ABSTRACT
Bats harbor many viruses asymptomatically, including several notorious for causing extreme virulence in humans. To identify differences between antiviral mechanisms in humans and bats, we sequenced, assembled, and analyzed the genome of Rousettus aegyptiacus, a natural reservoir of Marburg virus and the only known reservoir for any filovirus. We found an expanded and diversified KLRC/KLRD family of natural killer cell receptors, MHC class I genes, and type I interferons, which dramatically differ from their functional counterparts in other mammals. Such concerted evolution of key components of bat immunity is strongly suggestive of novel modes of antiviral defense. An evaluation of the theoretical function of these genes suggests that an inhibitory immune state may exist in bats. Based on our findings, we hypothesize that tolerance of viral infection, rather than enhanced potency of antiviral defenses, may be a key mechanism by which bats asymptomatically host viruses that are pathogenic in humans.
Subject(s)
Chiroptera/genetics , Genome , Immunity, Innate/genetics , Amino Acid Sequence , Animals , Cell Line , Chiroptera/classification , Chiroptera/immunology , Chromosome Mapping , Disease Reservoirs/virology , Egypt , Evolution, Molecular , Genetic Variation , Histocompatibility Antigens Class I/classification , Histocompatibility Antigens Class I/genetics , Humans , Interferon Type I/classification , Interferon Type I/genetics , Marburg Virus Disease/immunology , Marburg Virus Disease/pathology , Marburgvirus/physiology , NK Cell Lectin-Like Receptor Subfamily C/chemistry , NK Cell Lectin-Like Receptor Subfamily C/classification , NK Cell Lectin-Like Receptor Subfamily C/genetics , NK Cell Lectin-Like Receptor Subfamily D/chemistry , NK Cell Lectin-Like Receptor Subfamily D/classification , NK Cell Lectin-Like Receptor Subfamily D/genetics , Phylogeny , Sequence AlignmentABSTRACT
The NKG2 family of NK receptors includes activating and inhibitory members. With the exception of the homodimer-forming NKG2D, NKG2 receptors recognize the nonclassical MHC class I molecule HLA-E, and they can be subdivided into two groups: those that associate with and signal through DAP12 to activate cells, and those that contain an ITIM motif to promote inhibition. The function of NKG2 family member NKG2E is unclear in humans, and its surface expression has never been conclusively established, largely because there is no Ab that binds specifically to NKG2E. Seeking to determine a role for this molecule, we chose to investigate its expression and ability to form complexes with intracellular signaling molecules. We found that NKG2E was capable of associating with CD94 and DAP12 but that the complex was retained intracellularly at the endoplasmic reticulum instead of being expressed on cell surfaces, and that this localization was dependent on a sequence of hydrophobic amino acids in the extracellular domain of NKG2E. Because this particular sequence has emerged and been conserved selectively among higher order primates evolutionarily, this observation raises the intriguing possibility that NKG2E may function as an intracellular protein.
