Research

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Ofer  Levy, MD, PhD

Ofer Levy
Department:
Medicine Research
Division
Infectious Diseases Research
Hospital Title:
Director, Precision Vaccines Program
Academic Title:
Associate Professor of Pediatrics, Harvard Medical School
Research Focus Area:
Innate immunity of the human newborn
Contact Via Email
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Research Overview

Research in our laboratory centers on innate immunity of immunocompromised patients to microbial infection. Our interest in this area traces to my doctoral training during which I 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, we have discovered that neutrophils of human newborns are deficient in BPI, that possesses cytotoxic and endotoxin-neutralizing activity towards Gram-negative bacteria. Supplementing human newborn cord blood with recombinant BPI in vitro enhances bactericidal activity against Gram-negative bacteria and markedly reduces 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.

Translational work in our lab has recently demonstrated the importance of endotoxin-directed innate immunity in triggering graft-versus-host-disease in neutropenic pediatric and adult patients undergoing myeloablative chemotherapy for hematopoietic stem cell transplantation (bone marrow transplantation). Together with collaborators at the Dana Farber Cancer Institute, we are currently conducting a clinical trial of recombinant BPI (rBPI21, XOMA (U.S.) LLC) as a novel endotoxin antagonist, assessing safety, pharmacokinetics, and impact on endotoxin-directed innate immunity.

Another major innate immune focus of our laboratory is the expression and function of the Toll-like receptor (TLR) system in human newborns. Greater than 2,000,000 infants under the age of 6 months die every year of infection and therefore characterizing mechanisms of susceptibility and approaches to modulating neonatal host defense to prevent and or treat infection are global health priorities. We have discovered a marked impairment in TLR-mediated production of the Th1-polarizing cytokine TNF by human newborn blood monocytes. Remarkably, newborn plasma inhibits TLR2-mediated TNF production from monocytes, reflecting the presence of adenosine, an endogenous purine metabolite. Adenosine induces the secondary messenger cyclic adenosine monophosphate (cAMP), 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 impaired neonatal responses to most TLR agonists, we have discovered that TLR8 agonists, including single stranded viral RNAs and synthetic nucleoside imidazoquinoline compounds, fully activate robust production of TNF and IL-12 by human neonatal antigen-presenting cells, corresponding to robust activation of NF-kB and p38 MAP kinase pathways. Preservation of responses to TLR8 agonists may present unique opportunities for augmenting immunity in the human newborn, particularly as novel vaccine adjuvants that may be active at birth- a major public health priority. We have recently expanded this work to include a tissue engineering approach for in vitro modeling of neonatal antigen-presenting cell and lymphocyte responses to novel vaccine formulations incorporating TLR agonists and nanoparticles.

The overall goal of our work is to identify innate immune pathway defects as potential targets of immunomodulatory therapies to prevent and treat infection in newborns and those exposed to chemoradio-therapy.

About Ofer Levy

Ofer Levy received his MD and PhD degrees from New York University. He completed internship, residency, and clinical fellowship training at Children's Hospital, Boston and a research fellowship at Brigham and Women's Hospital.

Publications

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  1. Battersby AJ, Khara J, Wright VJ, Levy O, Kampmann B. Antimicrobial Proteins and Peptides in Early Life: Ontogeny and Translational Opportunities. Front Immunol. 2016; 7:309.
  2. Saadatian-Elahi M, Aaby P, Shann F, Netea MG, Levy O, Louis J, Picot V, Greenberg M, Warren W. Heterologous vaccine effects. Vaccine. 2016 Jul 25; 34(34):3923-30.
  3. Goodridge HS, Ahmed SS, Curtis N, Kollmann TR, Levy O, Netea MG, Pollard AJ, van Crevel R, Wilson CB. Harnessing the beneficial heterologous effects of vaccination. Nat Rev Immunol. 2016 Jun; 16(6):392-400.
  4. Ganapathi L, Arnold A, Jones S, Patterson A, Graham D, Harper M, Levy O. Use of cidofovir in pediatric patients with adenovirus infection. F1000Res. 2016; 5:758.
  5. Pettengill MA, Levy O. Circulating Human Neonatal Naïve B Cells are Deficient in CD73 Impairing Purine Salvage. Front Immunol. 2016; 7:121.
  6. Fish EN, Flanagan KL, Furman D, Klein SL, Kollmann TR, Jeppesen DL, Levy O, Marchant A, Namachivayam S, Netea MG, Plebanski M, Rowland-Jones SL, Selin LK, Shann F, Whittle HC. Changing oral vaccine to inactivated polio vaccine might increase mortality. Lancet. 2016 Mar 12; 387(10023):1054-5.
