Role of mast cell mediators in modulating the adenosinergic pathway of regulatory T cells

Human newborns suffer a high frequency and severity of bacterial infections, but the mechanisms underlying their susceptibility are incompletely defined. Moreover, neonatal immunologic memory responses to most vaccines are suboptimal, further frustrating efforts to protect this susceptible population. These deficiencies in newborn immunity are in part due to the diminished function at birth of a certain type of white blood cell known as monocytes. Efforts to prevent and treat neonatal infections are thus limited by our incomplete understanding of the neonatal innate immune response. The Levy Lab at Children¿s Hospital Boston is focussed on characterizing unique aspects of neonatal immunity, including the distinct neonatal function of cell receptors known as Toll-like receptors (TLRs)involved in recognizing bacteria. The lab has previously demonstrated that newborn cord blood contains a factor known as adenosine that acts on adenosine receptors present on newborn monocytes to inhibit the ability of these newborn cells to produce inflammatory responses to bacteria and bacterial products. The objective of this proposal is to understand the mechanisms by which adenosine and adenosine receptors inhibit the ability of newborn cells to respond to bacteria and bacterial products that activate cells thru TLRs. We propose to examine the effects of adenosine on the response of newborn monocytes to whole bacteria that activate these cells via TLRs, including: 1) Escherichia coli which is a common cause of neonatal meningitis and 2) Staphylococcus epidermidis that is responsible for approximately 50% of late-onset bacterial bloodstream infections in neonates worldwide. Insight into the nature of innate immune responses of newborns will inform novel approaches to detect, prevent and treat bacterial infections in newborns, a highly susceptible population.