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

Abstract

Following our recent findings on the presence of human cytomegalovirus (HCMV) in the normal human adrenal cortex and in adrenocortical tumors, especially in cortisol-secreting tumors, aim of the present study was to investigate the direct effects of HCMV infection on human adrenocortical cells. To this aim, both clinical isolates and laboratory strains of HCMV were used to assess the early effects of infection on human adrenocortical cell morphology, proliferation, gene expression, and steroidogenic function. Both clinical and laboratory HCMV strains could infect and replicate in primary human adrenocortical cell cultures and in adrenocortical carcinoma cell lines, leading to cytopathic changes. Most importantly, in the first hours post-infection (p.i.), adrenocortical cells showed a significant increase of cortisol and estrogen production, paralleled by up-regulation of steroidogenic acute regulatory protein and expression of steroidogenic enzymes involved in the last steps of adrenal steroidogenesis. This effect was probably due to HCMV immediate-early gene expression, since it was most evident in the early phases p.i. and UV-inactivated viral particles did not affect hormone production. Moreover, the effect on steroidogenesis was HCMV specific, since it was not observed after infection with herpes simplex virus. These data suggest that human adrenocortical cells are permissive to HCMV infection and acutely respond to infection with increased cortisol production. An acute glucocorticoid response is typically triggered by infections and is considered to be critical to host defense against pathogens, although, in the case of HCMV infection, it might also enhance viral replication and reactivation from latency.

Induction of CXCL10 chemokine in adrenocortical cells by stimulation through toll-like receptor 3

“…At present, the best characterized factors are by far the genetic ones, with specific alleles of the HLA complex conferring the highest risk (Erichsen et al, 2009b). Little is known about environmental factors, although the adrenal cortex has been described to be permissive to several viral, fungal and bacterial agents (Kelestimur, 2004;McLeod et al, 2011;Trevisan et al, 2009). Regarding endogenous factors, it has become increasingly recognized that adrenocortical cells have a wide range of immunological mediators in their repertoire, including HLA class II, TLRs, cytokines and chemokines.…”

Cytomegalovirus is associated with reduced telomerase activity in the Whitehall II cohort

“…For example, the immunosuppressive hormone cortisol inhibits TA in CD4 and CD8 T cells (Choi et al, 2008), whereas its analogue hydrocortisone promotes viral replication in latently infected cells (Lathey and Spector, 1991). Significantly, research has shown that CMV can directly increase cortisol production by its ability to infect and replicate in human adrenocortical cells, where it causes steroidogenesis (Trevisan et al, 2009). In conjunction, this group has previously reported an aberrant cortisol release in healthy CMV-positive individuals involving a flattened circadian decline (Steptoe et al, 2009), which implies a more constant level of exposure to the hormone.…”

Persistent Zika virus infection in porcine conceptuses is associated with elevated in utero cortisol levels

“…It is well known that several pathogens (hepatitis B virus, cytomegalovirus, and HIV) may affect cortisol balance [3][4][5]. Zika virus (ZIKV)-induced pathology in symptomatic human neonates comprises small-for-gestational-age phenotype, lesions in the brain, microcephaly, epilepsy, and altered behavior associated with irritability, impatient crying, and anxiety [6].…”