Viral Enhancer Mimicry of Host Innate-Immune Promoters

Kai A Kropp,Ana Angulo,Peter Ghazal,Glenn F Rall

doi:10.1371/journal.ppat.1003804

Abstract

The inflammatory milieu is the natural habitat for a pathogenic infection, characterised by activity of pro-inflammatory signalling pathways and inflammatory cytokines. Viral entry rapidly activates a range of innate-immune signalling events such as the activation of Pattern Recognition Receptors (PRRs) [1]–[5]. A virus must therefore counteract intrinsic cellular and innate-immune responses to successfully complete the replication cycle. Frequently this is accomplished by encoding viral effector molecules that block these cellular responses by working as either structural or functional mimics of host target proteins [6]–[11]. Nuclear DNA viruses are dependent on the host transcriptional machinery to express the first viral genes; for example the immediate-early (IE) control elements of DNA viruses are by definition absolutely dependent on host transcription factors (TF) [12]. Therefore, these viruses are particularly hostage to their host transcriptional environment [13], [14]. Here we propose that mimicry of regulatory DNA sequences by viral regulatory regions may also provide an additional strategy to counteract at IE times of infection the innate-immune response. In this context, viral IE control elements might functionally mimic innate-immune enhancers, taking advantage of the activated immune signalling TFs for promoting viral IE gene expression. In other words: “If you can't beat ‘em. Join ‘em.” In exploring this possibility, we present a synopsis of the promoter-regulatory elements from seven extensively studied mammalian viruses with a DNA stage, and seven promoters representing prototypical cellular innate-immune genes. These are the SV-40 early enhancer, the E1A enhancer of HAdV5, the long terminal repeat (LTR) of HIV-1, the E6/7 long control region (LCR) of both HPV-16 and HPV-18, the major IE (MIE) enhancer of HCMV, and the enhancer-1 (Eh-1) regulatory region of HBV for viral sequences, and the enhancer regions of human IFNB1, IFNG, TNF, IRF1, IL8, IL12B, and IL1B for host sequences. First, we consider similarities between the primary sequence structures of the enhancers. Second, we present arguments for convergent evolution and structural flexibility inherent to enhancer sequences. Third, we discuss functional features and regulatory hallmarks that may be used to define viral enhancer mimicry of cellular immune enhancers.

Highlights

In exploring this possibility, we present a synopsis of the promoter-regulatory elements from seven extensively studied mammalian viruses with a DNA stage, and seven promoters representing prototypical cellular innate-immune genes
To investigate if there is any similarity of primary sequences and structural mimicry between the selected viral and cellular enhancers, we used the BLAST tool to compare the sequences against each other (Table 1) and applied an exhaustive pairwise multi-way alignment (CloneManager suite 7.0) to search for similarities in this group of sequences (Figure 1A)
While multi-way alignment of the various selected viral and cellular promoter-regulatory regions (Figure 1A, top panel) reveals a lack of extended primary sequence homology, the pairwise BLAST comparison showed that small islands of sequence identity or high similarity are present (Table 1)

Summary

Do Viral and Cellular Enhancers Display Any Primary Sequence Similarity?

To investigate if there is any similarity of primary sequences and structural mimicry between the selected viral and cellular enhancers, we used the BLAST tool to compare the sequences against each other (Table 1) and applied an exhaustive pairwise multi-way alignment (CloneManager suite 7.0) to search for similarities in this group of sequences (Figure 1A). We randomly compared some of these short sequence motifs with the JASPAR CORE (Vertebrae) database [15] and found that all checked motifs have similarities with consensus binding motifs for TFs (e.g., AP1, SP1, YY1, or RelA with relative scores of .0.8) This finding raises the question of whether there might be functional similarity. The first possibility, acquisition of cellular sequences through horizontal sequence transfer, could arise through illegitimate recombination with host DNA, for example by retro-transposition of non-coding RNA transcripts, resulting in the virus hijacking host transcription control sequences. If this were the general case, we would, expect significant structural similarity, Citation: Kropp KA, Angulo A, Ghazal P (2014) Viral Enhancer Mimicry of Host Innate-Immune Promoters.

Viral Host

Shared Transcription Factor Interactions

Responsiveness to Negative Feedback Control

Findings

Concluding Remarks