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.
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(-/-) Kit(w41/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.
Lundberg
Patric
P
Division of Virology, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA.
Ramakrishna
Chandran
C
Brown
Jeffrey
J
Tyszka
J Michael
JM
Hamamura
Mark
M
Hinton
David R
DR
Kovats
Susan
S
Nalcioglu
Orhan
O
Weinberg
Kenneth
K
Openshaw
Harry
H
Cantin
Edouard M
EM
D000212:Acyclovir / Q000627:therapeutic use; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D016026:Bone Marrow Transplantation / Q000276:immunology; D001933:Brain Stem / Q000276:immunology* / Q000473:pathology / Q000821:virology; D004660:Encephalitis / Q000276:immunology* / Q000401:mortality / Q000821:virology*; D005123:Eye / Q000821:virology; D005434:Flow Cytometry; D006561:Herpes Simplex / Q000150:complications* / Q000276:immunology* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000276:immunology*; D007249:Inflammation / Q000276:immunology / Q000821:virology; D047589:Leukocyte Reduction Procedures; D008264:Macrophages / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology; D020395:Receptors, Interleukin-7 / Q000172:deficiency; D019089:Stem Cell Factor / Q000235:genetics; D016019:Survival Analysis; D016176:T-Lymphocyte Subsets / Q000276:immunology; D017201:Virus Shedding
D000998:Antiviral Agents; D020395:Receptors, Interleukin-7; D019089:Stem Cell Factor; D000212:Acyclovir