DAMPs, PAMPs, MAVS and HERVs
JP Saleeby, MD
DAMPs, PAMPs, MAVS and HERVs what they mean and what the Holy Hell do they have to do with my body is the focus on this short piece a bit tongue and cheek here. The acronyms are more than just four-letter words. They are popping up in popular scientific articles and in lofty presentations by leading experts in the scientific community. As I have said in the past, we medical and scientific blokes like to impress our audience whether it be the public or our patients or even what we would consider a lesser colleague with jargon. The more we wow them the brighter they think we are. Use of the terms DAMPs, PAMPs, MAVS and HERVs are such case, and I am here to try and dispel the mystery and put a kibosh on the wow-factor.
DAMPs stand for Damage Associated Molecular Patterns. These are endogenous danger molecules that are released from damaged or dying cells in our bodies and activate the innate part of our immune system by interacting with pattern recognition receptors (PRRs). Although DAMPs contribute to the host’s defense, they can promote pathological inflammatory responses. There are attributes of good, bad and ugly here. Protein DAMPs include intracellular proteins, such as heat-shock proteins and materials derived from the extracellular matrix that are generated following tissue injury, such as hyaluronan fragments. These interact with the aforementioned PRRs to produce an inflammatory effect. This can be good in the short term to recruit aspects of our immune system to fight off an infection or something else that is attacking our body. It can be harmful if it progresses beyond the good our immune system can do for us and turns on the dark side where we have runaway inflammation. This runaway inflammation or chronic inflammation is regarded by most as a bad thing. The DAMPs we have referred to are proteins in circulation. Non-protein DAMPs include ATP, uric acid, heparin sulfate and DNA.
PAMPs are similar to DAMPs but are referred to as Pathogen Associated Molecular Patterns and behave in a manner strikingly similar to DAMPs. They are inflammatory triggers. Pathogen is the key word here in that these bad players are responsible for being recognized by those PRRs. Once again, involving our innate immune system. Things like macrophage mannose receptors and scavenger receptors help mediate phagocytosis (gobbling up the bad guys) with our immune defense cells. Some examples of PAMPs are lipopolysaccharides (LPS) derived from gram-negative bacteria, lipoteichoic acids (LTA) derived from gram-positive bacteria, peptidoglycans, lipoproteins, lipoarabinomannans and double-stranded RNA. All these are more are examples of PAMPs. When they hit the Pattern recognition receptors (PRRs) in both animals and plants all hell can break loose. Toll-like receptors (TLRs) are another receptor that these PAMPs can bind to. TLRs are responsible for some aspects of inflammation. It is about balance, intended for helping an organism but when over stimulated the response can be harmful.
Now if all that shit ain’t bad enough we have MAVS and HERVs. MAVS are short for Mitochondrial antiviral-signaling protein and are a type of protein that is essential for antiviral innate immunity. MAVS protein is located in the inner membrane of the mitochondria, peroxisomes, and endoplasmic reticulum (ER). These are all parts of a mitochondria in our cells that we studied in high school biology. The mitochondria as you may remember is the ‘’powerhouse’’ of the cell, producing ATP for energy. Many millennia ago, these mitochondria were free living organisms that eventually infected the larger cells of more complex organisms. Now if MAVS have not given you a migraine headache it gets more complicated as MAVS contains three domains: an N-terminal caspase recruitment domain (CARD), a middle proline-rich region (PRR), and a C-terminal transmembrane (TM) domain. Oh, hell no… another PRR I thought that was used already for pattern recognition receptors. Are they playing with us here? Why not call then Proline-enhanced region (PER) to avoid confusion. Well, who am I to tell them anything. Before we leave MAVS want to mention that viruses impede mitochondrial biogenesis, causing alterations in mitochondrial function in order to promote viral translation and assembly (the main goal of a virus is to propagate itself). One theory is that virus–mitochondria interactions hamper mitochondria-associated antiviral signaling mechanisms that are protective of the host organism.
Finally, we arrive at HERVs. Human endogenous retroviruses (HERVs) are inherited genetic germline elements derived from exogenous retroviral infections throughout the evolution of the human genome, and account for about 8% of our genome. The majority of HERVs are defective due to evolutionarily acquired disruption or silencing mutations. Thank God or we would be all big virus producing bags of saltwater. While the youngest of these retroviruses, HERV-K(HML-2), termed HK2 for ease of use, is able to code for all viral proteins and produce virus-like particles, it is not really known if these virus particles package and transmit HK2-related sequences. Some of the newer HERVs (relatively speaking) that have become part of our human genome may have a more nefarious relationship with us and may be more of a detriment.
For heaven’s sake we can jump a few million years ahead if we do the “HERVs thing” to ourselves as we have seen recently with those advances in science with the advent of mRNA therapy. We have basically introduced virus particles into our genome intentionally without a clue to long-term effects. Playing with fire while blindfolded; nothing good comes of that in my opinion.
Well folks I hope this short explanation of these four-letter words was helpful and made things clear as mud. So next time you see these acronyms you will know a bit more then that person sitting next to you. Now to quell my massive headache I am off to have a glass of my favorite bourbon neat.