Restriction to human cytomegalovirus replication in vitro removed by physiological levels of cortisol

Abstract

Since viral infection is in most cases contrary to the survival of the host cell, it is reasonable to assume that cells possess innate viral replication inhibitory mechanisms. Even between strains of permissive cells, degrees of permissiveness are observed. Restriction to human cytomegalovirus (CMV) replication in vitro is well known, especially in epithelioid cells or cells derived from certain organs. We have studied restriction in a fibroblastic strain of human embryonic kidney cells. By treatment of cell cultures with maximum physiologic concentration of the hormone cortisol (25 micrograms%) both pre and post virus inoculation, susceptibility to laboratory strain Ad169 CMV and low-passaged clinical isolate JSS CMV was enhanced by factors of 6.4 +/- 0.7 and 11.1 +/- 0.4, respectively; effectively converting these cells to a totally permissive state. A linear dose response, which peaks at 25 micrograms% and declines thereafter up to 300 micrograms%, is evident for both virus strains in this enhancement system. Breakdown of restriction increases in linear fashion with increasing time of cortisol pretreatment of cells. The characterization of cortisol effects converting restrictive human fetal cells in vitro to the permissive state further indicates that human hormones may play a significant role in CMV susceptibility in vivo.

Glucocorticoids facilitate the transcription from the human cytomegalovirus major immediate early promoter in glucocorticoid receptor- and nuclear factor-I-like protein-dependent manner

“…Clinically, the virus is reactivated more often in the third trimester than in the second or the first of pregnant women [2], so that the babies are exposed to HCMV at delivery and acquire immunity against HCMV with subclinical infection. Furthermore, it is suggested that HCMV infection may be due to elevation of plasma hydroxycorticoid levels during pregnancy [12]. It has never been discussed how the HCMV was reactivated in the third trimester, and this study supports a notion that increased glucocorticoid in the third trimester may reactivates HCMV virus from latency.…”

“…Recently, it was reported that glucocorticoids trigger reactivation of HCMV from HCMV-latently infected myeloid cells and increases the incidence of HCMV infection in liver transplant patients when both donor and recipient are HCMV seropositive [11]. Furthermore, it is suggested that HCMV infection in the third trimester of pregnant women is probably due to elevation of the plasma hydroxycorticoid level [12]. However, it has never been clarified whether DEX-mediated signal pathway is directly involved in the transcriptional regulation of the MIE genes.…”

Estrogen-related receptor α is required for efficient human cytomegalovirus replication

“…Cortisol, the glucocorticoid receptor ligand, enhanced virus production in human embryonic kidney cells (16). Most recently, a PPAR response element was described within the MIEP, and a PPARγ antagonist reduced viral protein expression, lipid droplet formation, and virus production (17).…”

Human cytomegalovirus productively infects adrenocortical cells and induces an early cortisol response

“…We tested the hypothesis that glucocorticoids and other steroid hormones produced by human adrenocortical cells could facilitate HCMV replication, as demonstrated in fibroblasts and macrophages (Tanaka et al, 1984;Koment, 1989;Lee et al, 1999). But, when adrenocortical cells were treated with hydrocortisone or the general inhibitor of steroidogenesis L-aminoglutethimide, no marked effects were observed on HCMV replication, even though treatment with hydrocortisone seemed to facilitate virus release from cells, as revealed by peaks of increased viral titer in culture medium.…”

“…Indeed, experimental studies from the literature demonstrate that treatment of human fibroblasts and embryonic kidney cells with pharmacological concentrations of glucocorticoids, such as hydrocortisone (i.e., cortisol) and dexamethasone, enhances HCMV replication, whereas treatment with estrogens and androgens does not (Tanaka Genes are grouped according to their ontology. et al, 1984;Koment, 1989). To investigate whether HCMV replication in adrenocortical cells is modulated by steroid hormones, NCI-H295R and SW-13 adrenocortical cells were treated with hydrocortisone and L-aminoglutethimide, an inhibitor of several adrenal steroidogenic enzymes, in a time course experiment of infection with AD169 at MOI 0.1 pfu/cell.…”