Human cytomegalovirus inhibits erythropoietin production.
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 ultraviolet-inactivated virus had no effect and valganciclovir treatment showed that late gene expression was nonessential. Hypoxia-induced gene transcription is controlled by the transcription factors hypoxia-inducible transcription factor (HIF)-1α and HIF2α, which are constitutively produced but stable only under low oxygen conditions. We found that hCMV inhibited constitutive production of HIF2α mRNA. HIF2α is thought to be the master regulator of erythropoietin transcription. Single-cell analysis revealed that nuclear accumulation of HIF2α 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.
Department of Medicine, Centre for Molecular Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden; and Lynn.Butler@ki.se.
Lynn M
LM
Butler
Department of Medicine, Centre for Molecular Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden; and.
Mensur
M
Dzabic
Department of Medicine, Centre for Molecular Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden; and.
Frank
F
Bakker
Department of Medicine, Centre for Molecular Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden; and.
Belghis
B
Davoudi
Department of Medicine, Centre for Molecular Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden; and.
Hannah
H
Jeffery
Department of Medicine, Centre for Molecular Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden; and.
Piotr
P
Religa
Department of Internal Medicine, Warsaw Medical University, Warsaw, Poland.
Krzysztof
K
Bojakowski
Department of Medicine, Centre for Molecular Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden; and.
Koon-Chu
KC
Yaiw
Department of Medicine, Centre for Molecular Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden; and.
Afsar
A
Rahbar
Department of Medicine, Centre for Molecular Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden; and.
Cecilia
C
Söderberg-Naucler
D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D018929:Cell Culture Techniques; D015687:Cell Hypoxia; D003587:Cytomegalovirus / Q000502:physiology*; D004906:Erythrocyte Count; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism*; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007074:Immunoglobulin G / Q000378:metabolism; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000097:blood* / Q000473:pathology / Q000821:virology*; D000099162:Endothelial PAS Domain-Containing Protein 1
D000914:Antibodies, Viral; D051792:Basic Helix-Loop-Helix Proteins; D004921:Erythropoietin; D006454:Hemoglobins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007074:Immunoglobulin G; D012333:RNA, Messenger; D000099162:Endothelial PAS Domain-Containing Protein 1