Dampened STING-Dependent Interferon Activation in Bats

Abstract

Compared with terrestrial mammals, bats have a longer lifespan and greater capacity to co-exist with a variety of viruses. In addition to cytosolic DNA generated by these viral infections, the metabolic demands of flight cause DNA damage and the release of self-DNA into the cytoplasm. However, whether bats have an altered DNA sensing/defense system to balance high cytosolic DNA levels remains an open question. We demonstrate that bats have a dampened interferon response due to the replacement of the highly conserved serine residue (S358) in STING, an essential adaptor protein in multiple DNA sensing pathways. Reversing this mutation by introducing S358 restored STING functionality, resulting in interferon activation and virus inhibition. Combined with previous reports on bat-specific changes of other DNA sensors such as TLR9, IFI16, and AIM2, our findings shed light on bat adaptation to flight, their long lifespan, and their unique capacity to serve as a virus reservoir.

Novel Insights Into Immune Systems of Bats

“…While bats have evolved to detect and respond to RNA virus infections, studies indicate that responses to DNA viruses are dampened (94,95) (Figure 2). Ahn et al compared the genomic sequences of 10 bat species and discovered that the PYHIN family of genes were absent (94).…”

“…Ahn et al compared the genomic sequences of 10 bat species and discovered that the PYHIN family of genes were absent (94). In addition, a recent study found that the ability of stimulator of IFN genes (STING)-which is an essential adaptor protein that is involved in multiple DNA sensing pathways (93)-to induce IFN expression is dampened in bat cells due to the loss of a serine residue at position 358 (95). This mutation in STING led to higher levels of herpes simplex virus (HSV) replication in P. alecto kidney cells and re-introducing the serine residue at position 358 significantly inhibited HSV replication.…”

“…This family of receptors has been negatively selected for and lost in the genomic sequences of bats (94). A downstream signal mediator of cGAS, stimulator of IFN genes (STING) is less functional in bat cells, relative to human cells (95). The attenuated function of STING would likely extend to other DNA sensors that signal through STING, such as DDX41, DHX9, DHX36, and DAI.…”

Viruses in bats and potential spillover to animals and humans

“…Several recent studies, however, start to reveal that bats may have evolved a more balanced innate defence system. On one hand, bats have elevated level of certain defence genes or pathways from type I interferon [134] to apoptosis [135], at the same time bats exhibit more immune tolerance in different pathways, from inflammation [136], STING signalling [137] to NK cell activation [138]. However, it should be cautioned that these are very early and preliminary studies, many of them based on genomics and bioinformatics analysis only, more indepth functional studies are required to get a better understanding of the asymptomatic infection of bats by viruses highly lethal in other mammals.…”

Evolution of Hepatitis B Virus Receptor NTCP Reveals Differential Pathogenicities and Species Specificities of Hepadnaviruses in Primates, Rodents, and Bats

“…Bats are assumed to host most zoonotic viruses asymptomatically (68). Specific immunological features may allow them to tolerate or enhance the antiviral response to efficiently control viral infection and/or pathogenesis (69)(70)(71)(72)(73), including orthohepadnavirus infections.…”