|
Research in Dr. Levy's laboratory centers on innate immunity of the human newborn to microbial infection. His interest in this area traces to his doctoral training during which he isolated and studied human neutrophil-derived antimicrobial proteins and peptides including cathelicidins and the bactericidal/permeability-increasing protein (BPI) that possesses antibacterial and endotoxin-neutralizing activity against Gram-negative bacteria. Spurred by an interest in the functional immaturity of neutrophil function at birth, Dr. Levy has discovered that neutrophils of human newborns are deficient in BPI, a protein that possesses cytotoxic and endotoxin-neutralizing activity towards Gram-negative bacteria. Supplementing human newborn cord blood with recombinant BPI in vitro resulted in enhanced bactericidal activity against Gram-negative bacteria and markedly reduced bacteria-induced cytokine release, raising the possibility that BPI might represent a potential therapy for newborns with invasive Gram-negative bacterial infection and/or endotoxemia.
The current focus of Dr. Levy's laboratory is the expression and function of the Toll-like receptor system in human newborns. Levy and colleagues have discovered a striking 1-3 log decrease in sensitivity of monocytes in human neonatal cord blood, as compared to monocytes in adult peripheral blood, to the TNF-alpha-inducing effect of multiple Toll-like receptor ligands, including bacterial lipopeptides (TLR2), LPS (TLR4), and flagellin (TLR5). Remarkably, newborn plasma confers substantially reduced bacterial lipopeptide- and LPS-induced TNF-alpha release on adult monocytes, reflecting the presence of low molecular weight plasma factor that enhances synthesis of the secondary messenger cyclic adenosine monophosphate (cAMP), an agent that suppresses TLR-induced TNF production but preserves synthesis of the anti-inflammatory and Th2-polarizing cytokine IL-6. Skewed TLR-induced cytokine responses may significantly contribute to immature neonatal immunity.
In marked contrast to responses to other TLR agonists, Dr. Levy has discovered that TNF-alpha release in response to agonists that mimic single stranded viral RNA such as the synthetic nucleoside analogue R-848 (TLR 7/8), is equivalent in newborn and adult blood. Preservation of responses to R-848 may present unique opportunities for augmenting innate and acquired immunity in the human newborn.
The overall goal of this work is to identify innate immune pathways as potential targets of immunomodulatory therapies to prevent and treat microbial infection in neonates.
In addition to his basic research, Dr. Levy also maintains a strong and active interest in translational research. He has participated in the design and execution of clinical trials of antimicrobial proteins and peptides, including a recombinant N-terminal fragment of the Bactericidal/Permeability-Increasing Protein (rBPI21, XOMA (U.S.) LLC).
|