  7. Oh DY, Dowling DJ, Ahmed S, Choi H, Brightman S, Bergelson I, Berger ST, Sauld JF, Pettengill M, Kho AT, Pollack HJ, Steen H, Levy O. Adjuvant-induced Human Monocyte Secretome Profiles Reveal Adjuvant- and Age-specific Protein Signatures. Mol Cell Proteomics. 2016 Jun; 15(6):1877-94.
  8. Guinan E, Avigan DE, Soiffer RJ, Bunin NJ, Brennan LL, Bergelson I, Brightman S, Ozonoff A, Scannon PJ, Levy O. Pilot experience with opebacan/rBPI 21 in myeloablative hematopoietic cell transplantation. F1000Res. 2015; 4:1480.
  9. Nguyen DN, Fuglsang E, Jiang P, Birck MM, Pan X, Kamal SB, Pors SE, Gammelgaard PL, Nielsen DS, Thymann T, Levy O, Frøkiær H, Sangild PT. Oral antibiotics increase blood neutrophil maturation and reduce bacteremia and necrotizing enterocolitis in the immediate postnatal period of preterm pigs. Innate Immun. 2016 Jan; 22(1):51-62.
  10. Ganapathi L, Van Haren S, Dowling DJ, Bergelson I, Shukla NM, Malladi SS, Balakrishna R, Tanji H, Ohto U, Shimizu T, David SA, Levy O. The Imidazoquinoline Toll-Like Receptor-7/8 Agonist Hybrid-2 Potently Induces Cytokine Production by Human Newborn and Adult Leukocytes. PLoS One. 2015; 10(8):e0134640.
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  12. Amenyogbe N, Levy O, Kollmann TR. Systems vaccinology: a promise for the young and the poor. Philos Trans R Soc Lond B Biol Sci. 2015 Jun 19; 370(1671).
  13. Levy O, Levy O. Ready to benefit from training: heterologous effects of early life immunization. Trans R Soc Trop Med Hyg. 2015 Jan; 109(1):3-4.
  14. Pettengill MA, van Haren SD, Levy O. Soluble mediators regulating immunity in early life. Front Immunol. 2014; 5:457.
  15. Dowling DJ, Levy O. Ontogeny of early life immunity. Trends Immunol. 2014 Jul; 35(7):299-310.
  16. Strunk T, Inder T, Wang X, Burgner D, Mallard C, Levy O. Infection-induced inflammation and cerebral injury in preterm infants. Lancet Infect Dis. 2014 Aug; 14(8):751-62.
  17. Levy O, Wynn JL. A prime time for trained immunity: innate immune memory in newborns and infants. Neonatology. 2014; 105(2):136-41.
  18. Jans J, Vissers M, Heldens JG, de Jonge MI, Levy O, Ferwerda G. Fc gamma receptors in respiratory syncytial virus infections: implications for innate immunity. Rev Med Virol. 2014 Jan; 24(1):55-70.
  19. Levy O, Netea MG. Innate immune memory: implications for development of pediatric immunomodulatory agents and adjuvanted vaccines. Pediatr Res. 2014 Jan; 75(1-2):184-8.
  20. Guinan EC, Palmer CD, Mancuso CJ, Brennan L, Stoler-Barak L, Kalish LA, Suter EE, Gallington LC, Huhtelin DP, Mansilla M, Schumann RR, Murray JC, Weiss J, Levy O. Identification of single nucleotide polymorphisms in hematopoietic cell transplant patients affecting early recognition of, and response to, endotoxin. Innate Immun. 2014 Oct; 20(7):697-711.
  21. Power Coombs MR, Kronforst K, Levy O. Neonatal host defense against Staphylococcal infections. Clin Dev Immunol. 2013; 2013:826303.
  22. Kollmann TR, Levy O, Hanekom W. Vaccine-induced immunity in early life. Vaccine. 2013 May 17; 31(21):2481-2.
  23. Dowling DJ, Tan Z, Prokopowicz ZM, Palmer CD, Matthews MA, Dietsch GN, Hershberg RM, Levy O. The ultra-potent and selective TLR8 agonist VTX-294 activates human newborn and adult leukocytes. PLoS One. 2013; 8(3):e58164.
  24. Cuenca AG, Wynn JL, Moldawer LL, Levy O. Role of innate immunity in neonatal infection. Am J Perinatol. 2013 Feb; 30(2):105-12.
  25. Belderbos ME, Levy O, Meyaard L, Bont L. Plasma-mediated immune suppression: a neonatal perspective. Pediatr Allergy Immunol. 2013 Mar; 24(2):102-13.
