Enhanced Autophagy Contributes to Reduced Viral Infection in Black Flying Fox Cells

Abstract

Bats are increasingly implicated as hosts of highly pathogenic viruses. The underlying virus–host interactions and cellular mechanisms that promote co-existence remain ill-defined, but physiological traits such as flight and longevity are proposed to drive these adaptations. Autophagy is a cellular homeostatic process that regulates ageing, metabolism, and intrinsic immune defense. We quantified basal and stimulated autophagic responses in black flying fox cells, and demonstrated that although black flying fox cells are susceptible to Australian bat lyssavirus (ABLV) infection, viral replication is dampened in these bat cells. Black flying fox cells tolerated prolonged ABLV infection with less cell death relative to comparable human cells, suggesting post-entry mechanisms interference with virus replication. An elevated basal autophagic level was observed and autophagy was induced in response to high virus doses. Pharmacological stimulation of the autophagy pathway reduced virus replication, indicating autophagy acts as an anti-viral mechanism. Enhancement of basal and virus-induced autophagy in bat cells connects related reports that long-lived species possess homeostatic processes that dampen oxidative stress and macromolecule damage. Exemplifying the potential that evolved cellular homeostatic adaptations like autophagy may secondarily act as anti-viral mechanisms, enabling bats to serve as natural hosts to an assortment of pathogenic viruses. Furthermore, our data suggest autophagy-inducing drugs may provide a novel therapeutic strategy for combating lyssavirus infection.

Novel Insights Into Immune Systems of Bats

“…Receptors such as Lrrfip1 (90), TLR9 (96) and polIII (89) may have been positively selected for in bats to compensate for the loss of the PYHIN family of proteins and the lack of activation of STING (Figure 2). In addition, other pathways, such as autophagy may have undergone positive selection in bats (100). The DNA-dependent protein kinase catalytic subunit (DNA-PKcs, encoded by PRKDC) is involved in DNA-damage responses and has additionally been suggested to bind cytosolic DNA and promote type I IFN responses (101).…”

“…Lack of susceptible cell lines have led to maintenance and propagation of bat viruses in cells from other mammalian species, which could, in theory, lead to adaptive mutations in bat viruses. However, even with these caveats, the field of bat immunology and virology is slowly developing and discovering novel adaptations in the bat immune system that is redefining our understanding of mammalian immune responses (17,94,95,100).…”

Establishment of immortalized primary cell from the critically endangered Bonin flying fox (Pteropus pselaphon)

“…As the bat derived cells, the establishment of primary cells and cellular immortalization with TERT or SV40 large T expression was previously reported [13,14]. The establishment of the megabat derived cells were worth for the investigation since megabats mediate various types of infectious diseases, such as Nipah and Hendra viruses.…”

Egyptian Rousette IFN-ω Subtypes Elicit Distinct Antiviral Effects and Transcriptional Responses in Conspecific Cells

“…This blocking mechanism could be significant for MARV infection, given that MARV also relies on actin filaments to transport nucleocapsids to the budding sites (47). Given their close association with autophagy related proteins, GBPs can direct autophagy for pathogen clearance (45), which has recently been shown to be one mechanism by which bats can limit viral infection (48).…”