Certain pathogens can cause a healthy microbiome to shift towards a state of disease. How are many such pathogens able to persist in the human body?
Pathogens inside the cells can directly alter human gene expression
Humans are colonized by microbes acquired from parents and even siblings. Thereafter, a person is continually exposed to microbes in his or her environment. We acquire new microbes from the food and water we consume, the air we breathe, other animals in our environment, and many other sources. Some of these microbes are pathogens. These include species of bacteria, viruses, bacteriophages, fungi, and parasites, among others. If these pathogens persist in our bodies, they can directly alter the expression of our human genes. For example, one research team showed that upon infecting a cell, Mycobacterium tuberculosis alters the expression of 463 human genes.
Those pathogens capable of persisting inside humans cells, particularly the cells of the immune system, are most easily able to alter human gene expression. This is because human DNA is expressed, decoded, and repaired in the nucleus or center of the cell. If pathogens infect this nucleus, they can directly interfere with these vital human genomic processes. Many intracellular pathogens interfere with human gene expression in a manner that slows or disables the human immune response. This is an extremely logical survival mechanism, as doing so allows them to persist in their host with much greater ease.
Pathogens can slow the immune response by disabling the VDR receptor
The ability of several well-studied pathogens to dysregulate activity of the Vitamin D Nuclear Receptor (VDR) provides an excellent example of how pathogens slow the immune response in order to better survive. Nuclear receptors are proteins found in every human cell. In response to chemical signals, they direct these cells to express key genes that regulate human development, homeostasis, and metabolism.
The VDR is one of the body’s most important nuclear receptors. It regulates the expression of hundreds of genes, many connected to autoimmune conditions and cancers. It further expresses TLR2, a protein that helps the immune system recognize foreign substances and invading microbes.
The receptor further regulates expression of several families of antimicrobial peptides (AMPs). The AMPs are natural antibiotics that participate in every facet of immunity. When activated, the AMPs have widespread antibacterial, antiviral, and antifungal activity. For example, the immune system cannot mount an effective response to Mycobacterium tuberculosis without help from an antimicrobial peptide named cathelicidin.
It should come as little surprise then that many of the pathogens most commonly associated with inflammatory conditions have evolved to disrupt the ability of the VDR to function correctly. They do this by either directly disabling its activity, or by creating metabolites and proteins that bind the receptor and interfere with its function.
For example, when Epstein Barr Virus infects immune cells called lymphocytes, it slows VDR activity by a factor of around fifteen. The intracellular pathogens M. tuberculosis, cytomegalovirus, Borrelia burgdorferi, and Mycobacterium leprae also slow VDR activity to varying degrees. The fungus Aspergillus fumigatus, common in lungs of patients with cystic fibrosis, secretes a toxin which significantly slows VDR expression. Certain bacterial species in biofilm communities release a molecule called capnine. Molecular modeling data suggests that capnine can also bind the VDR and decrease its activity.
Because disabling the immune response via the VDR pathway is such a logical pathogen survival mechanism, other as yet undetected or uncharacterized microbes almost certainly survive in the same or similar fashion as those listed above.
If VDR function becomes impaired, the activity of other related nuclear receptors may also suffer. Several of these other receptors also express important antimicrobial peptides. If less of these AMPs are created, the host becomes even more immunocompromised. Indeed, patients with Crohn’s disease and sarcoidosis have been shown to express lower levels of the AMP cathelicidin as their diseases progress.
- Certain pathogens persist inside the cells of the immune system where they directly interfere with the ability of human cells to express important genes.
- Several well-studied pathogens – pathogens often detected in patients with inflammatory disease – slow activity of the human immune system by disabling the VDR nuclear receptor.
- The ability of pathogens to slow VDR function (or other components of the immune response) makes sense from an evolutionary perspective. Pathogens that disable the immune system are able to survive in their host with much greater ease.
- If VDR activity slows, the ability of other related nuclear receptors to regulate immune function additionally decreases. The host becomes more immunocompromised over time.