Lyme disease, the most common vector-borne illness in North America, is caused by the spirochete B. burgdorferi. Infection begins in the skin following an infected tick-bite and acute illness is characterized by headache, fever and myalgia. Currently, there is no human vaccine against Lyme disease and therapeutic administration of antibiotics remains the recommended treatment option. In the absence of a recollection of a tick bite, or if the early symptoms go unnoticed and untreated the spirochete can disseminate to distal regions of the skin, heart, nervous system and the joints, leading to clinical manifestations of disseminated Lyme disease including carditis, neuroborreliosis and arthritis. The treatment option for early and late disseminated Lyme disease is also oral antibiotic treatment for 14-21 days or longer, or intravenous antibiotic administration. In North America, 60 % of untreated Lyme disease patients develop Lyme arthritis and up to 10 % of these patients demonstrate synovitis even after prolonged antibiotic treatment. Adverse events from prolonged antibiotic treatment, and the growing understanding of the importance of the host microbiome in health, emphasize the need to develop effective alternative treatment options for the control of Lyme disease. Towards this goal, this proposal will determine the utility of Peptidoglycan Recognition Protein 1 (PYGLRP1) to control Borrelia burgdorferi infection in a murine model of Lyme disease. Using a yeast display library expressing over 1000 human immune receptors and secretory proteins we examined molecular interactions between human immune receptors and B. burgdorferi and showed that a vast majority of strains of B. burgdorferi sensu stricto bind specifically to PGLYRP1. In-vitro experiments demonstrated that PGLYRP1 has borreliacidal activity. We hypothesize that PGLYRP1, a peptidoglycan-recognition protein, may be used by the host to recognize and eradicate B. burgdorferi. Consistent with our hypothesis, B. burgdorferi burden in mice lacking PGLYRP1 was increased compared to that in control mice. Therefore, in Aim 1 of this proposal, we will evaluate the potential of recombinant PGLYRP1 as a therapeutic to eradicate B. burgdorferi infection in a murine model of Lyme disease. In Aim 2 of this study we will determine whether PGLYRP1 acts synergistically with beta-lactam antibiotics such as ceftriaxone to prophylactically treat B. burgdorferi infection. The results of this study will provide the basis for future efforts that will define an optimal formulation of PGLYRP1 as a therapeutic for Lyme disease. Public Health Relevance Statement NARRATIVE PGLYRP1 is a human protein that binds to and kills Borrelia burgdorferi, the bacterium that causes Lyme disease. We will determine whether PGLYRP1 can be used, alone or in combination with antibiotics, to treat Lyme disease.
Project Terms: Amoxicillin ; Amoxicilline ; Amoxil ; Amoxycillin ; Hydroxyampicillin ; Polymox ; Trimox ; Utimox ; Wymox ; Antibiotics ; Antibiotic Agents ; Antibiotic Drugs ; Miscellaneous Antibiotic ; Arthritis ; arthritic ; Bacteria ; Borrelia ; borrelial ; Borrelia burgdorferi ; B burgdorferi ; B. burgdorferi ; Borrelia burgdorferi sensu stricto ; Lyme Disease Spirochete ; lyme spirochete ; Ceftriaxone ; Cefatriaxone ; Cell Wall ; Combined Modality Therapy ; Multimodal Therapy ; Multimodal Treatment ; combination therapy ; combined modality treatment ; combined treatment ; multi-modal therapy ; multi-modal treatment ; Doxycycline ; Vibramycin ; alpha-6-Deoxyoxytetracycline ; Fever ; Pyrexia ; febrile ; febris ; Future ; Goals ; Headache ; Cephalalgia ; Cephalgia ; Cephalodynia ; Cranial Pain ; Head Pain ; head ache ; Health ; Heart ; Human ; Modern Man ; In Vitro ; Infection ; Joints ; Libraries ; Lyme Disease ; Lyme Borreliosis ; Inbred BALB C Mice ; BALB C Mouse ; BALB/c ; Monobactams ; Lactam Antibiotics ; Monobactam Antibiotics ; Monocyclic beta-Lactams ; beta lactam antibiotic ; Mus ; Mice ; Mice Mammals ; Murine ; Nervous system structure ; Nervous System ; Neurologic Body System ; Neurologic Organ System ; North America ; Parents ; Patients ; Peptides ; Peptidoglycan ; Murein ; Peptidyltransferase ; Peptidyl Transferases ; Peptidyl Translocases ; Transpeptidases ; Immunologic Receptors ; Immunological Receptors ; immune receptor ; Safety ; Order Spirochaetales ; Spirochaetales ; Spirochetes ; Synovitis ; inflamed synovial tissue ; inflamed synovium ; synovial inflammation ; Testing ; Tetracyclines ; Tissues ; Body Tissues ; Vaccines ; Yeasts ; cytokine ; Measures ; base ; dosage ; Organ ; improved ; Distal ; Acute ; Clinical ; Refractory ; Phase ; Knockout Mice ; KO mice ; Knock-out Mice ; Null Mouse ; Myalgia ; Aching muscles ; Muscle discomfort ; Muscle pain ; Muscle pain/fibrositis ; Muscle sorenesss ; Myalgic ; Myodynia ; Myoneuralgia ; Myosalgia ; Binding Proteins ; Ligand Binding Protein ; Ligand Binding Protein Gene ; Protein Binding ; bound protein ; Lyme Arthritis ; Arthritis in Lyme disease ; Integration Host Factors ; Host Factor ; Host Factor Protein ; Therapeutic ; Antibiotic Treatment ; bacterial disease treatment ; bacterial infectious disease treatment ; Antibiotic Therapy ; Intravenous ; Oral ; prophylactic ; Route ; Receptor Protein ; receptor ; secretory protein ; peptidoglycan recognition protein ; Carditis ; Property ; response ; Adverse Experience ; Adverse event ; Adverse effects ; Skin ; Molecular Interaction ; Binding ; Symptoms ; C3H/HeN Mouse ; Measurable ; Recombinants ; in vivo ; Characteristics ; Vector-transmitted infectious disease ; Vector-borne disease ; Vector-borne infectious disease ; Vector-transmitted disease ; vector-borne illness ; vectorborne disease ; vectorborne illness ; vectorborne infectious disease ; novel strategies ; new approaches ; novel approaches ; novel strategy ; Outcome ; cost effective ; clinically relevant ; clinical relevance ; mouse model ; murine model ; alternative treatment ; in vitro activity ; phase 2 study ; phase II study ; Formulation ; experimental study ; experiment ; experimental research ; Innate Immune Response ; host microbiome ; pharmacokinetics and pharmacodynamics ; PK/PD ; tick bite ;
