Altered growth, differentiation, and responsiveness to epidermal growth factor of human embryonic mesenchymal cells of palate by persistent rubella virus infection.

Abstract

We previously demonstrated that human embryonic mesenchymal cells derived from the palate (HEMP cells) retain alkaline phosphatase (ALP) content and capacity for collagen synthesis after long-term culture, and their growth is markedly stimulated by epidermal growth factor (EGF). There was a dramatic decrease in ALP content and capacity to synthesize collagen in HEMP cells (HEMP-RV cells) persistently infected with rubella virus (RV). EGF increased ALP activity and decreased collagen synthesis in HEMP cells, whereas EGF showed no effect on these activities in HEMP-RV cells. Growth of HEMP-RV cells was slightly reduced compared with that of HEMP cells. EGF stimulated growth of HEMP cells and to a lesser extent of HEMP-RV cells. Binding of '"I-EGF to cell-surface receptors in HEMP-RV cells was, to our surprise, twice as much as that in HEMP cells. However, internalization of bound '"I-EGF in HEMP-RV cells was profoundly diminished. Thus, persistent RV infection causes not only changes in HEMP cell growth and differentiation but a decrease in or loss of HEMP cell responsiveness to EGF. The effects of persistent RV infection on palatal cell differentiation as well as growth may be responsible for the pathogenesis of congenital rubella. Furthermore, since HEMP cells appear to be closely related to osteoblasts, these results suggest a mechanism for RV-induced osseous abnormalities manifested in congenital rubella patients.

Neurological Aspects of Rubella Virus Infection

“…The rubella virus has been shown to alter the cytoplasmic structural frame work, particularly actin-containing microfilaments, which could have an inhibitory effect on mitosis [ 18], One report characterized an extracellular factor released from infected cells that inhibited growth of neighboring, unin fected cells [19]. Rubella virus-infected cells have also been shown to exhibit decreased sensitivity to extracellu lar growth factors [20], Since the primary time in gesta tion when rubella virus exhibits profound teratogenicity (i.e., the first trimester) coincides with organogenesis in the developing fetus, the favored hypothesis is that altera tions induced in infected fetal progenitor cells ultimately affect organ development. The effect that rubella virus has on cell division would particularly explain the re duced cell number and small size of affected organs in CRS patients.…”

Altered membrane fatty acids of cultured human retinal pigment epithelium persistently infected with rubella virus may affect secondary cellular function

“…However, rubella virus may alter several metabolic systems during its subtle maintenance of viral persistence [3,7,19,25,29,30]. Poor RPE/RV phagocytic function may result from a combination of RV-altered cytoskeletal elements [5], distorted membrane FA composition, and possibly other physiological factors such as defective microvilli signalling as proposed in the dystrophic RPE rat model [7].…”

“…Human and animal cells persistently infected with rubella virus (RV) demonstrate altered secondary functions in a variety of cell types often envolving membrane functions [19,21,29,30], but without evidence of cytopathology [-20,29]. Major cellular metabolic pathways, including cellular replication, appear largely intact [29].…”

“…Major cellular metabolic pathways, including cellular replication, appear largely intact [29]. Examples of altered secondary functions include a marked inhibition of the normal capacity to synthesize collagen shown in human embryonic mesenchymal cells of the palate, possibly related to a membrane defect of internalizing epidermal growth factor or to inadequate transport or metabolism of this factor [30]. Cellular membrane action is again implicated in the decreased ability of human fetal pancreatic islet cell cultures that are persistently-infected with RV to secrete insulin [18].…”

Elevation of Mouse Mammary Tumor Virus Envelope Glycoprotein (Gp52) by Growth Factors

“…Viruses other than members of the retroviridae family have de monstrated important associations with growth factor regulatory systems. Persistent rubella virus infection has been demonstra ted to alter the response of human embryonic cells to EGF [6]; moreover, vaccinia virus codes for a protein related to EGF and trans forming growth factor a [7,8]. Three different retroviruses have the following oncogenes which are similar to either growth factors or growth factor receptors: (i) v-sis codes for the B chain of platelet-derived growth factor (PDGF); (ii) v-erb B codes for a truncated form of the EGF receptor, and (iii) v-fms codes fora productsimilarto the receptor for colony-stimulating factor I [9], These in stances of retroviruses encoding growth fac tors to regulate and transform cells suggest that this process may be reversed and that cellular growth factors may play a role in regulating retroviral expression.…”