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.
Highlights
Bats, order Chiroptera, host a significantly greater richness of virus species compared to other mammalian taxa [1]
Australian bat lyssavirus (ABLV), like all lyssaviruses, has a 3’-5’(-)ssRNA genome that encodes five proteins: nucleoprotein after recombinant Australian bat lyssavirus (rABLV)-GFP infection revealed that nearly double the number of human cells were infected (N), phosphoprotein (P), matrix protein (M), envelope glycoprotein (G), and large RNA polymerase compared to black flying fox cell lines at 48 and 72 hpi (Figure 1C)
As a potential mechanism underlying the reduction in ABLV, we examined whether treatment with RAPA or small molecule enhancer of autophagy-28 (SMER) resulted in degradation of virus proteins
Summary
Order Chiroptera, host a significantly greater richness of virus species compared to other mammalian taxa [1]. Viruses 2019, 11, 260; doi:10.3390/v11030260 www.mdpi.com/journal/viruses (EBOV) [9], and MARV [3,4,10], seroconverted, but did not develop pathology and only a minority of infected bats shed low level of virus in urine (NiV) [8] or high levels of virus orally (MARV) [4]. This combination of host–viral richness and apparent lack of clinical disease presentation after NiV, HeV, EBOV, or MARV infection raises the question how novel intrinsic traits or host adaptations might promote tolerance of virus infection in bats [11,12]. Positive selection of genes involved in DNA-damage repair pathways [11] and reduced free-radical production [15] in bats suggest an evolved response to the deleterious effects of an increased generation of reactive oxygen species (ROS) from the high aerobic demands of flight
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