  26. Kollmann TR, Levy O, Montgomery RR, Goriely S. Innate immune function by Toll-like receptors: distinct responses in newborns and the elderly. Immunity. 2012 Nov 16; 37(5):771-83.
  27. Levy O, Goriely S, Kollmann TR. Immune response to vaccine adjuvants during the first year of life. Vaccine. 2013 May 17; 31(21):2500-5.
  28. Kronforst KD, Mancuso CJ, Pettengill M, Ninkovic J, Power Coombs MR, Stevens C, Otto M, Mallard C, Wang X, Goldmann D, Levy O. A neonatal model of intravenous Staphylococcus epidermidis infection in mice &lt24 h old enables characterization of early innate immune responses. PLoS One. 2012; 7(9):e43897.
  29. Nathe KE, Mancuso CJ, Parad R, Van Marter LJ, Martin CR, Stoler-Barak L, Philbin VJ, Phillips MF, Palmer CD, Levy O. Innate immune activation in neonatal tracheal aspirates suggests endotoxin-driven inflammation. Pediatr Res. 2012 Aug; 72(2):203-11.
  30. Strunk T, Prosser A, Levy O, Philbin V, Simmer K, Doherty D, Charles A, Richmond P, Burgner D, Currie A. Responsiveness of human monocytes to the commensal bacterium Staphylococcus epidermidis develops late in gestation. Pediatr Res. 2012 Jul; 72(1):10-8.
  31. Belderbos ME, Levy O, Stalpers F, Kimpen JL, Meyaard L, Bont L. Neonatal plasma polarizes TLR4-mediated cytokine responses towards low IL-12p70 and high IL-10 production via distinct factors. PLoS One. 2012; 7(3):e33419.
  32. Guinan EC, Barbon CM, Kalish LA, Parmar K, Kutok J, Mancuso CJ, Stoler-Barak L, Suter EE, Russell JD, Palmer CD, Gallington LC, Voskertchian A, Vergilio JA, Cole G, Zhu K, D'Andrea A, Soiffer R, Weiss JP, Levy O. Bactericidal/permeability-increasing protein (rBPI21) and fluoroquinolone mitigate radiation-induced bone marrow aplasia and death. Sci Transl Med. 2011 Nov 23; 3(110):110ra118.
  33. Paludan SR, Levy O, Bowie AG. Toll2011 at Lago di Garda: studying danger sensors by the guard towers at the lake. Nat Immunol. 2011 Sep; 12(9):805-8.
  34. Palmer CD, Guinan EC, Levy O. Deficient expression of bactericidal/permeability-increasing protein in immunocompromised hosts: translational potential of replacement therapy. Biochem Soc Trans. 2011 Aug; 39(4):994-9.
  35. Sanchez-Schmitz G, Levy O. Development of newborn and infant vaccines. Sci Transl Med. 2011 Jul 6; 3(90):90ps27.
  36. Palmer CD, Mancuso CJ, Weiss JP, Serhan CN, Guinan EC, Levy O. 17(R)-Resolvin D1 differentially regulates TLR4-mediated responses of primary human macrophages to purified LPS and live E. coli. J Leukoc Biol. 2011 Sep; 90(3):459-70.
  37. PrabhuDas M, Adkins B, Gans H, King C, Levy O, Ramilo O, Siegrist CA. Challenges in infant immunity: implications for responses to infection and vaccines. Nat Immunol. 2011 Mar; 12(3):189-94.
  38. Power Coombs MR, Belderbos ME, Gallington LC, Bont L, Levy O. Adenosine modulates Toll-like receptor function: basic mechanisms and translational opportunities. Expert Rev Anti Infect Ther. 2011 Feb; 9(2):261-9.
  39. Zhang JP, Yang Y, Levy O, Chen C. Human neonatal peripheral blood leukocytes demonstrate pathogen-specific coordinate expression of TLR2, TLR4/MD2, and MyD88 during bacterial infection in vivo. Pediatr Res. 2010 Dec; 68(6):479-83.
  40. Strunk T, Richmond P, Prosser A, Simmer K, Levy O, Burgner D, Currie A. Method of bacterial killing differentially affects the human innate immune response to Staphylococcus epidermidis. Innate Immun. 2011 Dec; 17(6):508-16.
  41. Strunk T, Power Coombs MR, Currie AJ, Richmond P, Golenbock DT, Stoler-Barak L, Gallington LC, Otto M, Burgner D, Levy O. TLR2 mediates recognition of live Staphylococcus epidermidis and clearance of bacteremia. PLoS One. 2010 Apr 09; 5(4):e10111.
