Synthetic toll-like receptor 4 agonists stimulate innate resistance to infectious challenge.
A compound family of synthetic lipid A mimetics (termed the aminoalkyl glucosaminide phosphates [AGPs]) was evaluated in murine infectious disease models of protection against challenge with Listeria monocytogenes and influenza virus. For the Listeria model, intravenous administration of AGPs was followed by intravenous bacterial challenge 24 h later. Spleens were harvested 2 days postchallenge for the enumeration of CFU. For the influenza virus model, mice were challenged with virus via the intranasal/intrapulmonary route 48 h after intranasal/intrapulmonary administration of AGPs. The severity of disease was assessed daily for 3 weeks following challenge. Several types of AGPs provided strong protection against influenza virus or Listeria challenge in wild-type mice, but they were inactive in the C3H/HeJ mouse, demonstrating the dependence of the AGPs on toll-like receptor 4 (TLR4) signaling for the protective effect. Structure-activity relationship studies showed that the activation of innate immune effectors by AGPs depends primarily on the lengths of the secondary acyl chains within the three acyl-oxy-acyl residues and also on the nature of the functional group attached to the aglycon component. We conclude that the administration of synthetic TLR4 agonists provides rapid pharmacologic induction of innate resistance to infectious challenge by two different pathogen classes, that this effect is mediated via TLR4, and that structural differences between AGPs can have dramatic effects on agonist activity in vivo.
Cluff
Christopher W
CW
Corixa Corporation, 1900 9th Avenue, Suite 1100, Seattle, WA 98101, USA.
Baldridge
Jory R
JR
Stöver
Axel G
AG
Evans
Jay T
JT
Johnson
David A
DA
Lacy
Michael J
MJ
Clawson
Valerie G
VG
Yorgensen
Vonnie M
VM
Johnson
Craig L
CL
Livesay
Mark T
MT
Hershberg
Robert M
RM
Persing
David H
DH
D000818:Animals; D005260:Female; D007113:Immunity, Innate; D009980:Influenza A virus / Q000472:pathogenicity; D008050:Lipid A / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry / Q000276:immunology*; D008089:Listeria monocytogenes / Q000472:pathogenicity; D008088:Listeriosis / Q000276:immunology* / Q000821:virology; D008562:Membrane Glycoproteins / Q000819:agonists*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D018716:Molecular Mimicry; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000821:virology; D011956:Receptors, Cell Surface / Q000819:agonists*; D013329:Structure-Activity Relationship; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D008050:Lipid A; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors