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TLR9 Immune Evasion by Murine Gammaherpesvirus 68

  • Author(s): Pezda, Andrea Christiane
  • Advisor(s): Coscoy, Laurent
  • et al.

Multiple receptors within the innate immune system have evolved to recognize nucleic acids as signatures of viral infection. It is thought that this specificity is essential for viral detection, as viruses often lack other invariant features that can serve as suitable targets for innate receptors. One such innate receptor, Toll-like receptor 9 (TLR9) has been implicated in the detection of many double-stranded DNA viruses. Here, I investigate the detection of murine herpesvirus 68 (MHV68) by TLR9. I find that MHV68 genomic DNA poorly activates TLR9 compared to murine cytomegalovirus (MCMV), a very potent inducer of innate responses. Genome-wide analysis of the number of stimulatory versus non-stimulatory CpG motifs present in the genome of each virus reveals that the MHV68 genome contains only a fraction of the number of immunostimulatory motifs present in MCMV. Interestingly, MHV68 appears to have selectively suppressed the number of stimulatory motifs through cytosine to thymine conversion. These data suggest that certain viruses may have evolved and modified their genomic content to avoid recognition by nucleic acid-sensing receptors of the innate immune system. In order to enhance TLR9-mediated recognition, 54 highly stimulatory CpG or non-stimulatory GpC motifs were inserted into the MHV68 genome. Surprisingly, while the stimulatory CpG motifs by themselves were able to stimulate TLR9, no increased stimulation was observed when the motifs were presented within the context of the MHV68 genome compared to its wildtype or GpC motif-containing counterparts. Furthermore, I show that microfluidic-based protein - DNA interaction studies can be used to gain better understanding of the DNA sequence motifs that interact with TLR9.

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