Infection of neurons and encephalitis after intracranial inoculation of herpes simplex virus requires the entry receptor nectin-1.
Multiple entry receptors can mediate infection of cells by herpes simplex virus (HSV), permitting alternative pathways for infection and disease. We investigated the roles of two known entry receptors, herpesvirus entry mediator (HVEM) and nectin-1, in infection of neurons in the CNS and the development of encephalitis. Wild-type, HVEM KO, nectin-1 KO, and HVEM/nectin-1 double KO mice were inoculated with HSV into the hippocampus. The mice were examined for development of encephalitis or were killed at various times after inoculation for immunohistological analyses of brain slices. Nectin-1 KO mice showed no signs of disease after intracranial inoculation, and no HSV antigens were detectable in the brain parenchyma. However, HSV antigens were detected in non-parenchymal cells lining the ventricles. In the double KO mice, there was also no disease and no detectable expression of viral antigens even in non-parenchymal cells, indicating that infection of these cells in the nectin-1 KO mice was dependent on the expression of HVEM. Wild-type and HVEM KO mice rapidly developed encephalitis, and the patterns of HSV replication in the brain were indistinguishable. Thus, expression of nectin-1 is necessary for HSV infection via the intracranial route and for encephalitis; HVEM is largely irrelevant. These results contrast with recent findings that (i) either HVEM or nectin-1 can permit HSV infection of the vaginal epithelium in mice and (ii) nectin-1 is not the sole receptor capable of enabling spread of HSV infection from the vaginal epithelium to the PNS and CNS.
Kopp
Sarah J
SJ
Department of Microbiology-Immunology, Feinberg School of Medicine of Northwestern University, Chicago, IL 60611, USA.
Banisadr
Ghazal
G
Glajch
Kelly
K
Maurer
Ulrike E
UE
Grünewald
Kay
K
Miller
Richard J
RJ
Osten
Pavel
P
Spear
Patricia G
PG
D000818:Animals; D000956:Antigens, Viral / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020803:Encephalitis, Herpes Simplex / Q000503:physiopathology / Q000821:virology*; D005260:Female; D018258:Herpesvirus 2, Human / Q000276:immunology / Q000472:pathogenicity* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000075983:Nectins; D009474:Neurons / Q000821:virology; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D011991:Receptors, Virus / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D053586:Virus Internalization
D000956:Antigens, Viral; D015815:Cell Adhesion Molecules; C000619010:NECTIN1 protein, human; C000619015:Nectin1 protein, mouse; D000075983:Nectins; D053240:Receptors, Tumor Necrosis Factor, Member 14; D011991:Receptors, Virus; C506029:Tnfrsf14 protein, mouse