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Infection and Immunity, May 2005, p. 3044-3052, Vol. 73, No. 5
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.5.3044-3052.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Synthetic Toll-Like Receptor 4 Agonists Stimulate Innate Resistance to Infectious Challenge

Christopher W. Cluff,2 Jory R. Baldridge,2 Axel G. Stöver,1 Jay T. Evans,2 David A. Johnson,2 Michael J. Lacy,2 Valerie G. Clawson,2 Vonnie M. Yorgensen,2 Craig L. Johnson,2 Mark T. Livesay,2 Robert M. Hershberg,1,3 and David H. Persing1,3*

Corixa Corporation, 1900 9th Avenue, Suite 1100, Seattle, Washington 98101,1 Corixa Corporation, 553 Old Corvallis Road, Hamilton, Montana 59840,2 The Infectious Disease Research Institute, 1124 Columbia Street, Suite 600, Seattle, Washington 981043

Received 30 September 2004/ Returned for modification 5 November 2004/ Accepted 21 December 2004

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.

* Corresponding author. Mailing address: Corixa Corporation, 1900 9th Avenue, Suite 1100, Seattle, WA 98101. Phone: (206) 366-3759. Fax: (206) 366-4700. E-mail: david.persing{at}corixa.com.

Editor: F. C. Fang

Infection and Immunity, May 2005, p. 3044-3052, Vol. 73, No. 5
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.5.3044-3052.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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