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Journal of Virology, February 2007, p. 1796-1812, Vol. 81, No. 4
0022-538X/07/$08.00+0     doi:10.1128/JVI.01936-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Adenovirus Infection Triggers a Rapid, MyD88-Regulated Transcriptome Response Critical to Acute-Phase and Adaptive Immune Responses In Vivo{triangledown} ,{dagger}

Zachary C. Hartman,1 Anne Kiang,1 Ruth S. Everett,1,{ddagger} Delila Serra,1 Xiao Y. Yang,2 Timothy M. Clay,2 and Andrea Amalfitano1,3*

Division of Medical Genetics, Department of Pediatrics,1 Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710,2 Departments of Microbiology and Molecular Genetics, and Pediatrics, Michigan State University, East Lansing, Michigan 488243

Received 5 September 2006/ Accepted 14 November 2006

Nearly 50 years ago, the discovery of interferon prompted the notion that host cells innately respond to viral invasion. Since that time, technological advances have allowed this response to be extensively characterized and dissected in vitro. However, these advances have only recently been applied to highly complex, in vivo biological systems. To this end, we exploited high-titer adenovirus (Ad) vectors to globally investigate the innate immune response to nonenveloped viral infection in vivo. Our results indicated a potent cellular transcriptome response shortly after infection, with global assessments revealing significant dysregulation in ~15% of the measured transcripts derived from Ad vector-transduced tissue. Bioinformatics-based transcriptome analysis revealed a complex innate response to Ad infection, with induction of proinflammatory responses (and suppression of metabolism and mitochondrial genes) akin to those observed when mice are challenged with lipopolysaccharide. Despite this commonality, there were many unique aspects of the Ad-dependent transcriptome response, including the upregulation of several RNA regulatory mechanisms and apoptosis-related pathways, accompanied by the suppression of lysosomal and endocytic genes. Our results also implicated the Toll-like receptors (TLRs) in these responses, prompting specific investigations into this pathway. By using MyD88KO mice, our results confirmed that Ad-induced dysregulation of five functionally related gene clusters are significantly dependent on this TLR adaptor gene. MyD88 deficiency also resulted in significantly diminished, although not abolished, adaptive and acute-phase immune responses to Ad, confirming the transcriptome data, as well as specifically identifying MyD88 as a significant Ad immunity amplifier and regulator in vivo.

* Corresponding author. Mailing address: 4194 Biomedical and Physical Sciences Bldg., Michigan State University, East Lansing, MI 48823. Phone: (517) 355-6463. Fax: (517) 353-8957. E-mail: amalfit1{at}msu.edu.

{triangledown} Published ahead of print on 22 November 2006.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

{ddagger} Present address: Division of Pulmonary and Critical Care Medicine, University of Arkansas for the Medical Sciences, Little Rock, AR 72205.

Journal of Virology, February 2007, p. 1796-1812, Vol. 81, No. 4
0022-538X/07/$08.00+0     doi:10.1128/JVI.01936-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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  • Russell, W. C. (2009). Adenoviruses: update on structure and function. J. Gen. Virol. 90: 1-20 [Abstract] [Full Text]  
  • Appledorn, D. M., Patial, S., McBride, A., Godbehere, S., Van Rooijen, N., Parameswaran, N., Amalfitano, A. (2008). Adenovirus Vector-Induced Innate Inflammatory Mediators, MAPK Signaling, As Well As Adaptive Immune Responses Are Dependent upon Both TLR2 and TLR9 In Vivo. J. Immunol. 181: 2134-2144 [Abstract] [Full Text]  


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