  42. Belderbos M, Levy O, Bont L. Neonatal innate immunity in allergy development. Curr Opin Pediatr. 2009 Dec; 21(6):762-9.
  43. Stanietsky N, Simic H, Arapovic J, Toporik A, Levy O, Novik A, Levine Z, Beiman M, Dassa L, Achdout H, Stern-Ginossar N, Tsukerman P, Jonjic S, Mandelboim O. The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity. Proc Natl Acad Sci U S A. 2009 Oct 20; 106(42):17858-63.
  44. Demirjian A, Levy O. Neonatal vaccination: a once in a lifetime opportunity. Pediatr Infect Dis J. 2009 Sep; 28(9):833-5.
  45. Kliger Y, Levy O, Oren A, Ashkenazy H, Tiran Z, Novik A, Rosenberg A, Amir A, Wool A, Toporik A, Schreiber E, Eshel D, Levine Z, Cohen Y, Nold-Petry C, Dinarello CA, Borukhov I. Peptides modulating conformational changes in secreted chaperones: from in silico design to preclinical proof of concept. Proc Natl Acad Sci U S A. 2009 Aug 18; 106(33):13797-801.
  46. Nathe KE, Parad R, Van Marter LJ, Lund CA, Suter EE, Hernandez-diaz S, Boush EB, Ikonomu E, Gallington L, Morey JA, Zeman AM, Mcnamara M, Levy O. Endotoxin-directed innate immunity in tracheal aspirates of mechanically ventilated human neonates. Pediatr Res. 2009 Aug; 66(2):191-6.
  47. Canny G, Levy O. Bactericidal/permeability-increasing protein (BPI) and BPI homologs at mucosal sites. Trends Immunol. 2008 Nov; 29(11):541-7.
  48. Demirjian A, Levy O. Novel vaccines: bridging research, development and production. Expert Rev Vaccines. 2008 Nov; 7(9):1321-4.
  49. Wynn JL, Scumpia PO, Winfield RD, Delano MJ, Kelly-Scumpia K, Barker T, Ungaro R, Levy O, Moldawer LL. Defective innate immunity predisposes murine neonates to poor sepsis outcome but is reversed by TLR agonists. Blood. 2008 Sep 1; 112(5):1750-8.
  50. Philbin VJ, Levy O. Immunostimulatory activity of Toll-like receptor 8 agonists towards human leucocytes: basic mechanisms and translational opportunities. Biochem Soc Trans. 2007 Dec; 35(Pt 6):1485-91.
  51. Gonzalez M, Gueguen Y, Destoumieux-Garzón D, Romestand B, Fievet J, Pugnière M, Roquet F, Escoubas JM, Vandenbulcke F, Levy O, Sauné L, Bulet P, Bachère E. Evidence of a bactericidal permeability increasing protein in an invertebrate, the Crassostrea gigas Cg-BPI. Proc Natl Acad Sci U S A. 2007 Nov 6; 104(45):17759-64.
  52. Levy O, Elsbach P. Bactericidal/permeability-increasing protein in host defense and its efficacy in the treatment of bacterial sepsis. Curr Infect Dis Rep. 2007 Oct; 3(5):407-12.
  53. Strunk T, Richmond P, Simmer K, Currie A, Levy O, Burgner D. Neonatal immune responses to coagulase-negative staphylococci. Curr Opin Infect Dis. 2007 Aug; 20(4):370-5.
  54. Levy O. Innate immunity of the newborn: basic mechanisms and clinical correlates. Nat Rev Immunol. 2007 May; 7(5):379-90.
  55. Srivastava A, Casey H, Johnson N, Levy O, Malley R. Recombinant bactericidal/permeability-increasing protein rBPI21 protects against pneumococcal disease. Infect Immun. 2007 Jan; 75(1):342-9.
  56. Ezernitchi AV, Vaknin I, Cohen-Daniel L, Levy O, Manaster E, Halabi A, Pikarsky E, Shapira L, Baniyash M. TCR zeta down-regulation under chronic inflammation is mediated by myeloid suppressor cells differentially distributed between various lymphatic organs. J Immunol. 2006 Oct 1; 177(7):4763-72.
  57. Angelone DF, Wessels MR, Coughlin M, Suter EE, Valentini P, Kalish LA, Levy O. Innate immunity of the human newborn is polarized toward a high ratio of IL-6/TNF-alpha production in vitro and in vivo. Pediatr Res. 2006 Aug; 60(2):205-9.
