Abstract
Mammalian cells require iron to satisfy metabolic needs or to accomplish specialized functions, and DNA viruses, like bovine herpesvirus 1 (BHV-1), require an iron-replete host to efficiently replicate, so that iron bioavailability is an important component of viral virulence. Cellular iron metabolism is coordinately controlled by the Iron Regulatory Proteins (IRP1 and IRP2), whose activity is affected by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a current and persistent environmental contaminant. Considering that TCDD enhances BHV-1 replication, herein we analyzed the effects of TCDD on iron metabolism during BHV-1 infection in MDBK cells, and presented evidences of a divergent modulation of IRP1 and IRP2 RNA-binding capacity. Moreover, an up-regulation of transferrin receptor 1 (TfR1) and a concomitant down-regulation of ferritin were observed. This scenario led to an expansion of the labile iron pool (LIP) and induces a significant enhance of viral titer, as confirmed by increased levels of BHV-1 infected cell protein 0 (bICP0), the major transcriptional regulatory protein of BHV-1. Taken together, our data suggest that TCDD increases the free intracellular iron availability thereby promoting the onset of BHV-1 infection and rendering bovine cells more vulnerable to the virus.
Highlights
Bovine herpesvirus 1 (BHV-1), an enveloped large doublestranded DNA virus of the Alphaherpesvirus family, is an important pathogen of cattle and the etiological agent of many types of disease, such as severe respiratory infection, conjunctivitis, genital disorders, abortions and shipping fever [1,2]
In order to evaluate the effect of TCDD on cell viability during BHV-1 infection, Madin – Darby Bovine Kidney (MDBK) cells were infected with BHV-1, at a multiplicity of infection (MOI) of 1, alone or in association with different concentrations of TCDD (0.01, 1 or 100 pg/ml) and underwent, at different hours post infection, to MTT assay, as described in Method section
Confluent cultures of MDBK cells were infected with BHV-1 at multiplicity of infection (MOI) of 1 and exposed to different concentrations of TCDD (0.01, 1 and 100 pg/ml, lanes 4–6 of each experiment depicted in Fig. 2A, respectively) for 12, 24 and 48 h, and the RNA binding activity was evaluated on cell lysates by means of electrophoretic mobility shift assay (EMSA)
Summary
Bovine herpesvirus 1 (BHV-1), an enveloped large doublestranded DNA virus of the Alphaherpesvirus family, is an important pathogen of cattle and the etiological agent of many types of disease, such as severe respiratory infection, conjunctivitis, genital disorders, abortions and shipping fever [1,2]. BHV-1 can establish latency in ganglionic neurons of the infected host and may predispose animals to secondary bacterial infections leading to pneumonia and occasionally to death [1]. Among a variety of biological targets, it is well established that the immune system is one of the most liable for 2,3,7,8tetrachlorodibenzo-p-dioxin (TCDD), a persistent environmental contaminant that since 1997 has been classified as a cancer promoter [3]. TCDD causes a broad range of immunologic effects in experimental animals, including decreased host resistance to infectious disease and suppressed humoral and cell-mediated immune responses [4].
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