Friday, September 13, 2024
9/13/2024
The majority of symptoms of Lyme disease are due to the host immune response to the organism, Borrelia burgdorferi, and resolve over time, even without antibiotic treatment. In its natural host, little or no reaction to infection can be seen despite the fact that the organism persists for life. In humans and inbred mice (which do develop immune responses to the organism), inflammation is thought to be initiated by receptors of the innate immune system. In vitro, loss of innate, pathogen-sensing receptors that recognize B. burgdorferi such as toll- like receptor 2 (TLR2) results in a decrease inflammatory response. However, in vivo studies of animals deficient in these receptors or their adaptor molecules do not show reduced inflammation and in many cases show increased inflammation. Recently, in humans, a single nucleotide polymorphism (SNP) in the tlr1 gene that results in loss of expression of the receptor on the cell surface was found to be associated with increased inflammation and symptoms. This suggests that after the initial stimulus, a major role for these innate immune molecules is in dampening inflammation. One major difference between in vitro studies and the in vivo infections is that the in vitro experiments are typically conducted by measuring responses minutes to hours after exposure to the organism. We have evidence that more prolonged exposures in vitro result in the development of innate immune “tolerance” to stimulation by B. burgdorferi. In this proposal, we will study the role of the tlr1-1805GG SNP in disrupting innate immune tolerance, thereby leading to excessive inflammatory responses. The 1805GG SNP results in a loss of localization to the cell surface but does not affect the activity of the receptor. Therefore, in Aim 1, we will first determine the effects of the SNP on specific, localization-dependent signaling pathways and downstream cytokine responses. We have previously shown that the TLR1/TLR2 ligand Pam3CSK4 can initiate signaling from both intracellular and cell surface locations although the signals are different in each location. It is likely that the tlr1- 1805GG SNP continues to signal endosomally. We will track movements of the receptors and ligands as well as compare a tlr1 deletion to the tlr1-1805GG SNP. In Aim 2, we will assess the role of the tlr1-1805GG SNP on macrophage reprogramming leading to loss of innate immune tolerance to B. burgdorferi. We will focus on understanding its effects on macrophage polarization, cell death and the role of glucose metabolism. Finally, in Aim 3, using isogenic B. burgdorferi isolates that do or do not initiate tolerance, we will identify the role of specific components of the organism in moderating macrophage reprograming and loss of tolerance. We believe that B. burgdorferi infection, where there is prolonged infection with minimal evidence of inflammation over time, is an excellent model to understand how the immune system can control responses to invasive bacteria that pose less threat to health than continued efforts to clear the infection—in essence making the organism an invasive “commensal” through the development of innate immune tolerance.
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