  58. Fox LM, Wingerter S, Ahmed A, Arnold A, Chou J, Rhein L, Levy O. Neonatal babesiosis: case report and review of the literature. Pediatr Infect Dis J. 2006 Feb; 25(2):169-73.
  59. Canny G, Cario E, Lennartsson A, Gullberg U, Brennan C, Levy O, Colgan SP. Functional and biochemical characterization of epithelial bactericidal/permeability-increasing protein. Am J Physiol Gastrointest Liver Physiol. 2006 Mar; 290(3):G557-67.
  60. Orange JS, Levy O, Geha RS. Human disease resulting from gene mutations that interfere with appropriate nuclear factor-kappaB activation. Immunol Rev. 2005 Feb; 203:21-37.
  61. Levy O. Innate immunity of the human newborn: distinct cytokine responses to LPS and other Toll-like receptor agonists. J Endotoxin Res. 2005; 11(2):113-6.
  62. Orange JS, Levy O, Brodeur SR, Krzewski K, Roy RM, Niemela JE, Fleisher TA, Bonilla FA, Geha RS. Human nuclear factor kappa B essential modulator mutation can result in immunodeficiency without ectodermal dysplasia. J Allergy Clin Immunol. 2004 Sep; 114(3):650-6.
  63. Levy O. Genetic screening for susceptibility to infection in the NICU setting. Pediatr Res. 2004 Apr; 55(4):546-8.
  64. Levy O, Jean-Jacques RM, Cywes C, Sisson RB, Zarember KA, Godowski PJ, Christianson JL, Guttormsen HK, Carroll MC, Nicholson-Weller A, Wessels MR. Critical role of the complement system in group B streptococcus-induced tumor necrosis factor alpha release. Infect Immun. 2003 Nov; 71(11):6344-53.
  65. Levy O, Teixeira-Pinto A, White ML, Carroll SF, Lehmann L, Wypij D, Guinan E. Endotoxemia and elevation of lipopolysaccharide-binding protein after hematopoietic stem cell transplantation. Pediatr Infect Dis J. 2003 Nov; 22(11):978-81.
  66. Levy O, Orange JS, Hibberd P, Steinberg S, LaRussa P, Weinberg A, Wilson SB, Shaulov A, Fleisher G, Geha RS, Bonilla FA, Exley M. Disseminated varicella infection due to the vaccine strain of varicella-zoster virus, in a patient with a novel deficiency in natural killer T cells. J Infect Dis. 2003 Oct 1; 188(7):948-53.
  67. Levy O, Canny G, Serhan CN, Colgan SP. Expression of BPI (bactericidal/permeability-increasing protein) in human mucosal epithelia. Biochem Soc Trans. 2003 Aug; 31(Pt 4):795-800.
  68. Gonen-Gross T, Achdout H, Gazit R, Hanna J, Mizrahi S, Markel G, Goldman-Wohl D, Yagel S, Horejsí V, Levy O, Baniyash M, Mandelboim O. Complexes of HLA-G protein on the cell surface are important for leukocyte Ig-like receptor-1 function. J Immunol. 2003 Aug 1; 171(3):1343-51.
  69. Ofer Levy, Armando Teixeira-Pinto, Mark L. White, Stephen F. Carroll, Leslie Lehmann, David Wypij, and Eva Guinan. Endotoxemia and elevation of lipopolysachharide-binding protein after hematopoietic stem cell transplantation. Pediatric Infectious Disease Journal. 2003; 22:978-981.
  70. Jerrold Weiss, Peter Elsbach, and Ofer Levy. Journeys in the study of antibacterial host defenses: Conserved mechanisms, evolving insights and potential therapeutic opportunities [review]. Recent Research Developments in Antimicrobial Agents & Chemotherapy. 2003; 6:1-38.
  71. Ofer Levy, Geraldine Canny, Charles Serhan, and Sean Colgan. Expression of BPI by human mucosal epithelia [review]. Biochemical Society Transactions. 2003; 31:795-800.
  72. Ofer Levy, Kol Zarember, Rochelle Jean-Jacques, Dimitri Sigounas, Colette Cywes, Paul Godowski, and Michael R. Wessels. Newborn cord blood demonstrates impaired TNF responses to multiple pathogen-assocaited molecular pattern molecules (PAMPs) despite normal expression of monocyte Toll-like receptos 1 and 2, MD-2, MyD88 and TIRAP. Pediatric Research: Abstracts of the Pediatric Academic Societies' Annual Meeting. 2003; 350A.
