Borrelia burgdorferi is one of an increasing number of bacterial pathogens that can incorporate and metabolize cholesterol from the host. This organism requires cholesterol to grow but it lacks the metabolic machinery to synthetize it. In previous studies in our laboratory, we showed that cholesterol is key for maintaining the integrity and properties of the outer membrane of B. burgdorferi. Importantly, cholesterol is essential for pathogenesis of Lyme disease since cholesterol and cholesterol glycolipids form microdomains in the membranes of the spirochetes with all the hallmarks of eukaryotic lipid rafts, and that it may have important physiological functions. Despite the requirement for cholesterol, little is known regarding the effects of high cholesterol levels in serum, in tissues or in the accumulation of fat in tissues targeted by B. burgdorferi in Lyme disease patients. In a recent study [Toledo et al PNAS 2015], we showed that elevated levels of serum cholesterol, achieved with a short term high fat diet in cholesterol-transport deficient mice of two different genotypes [apolipoprotein E (apoE-), and low density lipoprotein receptor (LDLR-) deficient] resulted in increased arthritis as well as increased number of spirochetes in the joints. These results alerted us to the possibility that hyperlipidemias could be a comorbidity factor for: i. increased acute Lyme disease severity; ii. Increased persistence of spirochetes in tissue, and iii. dissemination to and colonization of tissues with high lipid concentrations. Based on the hyphotesis that B. burgdorferi can exploit the excess of serum cholesterol leading to enhanced acute and chronic infection, and that hyperlipidemias are comorbid factors for Lyme disease, we propose the following:
Specific Aim 1. To determine whether chronic hypercholesterolemia affect the overall pathogenicity of B. burgdorferi in the murine model of Lyme disease with two subaims to determine whether acute or chronic infection of B. burgdorferi is enhanced by hypercholesterolemia in WT and LDLR- mice;
Specific Aim 2. To evaluate the role of subcutaneous adipose and intra-abdominal fat in the dissemination of the spirochete.
High levels of serum cholesterol are a common medical condition of adults and even some children. We have evidence that high serum cholesterol enhances the inflammation of mouse joints infected with the agent of Lyme disease. Considering that Lyme is a very frequent infection, we have thought that serum cholesterol could be a factor in enhancing susceptibility. In this application, the effects of high serum cholesterol an the acute and chronic stages of Lyme disease will be studied.
|Toledo, Alvaro; Huang, Zhen; Benach, Jorge L et al. (2018) Analysis of Lipids and Lipid Rafts in Borrelia. Methods Mol Biol 1690:69-82|
|Toledo, Alvaro; Huang, Zhen; Coleman, James L et al. (2018) Lipid rafts can form in the inner and outer membranes of Borrelia burgdorferi and have different properties and associated proteins. Mol Microbiol 108:63-76|
|Coleman, James L; Toledo, Alvaro; Benach, Jorge L (2018) HtrA of Borrelia burgdorferi Leads to Decreased Swarm Motility and Decreased Production of Pyruvate. MBio 9:|