At the recent 10th annual Lyme Disease Foundation's conference held at the NIH in Bethesda, Maryland, there was a lecture by Dr. Catherine Luke, Ph.D., of the University of California, that went almost unnoticed. It was sandwiched between the controversial NIH Intramural Chronic Lyme Disease Study, and a provocative study showing persistent Borrelia infection in dogs post-antibiotic treatment. The lecture seemed innocuous at first glance, but a second look made me wonder if I was watching something out of a science fiction movie. You know the moment? It's where the hero has this sudden epiphany that the monster is out of the bottle, and only he seems to notice that the world is doomed!
So what is this monster in the bottle waiting to attack the "us"? Well, let's begin with a basic understanding of self In biology, we are what we are because our cells only express genes from our own chromosomes. Imagine how quickly we would be in trouble if we expressed all the genes of every virus or bacteria that we encountered. We wouldn't be ourselves for long - instead we would be a walking conglomeration of newly acquired genes. Although it sounds enticing to incorporate yeast genes into our cells, and be able to ferment our own alcohol right in our gut, it would shortly become very nonproductive if every time we ate sugar we got drunk! What I am saying is that we are us, and bacteria are bacteria, and wouldn't it be nice if it always stayed that way? Well, guess what? There is some evidence that mammalian cells may actually express foreign borrelia genes. Furthermore, that expression may also lead to autoimmunity!
We have known for some time that retroviruses like HIV use an enzyme called reverse transcriptase to trick our cells into making new HIV virus. Yet, in bacterial systems this insertion of bacterial genes into host mammalian genes is not heard of until now.
Dr. Catherine Luke took the plasmid that contains the gene for Borrelia burgdorferi OSP-A protein and immunized mice with it. (She only injected purified borrelia DNA. There were no live bacteria used at this stage.) Under the influence of the cytomegalovirus (CMV), the OSP-A gene was transcribed by the mouse cells. The OSP-A protein was produced, and inserted into mouse cell membrane. Further, this expression of the bacterial protein by the mouse cells caused the immune system of the mice to launch an attack by creating anti-OSP-A antibodies. The immune response was enough to prevent active infection in the same mice when they were challenged with live Borrelia burgdorferi. So, at the same time the mouse incorporates the bacterial OSP-A protein into itself, the mouse also launches an immune attack against itself. The mouse in essence becomes allergic to the very protein it created when it decoded the bacterial OSP-A DNA!
What does this all mean? Does this mouse model have any application to human systems? Many scientists will be quick to point out that the promoter of this anomaly in the mouse model was the CMV virus, but in 1996 Dr. Simon and his coworkers showed that the OSP-A gene can be expressed in mammalian cells under the control of its own endogenous promoter. (Simon, et al, Eur J Immunol, 26:2831-2840,1996) This implies that Borrelia burgdorferi is capable of inserting the OSP-A gene into mammalian cells all by itself, causing the expression of the bacterial protein within the membrane of mammalian host cells. Further, there is work supporting the expression of OSP-A protein in infected Lyme patient's joints in the absence of active infection. (Persing, et al, J Infect Dis, 169:668-72, 1994, and Persing DH, Ruteledge BJ, Rys PN, et al, Target Imbalance: Disparity of Borrelia burgdorferi Genetic Material in Synovial Fluid from Lyme Arthritis Patients. J Infect Dis, November 4, 1993; 169:668-672)
Although Dr. Catherine Luke tried to give her lecture a positive spin by suggesting that this mechanism of gene expression may one day be useful in developing a vaccine against Lyme disease, it seems impractical and quite risky. Instead of a potentially new vaccine, I see a new model for Lyme disease causing auto-immunity, even in the absence of live bacteria. Dr. Luke presented evidence that the mouse made antibodies against OSP-A bacterial protein that, for all practical purposes, had become part of the cell structure of the mice. This means the antibodies produced would now attack the healthy mouse cells.
Does this occur in infected humans? We don't know. The evidence is certainly sparse, because so few researchers have ever thought to look for the expression of Borrelia proteins within human cells. Does this mean that active infection is a myth, and that auto-immunity is the cause of persistent symptoms? No. There are many examples and case histories of culture positive Lyme patients, even after years of antibiotics. (Lawrence C, Lipton RB, Lowy FD, and Coyle PK. Seronegative Chronic Relapsing Neuroborreliosis. European Neurology, 1995;35(2):113-11 7)
The truth is, whether or not this exact model of autoimmunity occurs, there is much evidence that there are other autoimmune processes going on as well. It seems likely that both persistent infection and autoimmunity are occurring in patients who have persistent symptoms post-treatment. The narrow-minded view of just autoimmunity or just persistent infection occurring could lead to detrimental consequences in patients who receive only partial treatment based on a single minded belief. There needs to be a better understanding of the interplay of these bacteria in humans that goes beyond the belief there is a single cause to all Lyme patients' problems. This is a complex organism interacting with a complex system, and trying to define this disease by a single point of view is an oversimplification of what is really going on.
The more we look at this organism, the more we realize that the microbiology of this bacterium is highly unique, highly evolved, and poorly understood.
(An interesting side note: When the OSP-B gene is injected into mice, and the OSP-B protein is then expressed on the surface of mouse cells, there is no protection from a challenge of live Borrelia burgdorferi. In other words, the mouse antibodies against OSP-B seem to be ineffective against the live bacteria)