  73. Ofer Levy, Jordan S. Orange, Patricia Hibberd, Sharon Steinberg, Phillip LaRussa, Adriana Weinberg, S. Brian Wilson, Angela Shaulov, Gary Fleisher, Raif S. Geha, Francisco Bonilla, Mark Exley. Disseminated varicella infection due to vaccine (Oka) strain varicella zoster virus in a patient with a novel deficiency in natural killer T cells. Journal of Infectious Diseases. 2003; 188:948-953.
  74. Levy O. Impaired innate immunity at birth: deficiency of bactericidal/permeability-increasing protein (BPI) in the neutrophils of newborns. Pediatr Res. 2002 Jun; 51(6):667-9.
  75. Levy O, Sisson RB, Fryer HE, Goldmann D, Valore E, Ganz T, White ML, Carroll SF, Lehmann L, Guinan EC. Neutrophil defense in patients undergoing bone marrow transplantation: bactericidal/permeability-increasing protein (BPI) and defensins in graft-derived neutrophils. Transplantation. 2002 May 15; 73(9):1522-6.
  76. Canny G, Levy O, Furuta GT, Narravula-Alipati S, Sisson RB, Serhan CN, Colgan SP. Lipid mediator-induced expression of bactericidal/ permeability-increasing protein (BPI) in human mucosal epithelia. Proc Natl Acad Sci U S A. 2002 Mar 19; 99(6):3902-7.
  77. Levy O, Bourquin JP, McQueen A, Cantor AB, Lachenauer C, Malley R. Fatal disseminated Candida lusitaniae infection in an infant with chronic granulomatous disease. Pediatr Infect Dis J. 2002 Mar; 21(3):262-4.
  78. Levy O. Therapeutic potential of the bactericidal/permeability-increasing protein. Expert Opin Investig Drugs. 2002 Feb; 11(2):159-67.
  79. Ofer Levy, Jean-Pierre Bourquin, Alisa McQueen, Allan B. Cantor, Catherine Lauchenauer, and Richard Malley. Fatal disseminated Candida lusitania infection in an infant with chronic granulomatous disease. Pediatric Infectious Disease Journal. 2002; 21:262-264.
  80. Geraldine Canny, Ofer Levy, Glenn T. Furuta, Sailaja Narravula-Alipati, Richard B. Sisson, Charles N. Serhan, and Sean P. Colgan. Lipid-mediator-induced expression of bactericidal/permeability-increasing protein (BPI) in human mucosal epithelia. Proceedings of the National Academy of Sciences. 2002; 99:3902-3907.
  81. Ofer Levy and Peter Elsbach. BPI in host defense and its efficacy in the treatment of bacterial sepsis [review]. Current Infectious Disease Reports. 2001; 3:407-412.
  82. Levy O. A neutrophil-derived anti-infective molecule: bactericidal/permeability-increasing protein. Antimicrob Agents Chemother. 2000 Nov; 44(11):2925-31.
  83. Levy O. Antimicrobial proteins and peptides of blood: templates for novel antimicrobial agents. Blood. 2000 Oct 15; 96(8):2664-72.
  84. Levy O, Sisson RB, Kenyon J, Eichenwald E, Macone AB, Goldmann D. Enhancement of neonatal innate defense: effects of adding an N-terminal recombinant fragment of bactericidal/permeability-increasing protein on growth and tumor necrosis factor-inducing activity of gram-negative bacteria tested in neonatal cord blood ex vivo. Infect Immun. 2000 Sep; 68(9):5120-5.
  85. Ofer Levy. A neutrophil-derived anti-infective molecule: bactericidal/permeability-increasing protein [review]. Antimicrobial Agenst and Chemotherapy. 2000; 44:2925-2931.
  86. Levy O, Martin S, Eichenwald E, Ganz T, Valore E, Carroll SF, Lee K, Goldmann D, Thorne GM. Impaired innate immunity in the newborn: newborn neutrophils are deficient in bactericidal/permeability-increasing protein. Pediatrics. 1999 Dec; 104(6):1327-33.
  87. Jerrold Weiss, Peter Elsbach, and Ofer Levy. Oxygen-independent antimicrobial systems of phagocytes. Inflammation: Basic Principles and Clinical Correlates. 1999; 801-817.
  88. Ofer Levy. Therapeutic uses of BPI protein products in BPI-deficient humans. 1999.
  89. Ofer Levy. Antibacterial 15 kDa protein isoforms (p15s) of rabbit polymorphonuclear leukocytes. 1996.
  90. Yvette Weinrauch, Jerrold Weiss, Amy Forman, Kol Zarember, Ofer Levy, and Peter Elsbach. Extracellular accumulation of potently microbicidal bactericidal/permeability-increasing protein (BPI) and p15s in an evolving sterile rabbit peritoneal inflammatory exudate. Journal of Clinical Investigation. 1995; 95:1916-1924.
