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Journal of Virology, November 2008, p. 10634-10646, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.01323-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Eastern and Venezuelan Equine Encephalitis Viruses Differ in Their Ability To Infect Dendritic Cells and Macrophages: Impact of Altered Cell Tropism on Pathogenesis{triangledown}

Christina L. Gardner,1 Crystal W. Burke,1 Mulu Z. Tesfay,1 Pamela J. Glass,2 William B. Klimstra,1 and Kate D. Ryman1*

Center for Molecular and Tumor Virology and Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, Louisiana,1 Virology Division, United States Army Medical Research Institute for Infectious Diseases, Fort Detrick, Frederick, Maryland2

Received 24 June 2008/ Accepted 20 August 2008

Eastern and Venezuelan equine encephalitis viruses (EEEV and VEEV, respectively) cause severe morbidity and mortality in equines and humans. Like other mosquito-borne viruses, VEEV infects dendritic cells (DCs) and macrophages in lymphoid tissues, fueling a serum viremia and facilitating neuroinvasion. In contrast, EEEV replicates poorly in lymphoid tissues, preferentially infecting osteoblasts. Here, we demonstrate that infectivity of EEEV for myeloid lineage cells including DCs and macrophages was dramatically reduced compared to that of VEEV, whereas both viruses replicated efficiently in mesenchymal lineage cells such as osteoblasts and fibroblasts. We determined that EEEV infection of myeloid lineage cells was restricted after attachment, entry, and uncoating of the genome. Using replicon particles and translation reporter RNAs, we found that translation of incoming EEEV genomes was almost completely inhibited in myeloid, but not mesenchymal, lineage cells. Alpha/beta interferon (IFN-{alpha}/β) responses did not mediate the restriction, as infectivity was not restored in the absence of double-stranded RNA-dependent protein kinase, RNase L, or IFN-{alpha}/β receptor-mediated signaling. We confirmed these observations in vivo, demonstrating that EEEV is compromised in its ability to replicate within lymphoid tissues, whereas VEEV does so efficiently. The altered tropism of EEEV correlated with an almost complete avoidance of serum IFN-{alpha}/β induction in vivo, which may allow EEEV to evade the host's innate immune responses and thereby enhance neurovirulence. Taken together, our data indicate that inhibition of genome translation restricts EEEV infectivity for myeloid but not mesenchymal lineage cells in vitro and in vivo. In this regard, the tropisms of EEEV and VEEV differ dramatically, likely contributing to observed differences in disease etiology.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, 2-347B Medical School Bldg. B, Louisiana State University Health Sciences Center—Shreveport, 1501 Kings Highway, Shreveport, LA 71130-3932. Phone: (318) 675-6684. Fax: (318) 675-5764. E-mail: kryman{at}lsuhsc.edu

{triangledown} Published ahead of print on 3 September 2008.

Journal of Virology, November 2008, p. 10634-10646, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.01323-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Yin, J., Gardner, C. L., Burke, C. W., Ryman, K. D., Klimstra, W. B. (2009). Similarities and Differences in Antagonism of Neuron Alpha/Beta Interferon Responses by Venezuelan Equine Encephalitis and Sindbis Alphaviruses. J. Virol. 83: 10036-10047 [Abstract] [Full Text]  
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