus because they were so immunocompromised.
They also found that the bacterial microbiome in these patients infected with HIV moved towards a state in which there was decreased diversity decreased species richness it was moving towards a state of its own imbalance in which pathobionts were surely flourishing and functioning more. So in these patients with HIV the final symptoms that would be called, what they what they would sustain as patients, would be a mix of those driven by HIV the immunosuppression driven by the HIV virus and then the flow-on effects that that immunosuppression has on these communities in the gut, which meant that pathobionts and other pathogens in those communities were able to survive and drive further chronic symptoms. That would cause the final end disease process and symptoms in these patients. That same thing goes for the model of successive infection that can affect any other kind of chronic inflammatory condition tied to infection. If the microbiome and the virome itself in any area of the body - there's a microbiome in the lungs, there's a microbiome in the bladder, there's microbes in tissue and in blood -if any of these microbes already in us begin to move towards a state where they act as more pathogens that is also going to contribute to the final disease process any one patient develops.
And again because none of us harbor the same exact microbes and viruses and fungi in our microbiome ecosystems, the nature of the symptoms driven by that dysbiosis, that's part of what happens to immunocompromised patients, is never going to be exactly the same between two people and two patients. We are all born with different microbiomes we are all continually accumulate different microbes into our bodies over time. And so that when pathobionts become an issue we're never going to harbor the same ones as the person next to us. So all of this really helps account again for the variability we see in chronic inflammatory disease symptoms in these conditions that are spectrum disorders.
So and I'll bring up one more quick example of that because I'm going to tweet it. There was a study which just looked at patients who were hospitalized for bone marrow infections as a Stanford University study. And what they found is they actually tried looking at really serious pathogens that were in the hospital environment and it didn't seem that most of the infections that these bone marrow patients were getting (and by the way bone marrow transplant patients are very immunocompromised because they have to be put on a lot of immunosuppressive drugs to sustain the transplant so the body doesn't reject it). So in these immunocompromised patients in the hospital they didn't seem to be picking up very many external infections. What seemed to happen was that pathobionts especially in the guts of these patients acted up and moved more into the bloodstream and then began to cause more serious infections. So the overall takeaway point from the study was that many serious hospital infections may not result from external infection but may actually originate from pathobionts in these people's microbiomes that they already have that they've been living with possibly for years or even maybe even since they were born.
So a couple of takeaway messages here. The final disease state that anyone develops in a chronic inflammatory condition is going to be unique to that patient depending on the unique nature of the pathogens that they acquire over time, the unique mix of chemicals and environmental exposures that they sustain, the stressful events and the unique nature of those that they sustain, then finally the unique nature of their microbiome and virome and the pathobionts and how they're affected by immunosuppression over time. If we take all that into consideration we don't really need to be looking for the single pathogen in any of these disease states. The key to better understanding these conditions may instead be looking at how different pathogens facilitate the survival of each other and how mixes of pathogens and other exposures can contribute to a chronic inflammatory disease.
Okay that's it for now. I hope you followed me somewhat. Next time I want to give you a better idea my next behind the tweet of just some of the pathobionts and human microbiome ecosystems. want to give you a more visual idea of what I'm talking about. And I also want to go on and describe yet other sometimes fascinating mechanisms by which different pathogens interact together to cause a disease process by sustaining each other's activity or acting in ways that support each other's function, so be back then. Take care.
