The innate immune system recognizes pathogens via the interaction of molecular constituents of microorganisms with specialized pattern recognition molecules on host cells known as toll-like receptors (TLRs). Each of the 12 known toll-like receptors engages a different set of pathogenic markers, thereby recognizing in total a large variety of microorganisms. This engagement leads to activation and induction of inflammatory mediators via only two major intracellular pathways, known as the myeloid differentiation factor 88 (MyD88)-dependent and MyD88-independent signaling pathways. The objective of this proposal is to test the hypothesis that toll-like receptor signaling via the MyD88-dependent signal transduction pathway is an essential and modifiable mediator of pathogen-induced preterm labor. This hypothesis will be tested in a mouse model by first (Specific Aim #1) characterizing the roles of the MyD88-dependent and -independent pathways in pathogen-induced labor using peptidoglycan (a TLR-2 ligand derived from Gram positive bacterial cell walls) and group B beta-hemolytic streptococcus (GBBS, a Gram positive organism associated with preterm labor and neonatal sepsis). Mutant mice lacking either TLR-2 or MyD88 will be used to define the roles of these proteins in pathogen-induced labor.
In Specific Aim #2 the capacity of a negative regulator of MyD88 (a splice variant known as MyD88s) to prevent MyD88-dependent preterm birth will be tested. A new method of delivering exogenous proteins intracellularly (TAT-fusion proteins) will be used to ferry MyD88s into the gestational compartment. Finally, in Specific Aim #3 we will take advantage of a novel observation made since the first submission of this application, namely that E. coli-induced labor has an exclusive requirement for MyD88. Dissection of the respective roles of mothers and fetuses in signaling for E. coli induced labor will be conducted using pregnancies in which maternal and fetal MyD88 genotypes differ in informative ways.
Preterm birth affects over 12% of all deliveries in the U.S., or approximately 480,000 babies annually, and continues to be the most important cause of neonatal illness and death in developed countries. Fifty percent or more of unexplained cases of preterm birth are related to infection. The incidence of preterm delivery continues to rise in the U.S., a fact that reflects continuing deficiencies in our knowledge of the causes and mechanisms of parturition.
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