TLR9 agonist, but not TLR7/8, functions as an adjuvant to diminish FI-RSV vaccine-enhanced disease, while either agonist used as therapy during primary RSV infection increases disease severity.
Agonists for TLR7, TLR8, and TLR9 have been shown to enhance vaccine immunogenicity. We evaluated the impact of TLR activation on RSV disease in a murine model by administering TLR7/8 and TLR9 agonists during FI-RSV immunization or RSV infection. CpG administered during immunization reduced disease following challenge as evidenced by decreased lung pathology, illness, and cytokines. In marked contrast, TLR7/8 agonist had little impact. To evaluate potential therapeutic use, TLR agonists were administered during primary infection. Although type 2 cytokine responses decreased and type 1 cytokines and MIP-1-alpha/beta increased, both TLR7/8 and TLR9 agonists increased clinical symptoms and pulmonary inflammation when administered during primary infection. Thus, TLR9-induced signaling during FI-RSV immunization reduced vaccine-enhanced disease whereas immunostimulatory properties of TLR agonists enhanced disease severity when used during RSV infection. Immunomodulation elicited by TLR9 agonist confirms the adjuvant potential of TLR agonists during RSV immunization. However, in contrast to work done with HIV-1 vaccines, the inability of TLR7/8 agonist to boost type 1 vaccine-induced RSV immunity demonstrates pathogen-TLR specificity. These data reveal that the timing of administration of immunomodulatory agents is critical. Furthermore, these data underscore that amplification of anti-viral immune responses may result in immunopathology rather than immune-mediated protection.
Johnson
Teresa R
TR
Vaccine Research Center, Viral Pathogenesis Laboratory, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892-3017, USA. teresaj@nih.gov
Rao
Srinivas
S
Seder
Robert A
RA
Chen
Man
M
Graham
Barney S
BS
D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000818:Animals; D000917:Antibody Formation; D002460:Cell Line; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007111:Immunity, Cellular; D008562:Membrane Glycoproteins / Q000819:agonists* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy* / Q000276:immunology / Q000517:prevention & control*; D022261:Respiratory Syncytial Virus Vaccines / Q000627:therapeutic use*; D012136:Respiratory Syncytial Viruses / Q000276:immunology / Q000472:pathogenicity*; D051199:Toll-Like Receptor 7 / Q000819:agonists* / Q000276:immunology; D051200:Toll-Like Receptor 8 / Q000819:agonists* / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000819:agonists* / Q000276:immunology; D014774:Virulence
D000276:Adjuvants, Immunologic; D007093:Imidazoles; D008562:Membrane Glycoproteins; D022261:Respiratory Syncytial Virus Vaccines; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051217:Toll-Like Receptor 9; C453101:carboxyphenylglycine; D005998:Glycine; C402365:resiquimod