Hey there! Last podcast I talked about how many “harmless” microbes in the human body are able to evolve to a state where they cause inflammation and illness. I explained that this “shifting” towards virulence (or disease) is much more likely to occur in people whose immune systems are compromised or debilitated. There are many factors that can negatively impact the health of the human immune system. I plan to discuss many of them in greater depth. But today I will focus on one major factor – the ability of key pathogens to slow and dysregulate the human immune system as part of their most basic survival strategies.
The most fundamental way that pathogens “take down” the human immune system is by infecting and living inside human cells – especially human white blood cells. Under conditions of health, these white blood cells traffic the body, where they engulf or digest pathogens that originate from both the internal and external environment. BUT, many key pathogens have evolved to thwart this process. They have evolved to remain alive inside these white blood cells; inside the very cells that are supposed to kill them! They can survive this way for long periods of time in a chronic, persistent state. Doing so clearly gives them a HUGE advantage or “edge” over their human host. If the situation was compared to a human war, it would be as if a soldier were able to inhabit the body of its opponent, and then make the opponent act in its own interest.
There are two main implications of this “intracellular persistence”:
1. The infected cell is unable to perform its basic immune system duties.
2. Any pathogen inside the infected cell can interfere with the way the cell “encodes” its human DNA.
Let me explain this second point in more depth. The center of every human cell has a copy of a person’s DNA. This DNA “codes” for the ~ 21,000 human genes that determine who we are and how we deal with our environment. These genes are eventually “translated” into proteins – proteins that direct our human pathways to correctly regulate the immune system, the nervous system, human metabolism and other critical aspects of human function. It follows that any pathogen able to persist in the center of a human cell can directly “mess with” the cell’s DNA and the vital human processes it regulates. The situation could be compared to a computer hacker. Imagine a hacker that not only breaks into your computer, but gains access to the programming code that directs your operating system and websites. By either directly altering this code, or changing the way the code is translated into programs, the hacker can cause your computer to malfunction in an almost infinite number of ways.
Here’s an example of how a pathogen can dysregulate a human cell in the above fashion. A research team in Louisiana studied what happens when Cytomegalovirus (CMV) infects a human white blood cell. They found that CMV significantly changed how the cell expressed its human genes. In fact, the virus “turned up” the expression of 583 human genes, and “turned down” the expression of 621 human genes. These changes were so profound that the infected white blood cells actually changed into an entirely different type of cell – an “inflammatory” cell that promoted CMV’s ability to infect neighboring cells. No wonder then that, as the paper points out, chronic CMV infection is associated with retinitis, gastrointestinal disease, hepatitis and pneumonia – but also with chronic inflammatory conditions like multiple sclerosis and atherosclerosis (heart disease).
A recent study by researchers at Stanford confirms how broadly CMV can “re-program” the human immune response. The team studied identical twins and isolated cases in which one twin was infected with chronic CMV and the other was not. They tested the activity and function of 204 different parts of the human immune system in each twin. These 204 immune system “parameters” included the amount/frequency of certain immune cells, the ability of such cells to signal, and the concentrations of immune system proteins called cytokines. They found that, in general, 119 of these immune system “parameters” were altered in the twins with CMV. In fact they calculated that, in people infected with CMV, “the lifelong need” to control the virus causes approximately 10% of all T cells in the body to become directed against it. This led the team to conclude that the immune response is “very much shaped by the environment and most likely by the many different microbes an individual encounters in their lifetime.”
OK – but how exactly does this major pathogen interference happen? All human pathways that control the immune response, metabolism, cognition etc are regulated by receptors – protein molecules that control pathway signaling. In very simple terms, receptors function in a “lock and key” fashion. Imagine that you want to get into a very secure house. You might have to first open locks on an outside door. Then you might open or adjust a series of other locks on inner doors and/or other checkpoints before finally entering. Now, picture these locks as receptors associated with a human pathway. Under conditions of health, very specific human proteins bind into each receptor. These proteins are analogous to the keys in my house example. If the correct human protein or “key” fits into the correct human receptor or “lock,” the receptor/protein “complex” changes shape in a way that allows that part of the pathway to correctly move forward. This process happens over and over at each receptor “checkpoint” until the pathway fulfills its final, correct role in the body.
Now consider this: many pathogens have evolved to create proteins that are very similar in size/shape to human proteins (this redundancy is sometimes called molecular mimicry). If a pathogen with this ability survives inside a human cell, its OWN proteins may begin to “bind” into human receptors. Gradually, the human proteins meant to control a particular receptor may be increasingly replaced by these similar “enemy” or pathogen proteins. What happens? The slightly different shape of the pathogen proteins cause the receptor to act/signal differently than it would under conditions of health.
