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Journal of Virology, July 2008, p. 7078-7088, Vol. 82, No. 14
0022-538X/08/$08.00+0     doi:10.1128/JVI.00619-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The Immune Response to Herpes Simplex Virus Type 1 Infection in Susceptible Mice Is a Major Cause of Central Nervous System Pathology Resulting in Fatal Encephalitis{triangledown} ,{dagger}

Patric Lundberg,1,2,{ddagger} Chandran Ramakrishna,1 Jeffrey Brown,4 J. Michael Tyszka,5 Mark Hamamura,6 David R. Hinton,7 Susan Kovats,8 Orhan Nalcioglu,6 Kenneth Weinberg,4 Harry Openshaw,3 and Edouard M. Cantin1,2,3*

Divisions of Virology,1 Immunology,2 Neurology, Beckman Research Institute and City of Hope National Medical Center, Duarte, California 91010,3 Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, California 90033,4 Division of Biology, California Institute of Technology, Pasadena, California 91125,5 Center for Functional Onco-Imaging, University of California, Irvine, California 92697,6 Department of Pathology, Keck School of Medicine, Beckman Macular Research Center, University of Southern California, Los Angeles, California 90033,7 Arthritis and Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 731048

Received 19 March 2008/ Accepted 6 May 2008

This study was undertaken to investigate possible immune mechanisms in fatal herpes simplex virus type 1 (HSV-1) encephalitis (HSE) after HSV-1 corneal inoculation. Susceptible 129S6 (129) but not resistant C57BL/6 (B6) mice developed intense focal inflammatory brain stem lesions of primarily F4/80+ macrophages and Gr-1+ neutrophils detectable by magnetic resonance imaging as early as day 6 postinfection (p.i.). Depletion of macrophages and neutrophils significantly enhanced the survival of infected 129 mice. Immunodeficient B6 (IL-7R–/– Kitw41/w41) mice lacking adaptive cells (B6-E mice) and transplanted with 129 bone marrow showed significantly accelerated fatal HSE compared to B6-E mice transplanted with B6 marrow or control nontransplanted B6-E mice. In contrast, there was no difference in ocular viral shedding in B6-E mice transplanted with 129 or B6 bone marrow. Acyclovir treatment of 129 mice beginning on day 4 p.i. (24 h after HSV-1 first reaches the brain stem) reduced nervous system viral titers to undetectable levels but did not alter brain stem inflammation or mortality. We conclude that fatal HSE in 129 mice results from widespread damage in the brain stem caused by destructive inflammatory responses initiated early in infection by massive infiltration of innate cells.

* Corresponding author. Mailing address: Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010. Phone: (626) 301-8480. Fax: (626) 301-8457. E-mail: ecantin{at}coh.org

{triangledown} Published ahead of print on 14 May 2008.

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

{ddagger} Present Address: Department of Microbiology, Eastern Virginia Medical School, Norfolk, VA.

Journal of Virology, July 2008, p. 7078-7088, Vol. 82, No. 14
0022-538X/08/$08.00+0     doi:10.1128/JVI.00619-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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