The IFN-ω subfamily contributes most to this expansion, and members of this subfamily are induced after viral infection and show antiviral activity. We also observe that the type I IFN locus is considerably expanded and diversified in R. aegyptiacus. The expansion of NK cell receptors is matched by an expansion of potential MHC class I ligands, which are distributed both within and, surprisingly, outside the canonical MHC loci. We report an unusual expansion of the KLRC (NKG2) and KLRD (CD94) gene families in R. aegyptiacus relative to other species and show genomic evidence of unique features and expression of these receptors that may result in a net inhibitory balance within bat NK cells.
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Here, we use this genome, the most contiguous bat genome available, to understand the evolution of immune genes and gene families in bats, and describe several observations relevant to defense against viruses. To overcome this limitation, we used a hybrid strategy combining both short- and long-read NGS technologies to generate a high-quality annotated genome for the Egyptian rousette bat ( Rousettus aegyptiacus), an asymptomatic host of MARV ( Towner et al., 2009).
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These sequencing strategies impact the overall contiguity of genome assemblies and limit the ability to resolve repetitive genome loci where important immune gene loci reside. While these genome projects provide important insights into the unique biology of bats, the bat genomes currently available were generated with low-coverage sequencing or with only short-read next-generation sequencing (NGS) technologies ( Zhang et al., 2013, Seim et al., 2013). For example, the type I IFN locus has contracted in Pteropus alecto ( Zhou et al., 2016), but expanded in Pteropus vampyrus and Myotis lucifugus ( Kepler et al., 2010). A few studies suggest that significant differences exist in type I IFNs between bats and humans ( Zhang et al., 2017, Zhou et al., 2016, Kepler et al., 2010, De La Cruz-Rivera et al., 2018), although the precise nature of the differences remains unclear. Multiple studies have reported the absence of canonical NK cell receptors in bat genomes ( Shaw et al., 2012, Zhang et al., 2013, Lee et al., 2015), although a few receptors were identified in the P. alecto transcriptome ( Papenfuss et al., 2012). The most notable findings from these studies involve two large classes of immune genes: natural killer (NK) cell receptors and type I interferons (IFNs). Additional bat genomes have been studied to a more limited extent ( Seim et al., 2013, Zhang et al., 2013, Parker et al., 2013). The most thoroughly studied bat genome is that of Pteropus alecto ( Zhang et al., 2013), a reservoir host of Hendra virus. Genomic analyses of immune genes in bats have produced conflicting and surprising observations. This stark difference between bats and primates has motivated efforts to deeply characterize the genes involved in the immune system of bats and understand the antiviral immune mechanisms used to control viral infection. Such asymptomatic infection is especially noteworthy in the case of human pathogens such as henipaviruses (Nipah and Hendra viruses), coronaviruses (severe acute respiratory syndrome and Middle East respiratory syndrome coronaviruses), and filoviruses (Marburg virus ), which cause severe, and often lethal, systemic disease in humans and non-human primates ( Calisher et al., 2006, Smith and Wang, 2013).
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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.īats, members of the large, diverse order Chiroptera, appear to harbor significantly more zoonotic viruses than other mammals and do so without overt pathology ( Calisher et al., 2006, Olival et al., 2017). An evaluation of the theoretical function of these genes suggests that an inhibitory immune state may exist in bats. Such concerted evolution of key components of bat immunity is strongly suggestive of novel modes of antiviral defense. 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. 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.
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Bats harbor many viruses asymptomatically, including several notorious for causing extreme virulence in humans.