Checks and balances between human cytomegalovirus replication and indoleamine-2,3-dioxygenase

Abstract

Despite a rigorous blockade of interferon-c (IFN-c) signalling in infected fibroblasts as a mechanism of immune evasion by human cytomegalovirus (HCMV), IFN-c induced indoleamine-2,3-dioxygenase (IDO) has been proposed to represent the major antiviral restriction factor limiting HCMV replication in epithelial cells. Here we show that HCMV efficiently blocks transcription of IFN-c-induced IDO mRNA both in infected fibroblasts and epithelial cells even in the presence of a preexisting IFN-induced antiviral state. This interference results in severe suppression of IDO bioactivity in HCMV-infected cells and restoration of vigorous HCMV replication. Depletion of IDO expression nonetheless substantially alleviated the antiviral impact of IFN-c treatment in both cell types. These findings highlight the effectiveness of this IFN-c induced effector gene in restricting HCMV productivity, but also the impact of viral counter-measures.

Who’s Driving? Human Cytomegalovirus, Interferon, and NFκB Signaling

“…Interferons (IFN) are a broad class of cytokines initially recognized for their ability to protect cells from viral infection. Anti-viral IFN signaling in response to infection is capable of inducing a variety of host cell defenses targeting various aspects of virus biology, including global inhibition of translation via activation of protein kinase R (PKR), induction of RNAse L-mediated degradation of viral RNA, production of anti-viral nitric oxide through inducible nitric oxide synthase (iNOS), depletion of tryptophan via the indoleamine 2,3 dioxygenase (IDO) pathway, and upregulation of antigen presentation via major histocompatibility (MHC) complex constituents [ 6 , 7 , 8 , 9 , 10 ]. IFN signaling is sub-classified into Type I, Type II, and Type III groups based on their specific signaling architectures and outcomes.…”

The Kynurenine Pathway of Tryptophan Catabolism and AIDS-Associated Kaposi Sarcoma in Africa

“…That an inflammatory microenvironment fosters KS lesions suggests that IDO-derived local immune suppression could impair the development of KS. Alternatively, high levels of KSHV infection might suppress interferon-gamma-induced IDO and lower KT levels as previously observed in other viral infections [47]. Experiments on KS tissue, and appropriate controls, to directly examine KT levels would be a natural next step to evaluate the biological plausibility of our finding.…”

Human cytomegalovirus evades ZAP detection by suppressing CpG dinucleotides in the major immediate early genes

“…The green box in figure 1B highlights ISGs that inhibit HCMV virus production in both wild type fibroblast cells and IRF3 KO cells, with figure 1D showing the relative virus production levels in each cell type. These IRF3-independent ISGs include those that signal through IRF3 independent pathways (eg IRF7) or are known to inhibit HCMV directly (IDO and RIPK2) validating the screening approach 45,46 . Interestingly, both ZAPS and TRIM25 inhibited HCMV virus production in an IRF3 independent manner, indicating they may play a role in directly inhibiting the virus.…”

“…By combining screens in wild type and IRF3 knockout cells we were able to define specific subsets of ISGs that were IRF3 independent and therefore more likely to represent direct inhibitors of virus replication. These included IDO and RIPK2, which have previously been identified as important antiviral factors during HCMV infection 45,46 . In addition, multiple novel inhibitors were identified, including ZAP and TRIM25, which have previously been shown to act in a coordinated antiviral fashion 18,19 .…”