  91. Ofer Levy, Chean Eng Ooi, Peter Elsbach, Martin E. Doerfler, Robert I. Lehrer, and Jerrold Weiss. Antibacterial proteins of granulaocytes differ in interaction with endotoxin: comparison of BPI, p15s, and defensins. Journal of Immunology. 1995; 154:5403-5410.
  92. Levy O, Ooi CE, Weiss J, Lehrer RI, Elsbach P. Individual and synergistic effects of rabbit granulocyte proteins on Escherichia coli. J Clin Invest. 1994 Aug; 94(2):672-82.
  93. Peter Elsbach, Jerrold Weiss, and Ofer Levy. Integration of antimicrobial host defenses against Gram-negative bacteria [review]. Trends in Microbiology. 1994; 2:324-328.
  94. Levy O, Weiss J, Ooi CE, Elsbach P. Structural characterization of BPI-modulating 15 kDa proteins from rabbit polymorphonuclear leukocytes: identification of a novel family of leukocyte proteins. Agents Actions. 1993; 39 Spec No:C207-10.
  95. Ofer Levy, Jerrold Weiss, Kol Zarember, Chean Eng Ooi, and Peter Elsbach. Antibacterial 15 kDa protein isoforms (p15s) are members of a novel family of leukocyte proteins. Journal of Biological Chemistry. 1993; 268:6058-6063.
  96. Chean Eng Ooi, Jerrold Weiss, Ofer Levy, and Peter Elsbach. Isolation of two isoforms of a novel 15 kDa protein from rabbit polymorphonuclear leukocytes that modulates the antibacterial actions of other leukocyte proteins. Journal of Biological Chemistry. 1990; 265:15956-15962.
  97. Burl S, Townend J, Njie-Jobe J, Cox M, Adetifa UJ, Touray E, Philbin VJ, Mancuso C, Kampmann B, Whittle H, Jaye A, Flanagan KL, Levy O. Age-dependent maturation of Toll-like receptor-mediated cytokine responses in Gambian infants. PLoS One. 2011 Apr 13; 6(4):e18185.
  98. Pai SY, Levy O, Jabara HH, Glickman JN, Stoler-Barak L, Sachs J, Nurko S, Orange JS, Geha RS. Allogeneic transplantation successfully corrects immune defects, but not susceptibility to colitis, in a patient with nuclear factor-kappaB essential modulator deficiency. J Allergy Clin Immunol. 2008 Dec; 122(6):1113-1118.e1.
  99. Picard C, von Bernuth H, Ghandil P, Chrabieh M, Levy O, Arkwright PD, McDonald D, Geha RS, Takada H, Krause JC, Creech CB, Ku CL, Ehl S, Maródi L, Al-Muhsen S, Al-Hajjar S, Al-Ghonaium A, Day-Good NK, Holland SM, Gallin JI, Chapel H, Speert DP, Rodriguez-Gallego C, Colino E, Garty BZ, Roifman C, Hara T, Yoshikawa H, Nonoyama S, Domachowske J, Issekutz AC, Tang M, Smart J, Zitnik SE, Hoarau C, Kumararatne DS, Thrasher AJ, Davies EG, Bethune C, Sirvent N, de Ricaud D, Camcioglu Y, Vasconcelos J, Guedes M, Vitor AB, Rodrigo C, Almazán F, Méndez M, Aróstegui JI, Alsina L, Fortuny C, Reichenbach J, Verbsky JW, Bossuyt X, Doffinger R, Abel L, Puel A, Casanova JL. Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency. Medicine (Baltimore). 2010 Nov; 89(6):403-25.
  100. Levy O, Coughlin M, Cronstein BN, Roy RM, Desai A, Wessels MR. The adenosine system selectively inhibits TLR-mediated TNF-alpha production in the human newborn. J Immunol. 2006 Aug 1; 177(3):1956-66.
  101. Wynn JL, Levy O. Role of innate host defenses in susceptibility to early-onset neonatal sepsis. Clin Perinatol. 2010 Jun; 37(2):307-37.
  102. Demirjian A, Levy O. Safety and efficacy of neonatal vaccination. Eur J Immunol. 2009 Jan; 39(1):36-46.
  103. Levy O. Antibiotic proteins of polymorphonuclear leukocytes. Eur J Haematol. 1996 May; 56(5):263-77.
  104. Philbin VJ, Levy O. Developmental biology of the innate immune response: implications for neonatal and infant vaccine development. Pediatr Res. 2009 May; 65(5 Pt 2):98R-105R.
