Human Cytomegalovirus Inhibits Erythropoietin Production

Abstract

Anemia is a feature of CKD and a complication of renal transplantation, often caused by impaired production of erythropoietin. The kidney is a target organ for human cytomegalovirus (hCMV) in such patients, but it is not known whether hCMV effects erythropoietin production. We found that kidneys from patients with CKD were positive for hCMV protein and that blood levels of hCMV IgG inversely correlated with red blood cell count. In mice, systemic murine cytomegalovirus infection decreased serum erythropoietin levels. In human erythropoietin-producing cells, hCMV inhibited hypoxia-induced expression of erythropoietin mRNA and protein. hCMV early gene expression was responsible, as ultravioletinactivated virus had no effect and valganciclovir treatment showed that late gene expression was nonessential. Hypoxia-induced gene transcription is controlled by the transcription factors hypoxiainducible transcription factor (HIF)-1a and HIF2a, which are constitutively produced but stable only under low oxygen conditions. We found that hCMV inhibited constitutive production of HIF2a mRNA. HIF2a is thought to be the master regulator of erythropoietin transcription. Single-cell analysis revealed that nuclear accumulation of HIF2a was inhibited in hCMV-infected cells, and the extent of inhibition correlated with hCMV protein expression. Our findings suggest that renal hCMV infection could induce or exacerbate anemia in patients. 25: 166925: -167825: , 201425: . doi: 10.1681 Anemia is a frequent feature of CKD and a common complication of renal transplantation. Large cohort studies have shown that around 40% of patients develop anemia following transplant surgery. 1-4 Interestingly, the incidence of anemia is unexpectedly high in patients with an otherwise functioning renal transplant (for review, see Vanrenterghem 5 ). Most evidence to date suggests that impaired erythropoietin (EPO) production by the renal allograft is the most common cause of post-transplant anemia. 5 In patients with CKD, as renal function decreases the incidence of anemia increases, to .70% in patients with CKD stage 5. Although its cause is multifactorial, a significant factor is inadequate production of EPO. The mechanisms behind the impaired renal EPO production remain to be elucidated. 6 EPO is a glycoprotein hormone, produced primarily in the kidney, that controls erythropoiesis and regulates hematocrit. 7 Treatment with recombinant EPO can correct post-transplant and renal diseaseassociated anemia, 8 although the cause of EPO loss is unknown. In adults, EPO originates mainly from fibroblast-type cells in the renal cortex 9 and is controlled by heterodimeric (a/b) hypoxia-inducible transcription (HIF) factors. Under normoxic conditions, HIFa subunits (HIF1a and HIF2a) are constitutively produced but are subject to rapid proteasomal degradation by the von Hippel-Lindau tumor suppressor, the recognition complex of an E3 ubiquitin J Am Soc Nephrol

Viral microRNAs Target a Gene Network, Inhibit STAT Activation, and Suppress Interferon Responses

“…Therefore, loss of EPOR expression in endothelial cells can accelerate loss of THBS1 expression due to KSHV miRNAs. Human CMV, a β-herpesvirus, was shown to reduce erythropoietin levels under hypoxic conditions52. The observation that KSHV can repress EPOR-dependent STAT5 activation is novel and highlights the differences in the mechanisms adopted by related herpesviruses to inhibit the EPO pathway.…”

Correlation between systemic lupus erythematosus and cytomegalovirus infection detected by different methods

“…Direct infection of CD34+ progenitor cells by human cytomegalovirus may be involved in the viral-induced myelosuppression [25]. In addition, HCMV infection can inhibit the production of erythropoietin and induce or exacerbate anemia [26]. It has been reported that human cytomegalovirus can sequestrate in human renal and mammary epithelial cells [27] and induce TGF-β1 activation in renal tubular epithelial cells after epithelial-tomesenchymal transition [28].…”

Investigation of risk factors associated with erythrocyte engraftment after ABO‐incompatible hematopoietic stem cell transplantation

“…As CMV antigenemia‐positive patients are often administered preemptive therapy with ganciclovir, it is possible that myelosuppression due to ganciclovir will also affect erythropoiesis in these patients 25,26 . As for another possible reason, CMV also shows an inhibitory effect on BFU‐E in vitro assays and on erythropoietin, indicating that CMV may have a direct inhibitory effect on erythrocyte generation 27–29 . In our previous study on pediatric cord blood transplantation, CMV infection was not observed after upon transfusion of leukoreduced blood components 30 .…”