Co-evolutionary analysis suggests a role for TLR9 in papillomavirus restriction

Abstract

Upon infection, DNA viruses can be sensed by pattern recognition receptors (PRRs) leading to the activation of type I and III interferons, aimed at blocking infection. Therefore, viruses must inhibit these signaling pathways, avoid being detected, or both. Papillomavirus virions are trafficked from early endosomes to the Golgi apparatus and wait for the onset of mitosis to complete nuclear entry. This unique subcellular trafficking strategy avoids detection by cytoplasmic PRRs, a property that may contribute to establishment of infection. However, as the capsid uncoats within acidic endosomal compartments, the viral DNA may be exposed to detection by toll-like receptor (TLR) 9. In this study we characterize two new papillomaviruses from bats and use molecular archeology to demonstrate that their genomes altered their nucleotide composition to avoid detection by TLR9, providing evidence that TLR9 acts as a PRR during papillomavirus infection. Furthermore, we demonstrate that TLR9, like other components of the innate immune system, is under evolutionary selection in bats, providing the first direct evidence for co-evolution between papillomaviruses and their hosts.

Synonymous nucleotide changes drive papillomavirus evolution

“…Since the authors detected evidence of co-evolution between TLR9 and the viral nucleotide ratio, these changes are likely due to evolutionary pressure provided by evading recognition by the TLR9 protein. Similar to what was seen as a response to APOBEC3 editing, the depletion of CpG does not appear to drastically alter the amino acid content of the viral proteins [ 68 ]. These data support the idea that papillomavirus protein sequences are evolutionarily constrained but that nucleotide sequences are evolving to escape antiviral responses shaping host-virus interactions.…”

“…These data suggest that evolution may select nucleotide sequences and not only amino acid residues. By analyzing dinucleotide patterns, we and others identified that specific dinucleotide pairs are less common than what would be expected by chance [ [67] , [68] , [69] , [70] ]. Specifically, there is a dramatic reduction in CpG and TpC dinucleotides ( Fig.…”

“…King and colleagues analyzed papillomavirus genomes isolated from bats. It was previously shown that bat TLR9 is under diversifying selection in bats [ 68 , 93 ]. Given the co-evolution theory between PVs and their hosts, this change in TLR9's DNA recognition should induce a complementary response in the viral genome.…”

“…As discussed above, papillomavirus genomes are depleted in CpG to evade detection by TLR9 [ 68 ]. However, the viral oncogenes regulate the steady-state levels of this protein in infected cells [ [101] , [102] , [103] , [104] ].…”