| Institution: | 1. Department of Microbiology and Immunology, University of Maryland School of Medicine (UMSOM), Baltimore, MD, United States;2. Department of Microbial Pathogenesis, University of Maryland School of Dentistry (UMSOD), Baltimore, MD, United States;3. Genome Informatics Core, Institute for Genome Sciences (IGS), UMSOM, Baltimore, MD, United States;4. G2D2, Eisai Inc., Cambridge, MA, United States;1. Influenza Division, Centers for Disease Control and Prevention, Atlanta, GA, United States;2. Influenza Program, Centers for Disease Control and Prevention, Pretoria, South Africa;3. Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa;4. MassGenics, Duluth, GA, United States;5. School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa;6. Department of Immunization, Vaccines and Biological, World Health Organization, Geneva, Switzerland;7. South Africa Medical Research Council/Wits Centre for Health Economics and Decision Science, PRICELESS SA, University of Witwatersrand School of Public Health, Faculty of Health Sciences, Johannesburga South Africa;8. School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa;9. Department of Medicine, Pietermaritzburg Metropolitan Hospital, Pietermaritzburg, South Africa;10. Department of Medicine, University of KwaZulu-Natal, Pietermaritzburg, South Africa;11. Department of Medicine, Klerksdorp-Tshepong Hospital Complex, Klerksdorp, South Africa;12. Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa;13. Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa;1. Medical Virology Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA;2. Clinical Services Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA;1. Department of Medicine, Center for Emerging Pathogens, Rutgers, New Jersey Medical School, Newark, NJ, USA;2. Rutgers-Graduate School of Biomedical Sciences, Newark, NJ, USA;1. Centre for Immunology and Infection, University of York, York YO10 5DD, United Kingdom;2. York Structural Biology Laboratory, University of York, York YO10 5DD, United Kingdom;3. Infectious Disease Research Institute, Seattle, WA 98102, United States;4. Department of Health Sciences, University of York, York YO10 5DD, United Kingdom |
| Abstract: | Toll-like receptors (TLRs), a family of “pattern recognition receptors,” bind microbial and host-derived molecules, leading to intracellular signaling and proinflammatory gene expression. TLR4 is unique in that ligand-mediated activation requires the co-receptor myeloid differentiation 2 (MD2) to initiate two signaling cascades: the MyD88-dependent pathway is initiated at the cell membrane, and elicits rapid MAP kinase and NF-κB activation, while the TIR-domain containing adaptor inducing interferon-β (TRIF)-dependent pathway is initiated from TLR4-containing endosomes and results in IRF3 activation. Previous studies associated inflammation with the MyD88 pathway and adjuvanticity with the TRIF pathway. Gram-negative lipopolysaccharide (LPS) is a potent TLR4 agonist, and structurally related molecules signal through TLR4 to differing extents. Herein, we compared monophosphoryl lipid A (sMPL) and E6020, two synthetic, non-toxic LPS lipid A analogs used as vaccine adjuvants, for their capacities to activate TLR4-mediated innate immune responses and to enhance antibody production. In mouse macrophages, high dose sMPL activates MyD88-dependent signaling equivalently to E6020, while E6020 exhibits significantly more activation of the TRIF pathway (a “TRIF bias”) than sMPL. Eritoran, a TLR4/MD2 antagonist, competitively inhibited sMPL more strongly than E6020. Despite these differences, sMPL and E6020 adjuvants enhanced antibody responses to comparable extents, with balanced immunoglobulin (Ig) isotypes in two immunization models. These data indicate that a TRIF bias is not necessarily predictive of superior adjuvanticity. |
