Up-Regulation of Fas Ligand Expression by Human Cytomegalovirus Immediate-Early Gene Product 2: A Novel Mechanism in Cytomegalovirus-Induced Apoptosis in Human Retina

Abstract

Human CMV (HCMV) is an important pathogen that causes widespread diseases in immunocompromised individuals. Among the opportunistic HCMV infections, HCMV retinitis is most common in transplant recipients and AIDS patients. It often leads to blindness if left untreated. The question as to how HCMV infection causes retinal pathogenesis remains unresolved. Here, we report that viral immediate-early gene product 2 (IE2), but not IE1, up-regulates the Fas ligand (FasL) expression in HCMV-infected human retinal pigment epithelium cells. Increased secretion of FasL from virally infected cells into cultured medium was observed upon HCMV infection. The capability of such cell-free medium to induce apoptosis of Fas (CD95)-expressing Jurkat cells further implies that Fas-FasL interaction might mediate cell death in the lesion of HCMV retinitis. To support this idea, we observed augmented soluble FasL levels in vitreous from AIDS patients with HCMV retinitis as compared with that from AIDS patients without HCMV infection. In addition, by in situ hybridization and immunohistochemistry, we detected enhanced signals of FasL, the existence of viral IE Ags and apoptotic cells at the same sites in the lesion of HCMV-infected retina. These results strongly suggest that IE2 induction of FasL expression in human retina might be an important event that takes place in the early stage of infection and finally leads to visual loss in individuals affiliated with HCMV retinitis.

p53-dependent inhibition of mammalian cell survival by a genetically selected peptide aptamer that targets the regulatory subunit of protein kinase CK2

“…Thus, the significant sequence homology between P1 and the murine cytomegalovirus IE2 protein (Messerle et al, 1991) raises the interesting possibility that this peptide might interact with a domain on CK2b that is targeted by viral proteins. The cytomegalovirus IE2 protein is known to interact with CK2b, inhibits the cell cycle (Wiebusch and Hagemeier, 2001) and triggers cell apoptosis (Chiou et al, 2001). Noteworthy, the interacting domain for the HHV-6 IE2 protein was mapped to the N-terminal region of CK2b extending between aa 1 and 55 (Shimada et al, 2004), and it is suspected that the tight interaction of this viral protein to CK2b may affect cellular functions specifically involved in cell survival.…”

“…The variable region of TrxA-P1 is enriched in hydrophobic amino acids (26% of leucine), and a BLAST analysis of the publicly available databases reveals that its sequence has significant homology to murine cytomegalovirus IE2 protein (Genbank accession number AY037931) (Messerle et al, 1991) (Figure 1a). Interestingly enough, the cytomegalovirus IE2 protein is known to interact with CK2b, inhibits the cell cycle (Wiebusch and Hagemeier, 2001) and triggers cell apoptosis (Chiou et al, 2001).…”

Modulación de la apoptosis por cytomegalovirus en la perspectiva del sistema nervioso central

“…Apoyando la noción de que CMV es capaz de inducir apoptosis, se encontró que en etapas tempranas de la infección, la proteína IE2 conduce a la sobre-expresión del ligando de Fas (FasL) en células epiteliales de retina infectadas con CMV humano 51 . Tras la infección, se incrementó la secreción de FasL en el medio de cultivo, siendo comprobado este hallazgo al cultivar células Jurkat en presencia de medio proveniente de las células de retina infectadas y evidenciándose una alta tasa de apoptosis 51 .…”

“…Tras la infección, se incrementó la secreción de FasL en el medio de cultivo, siendo comprobado este hallazgo al cultivar células Jurkat en presencia de medio proveniente de las células de retina infectadas y evidenciándose una alta tasa de apoptosis 51 . Además, las concentraciones de FasL en el humor vítreo de las pacientes con SIDA infectados con CMV era mayor que en aquellos no infectados con CMV 51 . Es bien sabido que la infección por CMV en los ojos humanos causa muerte celular y profundas disfunciones visuales.…”

“…Es bien sabido que la infección por CMV en los ojos humanos causa muerte celular y profundas disfunciones visuales. Este incremento en la secreción de FasL podría ser la causa de la pérdida de visión en las personas afectadas con retinitis por CMV 51 . Como consecuencia de este hallazgo, se piensa que CMV puede ser capaz de eliminar células vecinas con potencial letal para su célula hospedera, causando un efecto espectador, ya que CMV cuenta con una amplia gama de mediadores anti-apoptóticos que pueden evitar la muerte en las células infectadas.…”