| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
,¶,||,#
* Graduate Program in Immunology,
Department of Radiology,
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine,
Department of Pathology,
¶ Comprehensive Cancer Center,
|| Department of Veterans Affairs Health System, and
# Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109
Innate immunity is required for effective control of poxvirus infections, but cellular receptors that initiate the host response to these DNA viruses remain poorly defined. Given this information and the fact that functions of TLRs in immunity to DNA viruses remain controversial, we investigated effects of TLR3 on pathogenesis of vaccinia virus, a prototype poxvirus. We used a recombinant strain Western Reserve vaccinia virus that expresses firefly luciferase to infect wild-type C57BL/6 and TLR3–/– mice through intranasal inoculation. Bioluminescence imaging showed that TLR3–/– mice had substantially lower viral replication in the respiratory tract and diminished dissemination of virus to abdominal organs. Mice lacking TLR3 had reduced disease morbidity, as measured by decreased weight loss and hypothermia after infection. Importantly, TLR3–/– mice also had improved survival relative to wild-type mice. Infected TLR3–/– mice had significantly reduced lung inflammation and recruitment of leukocytes to the lung. Mice lacking TLR3 also had lower levels of inflammatory cytokines, including IL-6, MCP-1, and TNF-
in serum and/or bronchoalveolar lavage fluid, but levels of IFN-β did not differ between genotypes of mice. To our knowledge, our findings show for the first time that interactions between TLR3 and vaccinia increase viral replication and contribute to detrimental effects of the host immune response to poxviruses.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by R21AI066192, R1 HL082480, and R1 HL056309 from the National Institutes of Health (NIH), and Merit Review funds from the Department of Veterans Affairs. Support for imaging experiments was provided by NIH R24CA083099 for the University of Michigan Small Animal Imaging Resource.
2 Address correspondence and reprint requests to Dr. Gary D. Luker, Center for Molecular Imaging, University of Michigan Medical School, 109 Zina Pitcher Place, A526 BSRB, Ann Arbor, MI 48109-2200. E-mail address: gluker{at}umich.edu
3 Abbreviations used in this paper: TRIF, Toll-IL-1R domain-containing adapter inducing IFN-β; IRF3, IFN regulatory factor 3; WT, wild type; WR, Western Reserve; BAL, bronchoalveolar lavage; i.n., intranasal(ly); AUC, area under the curve.
This article has been cited by other articles:
|
|
 |
|
  S. M. Ngoi, M. G. Tovey, and A. T. Vella Targeting Poly(I:C) to the TLR3-Independent Pathway Boosts Effector CD8 T Cell Differentiation through IFN-{alpha}/{beta} J. Immunol., December 1, 2008; 181(11): 7670 - 7680. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Daffis, M. A. Samuel, M. S. Suthar, M. Gale Jr., and M. S. Diamond Toll-Like Receptor 3 Has a Protective Role against West Nile Virus Infection J. Virol., November 1, 2008; 82(21): 10349 - 10358. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
