Herpes simplex virus US3 protein kinase regulates virus-induced apoptosis in olfactory and vomeronasal chemosensory neurons in vivo.
A role for the US3 protein kinase of herpes simplex virus (HSV) in regulating virus-induced neuronal apoptosis was investigated in an experimental mouse system, in which wild-type HSV invades the central nervous system (CNS) via the olfactory and vomeronasal systems upon intranasal infection. Wild-type HSV-2 strain 186 infected a fraction of olfactory and vomeronasal chemosensory neurons without inducing apoptosis and was transmitted to the CNS, precipitating lethal encephalitis. In sharp contrast, an US3-disrupted mutant, L1BR1, induced neuronal apoptosis in these peripheral conduits upon infection, blocking viral transmission to the CNS and causing no signs of disease. An US3-repaired mutant, L1B(-)11, behaved similarly to the wild-type virus. Only 5 p.f.u. of L1BR1 was sufficient to compromise mice when the mutant virus was introduced directly into the olfactory bulb, a viral entry site of the CNS. These results suggest that the US3 protein kinase of HSV regulates virus-induced neuronal apoptosis in peripheral conduits and determines the neuroinvasive phenotype of HSV. Furthermore, virus-induced neuronal apoptosis of peripheral nervous system cells may be a protective host response that blocks viral transmission to the CNS.
Mori
Isamu
I
Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan. isamor@aichi-med-u.ac.jp
Goshima
Fumi
F
Watanabe
Daisuke
D
Ito
Hiroyasu
H
Koide
Naoki
N
Yoshida
Tomoaki
T
Liu
Beixing
B
Kimura
Yoshinobu
Y
Yokochi
Takashi
T
Nishiyama
Yukihiro
Y
D000818:Animals; D017209:Apoptosis; D001835:Body Weight; D001921:Brain / Q000821:virology; D004195:Disease Models, Animal; D004660:Encephalitis / Q000821:virology; D005260:Female; D017353:Gene Deletion; D006561:Herpes Simplex / Q000276:immunology / Q000473:pathology; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D009475:Neurons, Afferent / Q000166:cytology* / Q000821:virology*; D009832:Olfactory Nerve / Q000821:virology; D018034:Olfactory Receptor Neurons / Q000166:cytology / Q000821:virology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D018139:Simplexvirus / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity; D016019:Survival Analysis; D014764:Viral Proteins / Q000235:genetics / Q000502:physiology*; D019147:Vomeronasal Organ / Q000166:cytology / Q000821:virology*
D014764:Viral Proteins; D017346:Protein Serine-Threonine Kinases; C084395:US3 protein, Human herpesvirus 2