Expression of iron‐related proteins during infection by bovine herpes virus type‐1

Abstract

Bovine herpesvirus 1 (BHV-1), a dsDNA animal virus, is an economically important pathogen of cattle and the aetiological agent of many types of disease. The efficient replication of a DNA virus is strictly dependent on iron since this metal plays a crucial role in the catalytic center of viral ribonucleotide reductase. Consequently, iron metabolism is an important area for virus/host interaction and a large body of evidence suggests that viral infection is potentially influenced by the iron status of the host. The aim of the present study was to address the effects of BHV-1 on iron metabolism in Madin-Darby bovine kidney (MDBK) cells at different times of post-infection. For this purpose, cell viability, iron regulatory proteins (IRPs) activity and levels, transferrin receptor 1 (TfR-1), ferritin expression and LIP were evaluated. Our data demonstrate that a productive BHV-1 infection in MDBK cells determines an overall decrease of IRPs RNA-binding activity without affecting their expression. As consequence of this modulation, an increased ferritin mRNA translation and a decreased TfR-1 mRNA translation were also observed. Moreover, the LIP level was decreased following viral infection. These results are consistent with the hypothesis that by reducing the iron up-take and by enhancing the sequestration of free iron, animal cells will limit the iron availability for virus proliferation. Therefore, the results presented herein support the view that iron metabolism could be critical for the interaction between DNA viruses, such as BHV-1, and mammalian cells. Delineation of the interplay among pathogen and host may provide new antimicrobial agents.

2,3,7,8-Tetrachlorodibenzo-p-Dioxin Promotes BHV-1 Infection in Mammalian Cells by Interfering with Iron Homeostasis Regulation

“…As clearly shown in the graphs in Fig. 2C by comparing between the effects of BHV-1 infection and TCDD exposure taken individually or in combination, the increase in IRP2 RNA-binding activity was exclusively induced by the dioxin, whereas the decreasing trend in IRP1 activity was induced by both BHV-1 and dioxin alone [36], [38].…”

“…Moreover, in a previous study we have shown that iron metabolism is critical for the interaction between BHV-1 and mammalian cells, where the association between host iron status and virus infectivity appears to be bidirectional: host iron status may alter the severity of disease as well as infection can alter cellular iron homeostasis [36]. Hence, considering that regulation of iron homeostasis is a critical point in the virus-host interaction, the current dioxin emergency [10]–[12], and the widespread diffusion of BHV-1 [13], [14], in this study we have investigated the iron metabolism during BHV-1 infection in the presence of TCDD in a bovine cell line, focusing on its possible impact on disease progression.…”

“…The labile iron pool primarily regulates RNA-binding capacity by IRP1 [4Fe-4S] cluster assembly/disassembly and by IRP2 degradation [30], [31]. However, the IRPs RNA-binding activity is also regulated by several other exogenous and endogenous factors, such as oxidative stress [32], nitric oxide signaling [33], protein phosphorylation [34], hypoxia/reoxygenation [35], viral infections [36], estrogens [37], TCDD exposure [38], as well as oxalomalic acid, an inhibitor of IRP1/c-aconitase [39].…”

Iron Regulatory Proteins: From Molecular Mechanisms to Drug Development

“…Virus infections may affect the RNA binding activity of IRPs, as has been shown in the case of BHV-1 infection in MDBK cells (120). However, this may often be due to other factors, such as increased ROS production in the case of the IRP1 downmodulation induced by hepatitis B virus X protein (69).…”

Ovariectomy and estrogen treatment modulate iron metabolism in rat adipose tissue

“…The IRPs RNA-binding activity is also regulated by iron-independent factors, such as oxidative stress [17], nitric oxide signalling [18], protein phosphorylation [19], hypoxia [20,21], as well as oxalomalic acid, an inhibitor of aconitase/IRP1 [22,23], and virus infection [24]. Among hormones, thyroid hormones regulate post-transcriptionally the synthesis of proteins involved in iron metabolism by affecting IRPs ability to bind to IRE [25].…”