title: Rescue of HSV-1 neurovirulence is associated with induction of brain interleukin-1 expression, prostaglandin synthesis and neuroendocrine responses.
abstract: Several HSV-1 neurovirulence genes have been mapped but the mechanisms by which they affect host-virus interactions are not known. We have previously mapped HSV-1 neurovirulence to the UL53 gene region of the viral DNA by transfer of this gene from the neurovirulent R-19 strain to the non-neurovirulent R-15 strain in the generation of the p-71 recombinant, in which neurovirulence was rescued. In the present study we inoculated these strains into the paraventricular nucleus (PVN) of the hypothalamus of rats. We examined: (1) Clinical course of encephalitis. (2) Hypothalamic-pituitary-adrenocortical (HPA) axis function. (3) Brain cytokine gene mRNA expression and prostaglandin E2 (PGE2) production. (4) The relation of these parameters to viral replication and to cellular inflammation. In R-15 infected rats no signs of disease were observed. There was a temporary inflammatory reaction and IL-1 beta transcription in the PVN area. The function of the HPA axis was similar to control rats. Only slight increase in brain PGE2 production was found. In R-19 and p-71 infected rats, overt clinical signs of encephalitis and cellular inflammation in the PVN area were observed within 3 days post-infection (p.i). All rats died between 4-7 days p.i. These strains induced IL-1 beta transcription in the hypothalamus as well as in extra-hypothalamic brain regions in which no cellular inflammation was found. Basal serum ACTH and' CS were markedly elevated and hypothalamic CRF-41 content was significantly reduced as compared to R-15 infected rats. Both strains markedly increased brain PGE2 production. HSV-1 brain titers at 3 days p.i. were 100-fold lower than the inoculum titer although clinical signs of encephalitis were prominent. The results suggest that rescue of HSV-1 neurovirulence by the UL53 gene region of the viral genome is associated with enhancement of viral-induced brain IL-1 beta gene expression, increased brain PGE2 synthesis and hypersecretion of HPA axis hormones. Viral-induced brain derived cytokines and prostaglandins may contribute to the clinical syndrome of acute herpetic encephalitis in particular at early stages of the disease when virus load in the brain is low and cellular infiltrates are not widespread.
authors.affiliation: Department of Neurology, Hebrew University, Hadassah Medical School, Jerusalem, Israel.
authors.forename: T
authors.initials: T
authors.lastname: Ben-Hur
authors.forename: J
authors.initials: J
authors.lastname: Rosenthal
authors.forename: A
authors.initials: A
authors.lastname: Itzik
authors.forename: J
authors.initials: J
authors.lastname: Weidenfeld
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000378:metabolism* / Q000821:virology; D002522:Chlorocebus aethiops; D003346:Corticotropin-Releasing Hormone / Q000097:blood; D018076:DNA, Complementary / Q000235:genetics; D015232:Dinoprostone / Q000096:biosynthesis*; D005625:Frontal Lobe / Q000378:metabolism / Q000821:virology; D006566:Herpesviridae Infections / Q000503:physiopathology*; D018259:Herpesvirus 1, Human / Q000254:growth & development / Q000472:pathogenicity*; D006624:Hippocampus / Q000378:metabolism / Q000821:virology; D006854:Hydrocortisone / Q000097:blood; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D009490:Neurosecretory Systems / Q000821:virology*; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism / Q000821:virology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D014709:Vero Cells / Q000821:virology; D014774:Virulence
chemical_list: D018076:DNA, Complementary; D007375:Interleukin-1; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D015232:Dinoprostone; D006854:Hydrocortisone