  105. Levy O, Zarember KA, Roy RM, Cywes C, Godowski PJ, Wessels MR. Selective impairment of TLR-mediated innate immunity in human newborns: neonatal blood plasma reduces monocyte TNF-alpha induction by bacterial lipopeptides, lipopolysaccharide, and imiquimod, but preserves the response to R-848. J Immunol. 2004 Oct 1; 173(7):4627-34.
  106. Philbin VJ, Dowling DJ, Gallington LC, Cortés G, Tan Z, Suter EE, Chi KW, Shuckett A, Stoler-Barak L, Tomai M, Miller RL, Mansfield K, Levy O. Imidazoquinoline Toll-like receptor 8 agonists activate human newborn monocytes and dendritic cells through adenosine-refractory and caspase-1-dependent pathways. J Allergy Clin Immunol. 2012 Jul; 130(1):195-204.e9.
  107. Du X, Fleiss B, Li H, D'angelo B, Sun Y, Zhu C, Hagberg H, Levy O, Mallard C, Wang X. Systemic stimulation of TLR2 impairs neonatal mouse brain development. PLoS One. 2011 May 06; 6(5):e19583.
  108. Ku CL, von Bernuth H, Picard C, Zhang SY, Chang HH, Yang K, Chrabieh M, Issekutz AC, Cunningham CK, Gallin J, Holland SM, Roifman C, Ehl S, Smart J, Tang M, Barrat FJ, Levy O, McDonald D, Day-Good NK, Miller R, Takada H, Hara T, Al-Hajjar S, Al-Ghonaium A, Speert D, Sanlaville D, Li X, Geissmann F, Vivier E, Maródi L, Garty BZ, Chapel H, Rodriguez-Gallego C, Bossuyt X, Abel L, Puel A, Casanova JL. Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity. J Exp Med. 2007 Oct 1; 204(10):2407-22.
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  110. Levy O, Suter EE, Miller RL, Wessels MR. Unique efficacy of Toll-like receptor 8 agonists in activating human neonatal antigen-presenting cells. Blood. 2006 Aug 15; 108(4):1284-90.
  111. Pettengill M, Robson S, Tresenriter M, Millán JL, Usheva A, Bingham T, Belderbos M, Bergelson I, Burl S, Kampmann B, Gelinas L, Kollmann T, Bont L, Levy O. Soluble ecto-5'-nucleotidase (5'-NT), alkaline phosphatase, and adenosine deaminase (ADA1) activities in neonatal blood favor elevated extracellular adenosine. J Biol Chem. 2013 Sep 20; 288(38):27315-26.
  112. Palmer CD, Ninkovic J, Prokopowicz ZM, Mancuso CJ, Marin A, Andrianov AK, Dowling DJ, Levy O. The effect of stable macromolecular complexes of ionic polyphosphazene on HIV Gag antigen and on activation of human dendritic cells and presentation to T-cells. Biomaterials. 2014 Oct; 35(31):8876-86.
  113. Bi D, Qiao L, Bergelson I, Ek CJ, Duan L, Zhang X, Albertsson AM, Pettengill M, Kronforst K, Ninkovic J, Goldmann D, Janzon A, Hagberg H, Wang X, Mallard C, Levy O. Staphylococcus epidermidis Bacteremia Induces Brain Injury in Neonatal Mice via Toll-like Receptor 2-Dependent and -Independent Pathways. J Infect Dis. 2015 Nov 1; 212(9):1480-90.
  114. Dowling DJ, Levy O. Pediatric Vaccine Adjuvants: Components of the Modern Vaccinologist's Toolbox. Pediatr Infect Dis J. 2015 Dec; 34(12):1395-8.
  115. van Haren SD, Ganapathi L, Bergelson I, Dowling DJ, Banks M, Samuels RC, Reed SG, Marshall JD, Levy O. In vitro cytokine induction by TLR-activating vaccine adjuvants in human blood varies by age and adjuvant. Cytokine. 2016 Jul; 83:99-109.
  116. Pettengill MA, van Haren SD, Li N, Dowling DJ, Bergelson I, Jans J, Ferwerda G, Levy O. Distinct TLR-mediated cytokine production and immunoglobulin secretion in human newborn naïve B cells. Innate Immun. 2016 Aug; 22(6):433-43.
  117. van Haren SD, Dowling DJ, Foppen W, Christensen D, Andersen P, Reed SG, Hershberg RM, Baden LR, Levy O. Age-Specific Adjuvant Synergy: Dual TLR7/8 and Mincle Activation of Human Newborn Dendritic Cells Enables Th1 Polarization. J Immunol. 2016 Dec 1; 197(11):4413-4424.
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