Glycerophospholipids are major components of cell membranes.
Phosphatidylethanolamine (PE) is a
glycerophospholipid that is involved in multiple cellular processes, such as membrane fusion, the cell cycle, autophagy, and apoptosis. In this study, we investigated the role of PE biosynthesis in herpes simplex virus 1 (HSV-1)
infection by knocking out the host cell gene encoding
phosphate cytidylyltransferase 2,
ethanolamine (Pcyt2), which is a key rate-limiting
enzyme in one of the two major pathways for PE biosynthesis. Pcyt2 knockout reduced HSV-1 replication and caused an accumulation of unenveloped and partially enveloped nucleocapsids in the cytoplasm of an HSV-1-infected cell culture. A similar phenotype was observed when infected cells were treated with
meclizine, which is an inhibitor of Pcyt2. In addition, treatment of HSV-1-infected mice with
meclizine significantly reduced HSV-1 replication in the mouse brains and improved their survival rates. These results indicated that PE biosynthesis mediated by Pcyt2 was required for efficient HSV-1 envelopment in the cytoplasm of infected cells and for viral replication and pathogenicity in vivo The results also identified the PE biosynthetic pathway as a possible novel target for
antiviral therapy of HSV-associated diseases and raised an interesting possibility for
meclizine repositioning for treatment of these diseases, since it is an
over-the-counter drug that has been used for decades against
nausea and
vertigo in
motion sickness.IMPORTANCE
Glycerophospholipids in cell membranes and virus envelopes often affect viral entry and budding. However, the role of
glycerophospholipids in membrane-associated events in viral replication in herpesvirus-infected cells has not been reported to date. In this study, we have presented data showing that cellular PE biosynthesis mediated by Pcyt2 is important for HSV-1 envelopment in the cytoplasm, as well as for viral replication and pathogenicity in vivo This is the first report showing the importance of PE biosynthesis in
herpesvirus infections. Our results showed that inhibition of Pcyt2, a key cell
enzyme for PE synthesis, significantly inhibited HSV-1 replication and pathogenicity in mice. This suggested that the PE biosynthetic pathway, as well as the HSV-1 virion maturation pathway, can be a target for the development of novel anti-HSV drugs.