An excellent example of the above (that I’ve discussed in several published papers) is the ability of pathogens to dysregulate activity of the human Vitamin D Receptor (VDR). The VDR is an extremely important receptor located at the heart of every human cell. It controls the expression of almost 1000 human genes. It also controls the activity of very important parts of the human immune response. These include TLR2 (a protein the body uses to identify and target pathogens), and several kinds of antimicrobial peptides (natural antibiotic molecules the body uses against infectious threats).
It comes as little surprise then that the fungus Aspergillus fumigates has evolved to create a protein or gliotoxin that can bind into the VDR and directly slow its activity. This results in tremendous survival gains for Aspergillus – the altered VDR can no longer correctly express many of the human genes it regulates. The expression of TLR2 and the antimicrobial peptides under VDR control also diminishes. Now, Aspergillus can flourish in the face of the host’s weakened immune defenses.
In fact slowing VDR activity (and subsequently parts of the human immune system) is such a logical survival mechanism that many other key pathogens have also evolved ways to dysregulate the receptor. When Epstein Barr virus infects human B cells it dramatically lowers VDR activity. Mycobacterium tuberculosis slows VDR activity by a factor of ~3.3. Borrelia burgdorferi, Cytomegalovirus, and Mycobacterium leprae also slow VDR activity to varying degrees. HIV almost completely “shuts down” the VDR. I should be clear that some of these pathogens don’t create proteins that directly bind into the VDR. They interfere with the VDR receptor in ways a little too hard to explain here:) But you get the overall trend right!?
Now factor this in: the human body’s pathways are tightly interconnected. So any change in human signaling has “flow-on” effects that impact yet other pathways and systems. In the case of the VDR, the receptor’s activity is tied to that of related receptors that control hormone signaling (especially the estrogen-beta receptor). It follows that the “original” intracellular infection may also prevent these related receptors/pathways from functioning correctly.
But let’s go back to the immune system, and continue to use the VDR pathway as an example. Let’s say CMV infects a person’s B cells and lowers VDR activity. The person’s immune response suffers as a result. Now, it becomes easier for that person to pick up OTHER pathogens from the external environment. Or, pathogens already in that person’s microbiome find it easier to act in a more virulent fashion. These “new” pathogens may also infect the person’s cells, where the interference they cause further slows the immune response. A “snowball effect” may ensue, where each “new” pathogen begins to facilitate the survival of the next.
In many of my papers I’ve referred to this snowball effect as “successive infection.” When I think of successive infection I literally picture a snowball rolling down a hill. The snowball begins with one intracellular infection, and then grows, as more and more pathogens take advantage of the dysregulated atmosphere in the body. As more pathogens “join” the snowball, the disease state that the snowball represents pushes the human body farther and farther away from a state of health.
It’s important to realize that once the “successive infection” process has started, environmental factors besides infection can “add” to the snowball. These include chemical exposures, stress, immunosuppressant drugs, over-used antibiotics and any other factors that cause either the immune response or microbiome balance to suffer. In fact, any of these other factors can “start” the snowball too.
I realize this is a major claim, but in my mind, a successive infection snowball could drive almost any form of inflammatory disease. That’s because such wide-range of different pathogens and negative environmental exposures can contribute to the process. Pathogens are also able to infect so many parts of the human body (nerves, brain tissue, lung tissue). If the snowball represents disease, the specific illness any one person develops would stem from their UNIQUE infectious history, their unique medication history, their unique chemical exposure history, and the many, many different ways these and other variables can interact with/feed into each other.
If you think that’s a stretch, consider this: almost every analysis of the human microbiome identifies new microbes never before detected by previous studies. For example, just a few months ago, Steven Quake at Stanford identified thousands of “new” microbes in human tissue and blood. Many of them are potential intracellular pathogens we didn’t even realize could survive in humans. This led Quake and team to state that these novel microbes “may prove to be the cause of acute or chronic diseases that, to date, have unknown etiology…”
Also, research teams continue to discover new examples of how pathogens might interfere with human pathways. For example, a team in Indiana just identified viruses that create proteins similar in size/shape to the human protein insulin. They found these viral proteins could bind into human insulin receptors that determine how the body correctly regulates blood sugar levels. The viruses that create these insulin-like proteins are regularly detected in human blood and fecal samples. The team concluded that “since only 2% of (human) viruses have been sequenced, this study raises the potential for discovery of other viral hormones which, along with known virally encoded growth factors, may modify human health and disease.”
So I’ll end on the following note: never underestimate the “power” of intracellular infection. Human microbiome studies that fail to account for possible intracellular pathogens may miss part of a larger, more important picture of disease. For example, the gut microbiome dysbiosis now tied to many inflammatory conditions may be a downstream result of intracellular infection in the blood or other tissues. AKA: the widespread drop in immune system activity driven by intracellular pathogens may “set the stage” for an atmosphere that favors gut microbiome imbalance. This is certainly the case in HIV/AIDS, for example (for more context read this blog post).
Ok phew! That’s it for now. Next podcast I’ll go more into immunosuppressive drugs, antibiotics, and other factors that can also compromise the human immune system and/or the human microbiome. Talk then!