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

Abstract

Bats host a number of viruses that cause severe disease in humans without experiencing overt symptoms of disease themselves. While the mechanisms underlying this ability to avoid sickness are not known, deep sequencing studies of bat genomes have uncovered genetic adaptations that may have functional importance in the antiviral response of these animals. Egyptian rousette bats (Rousettus aegyptiacus) are the natural reservoir hosts of Marburg virus (MARV). In contrast to humans, these bats do not become sick when infected with MARV. A striking difference to the human genome is that Egyptian rousettes have an expanded repertoire of IFNW genes. To probe the biological implications of this expansion, we synthesized IFN-ω4 and IFN-ω9 proteins and tested their antiviral activity in Egyptian rousette cells. Both IFN-ω4 and IFN-ω9 showed antiviral activity against RNA viruses, including MARV, with IFN-ω9 being more efficient than IFN-ω4. Using RNA-Seq, we examined the transcriptional response induced by each protein. Although the sets of genes induced by the two IFNs were largely overlapping, IFN-ω9 induced a more rapid and intense response than did IFN-ω4. About 13% of genes induced by IFN-ω treatment are not found in the Interferome or other ISG databases, indicating that they may be uniquely IFN-responsive in this bat.

A comparative analysis of the antiviral response in two bat species reveals conserved and divergent innate immune pathways

“…One suggested mechanism of greater disease resistance in bats is heightened innate immune response that is manifested in relatively high expression levels of type-I IFN or IFN-stimulated genes in bat cells and tissues 29,31,42,[81][82][83] . A recent study suggested that cells of Black Flying Fox (Pteropus alecto), a fruit bat from the Pteropodidae family (the same as Rousettus), show increased levels of the IRF transcription factors across bat tissues as well as higher basal expression of a set of IFN-stimulated genes 31 .…”

“…We focus on representatives of the major bat subordinal clades 40 -the Egyptian fruit bat, Rousettus aegyptiacus, and the insectivore bat Pipistrellus kuhlii (Kuhl's pipistrelle). Various aspects of Rousettus innate and adaptive immunity have been studied 13,[41][42][43][44][45][46] , due to its asymptomatic infection of filoviruses, as well as its association with infection with other viruses 47,48 . In contrast, antiviral immunity of Pipistrellus, a distantly related bat to Rousettus, remains poorly characterized, despite studies that suggested the presence of several Alpha-and Beta-coronaviruses (including closely related variants to MERS-CoV) in its population in Europe and the Middle East [49][50][51][52][53][54] .…”

Of bats and men: Immunomodulatory treatment options for COVID-19 guided by the immunopathology of SARS-CoV-2 infection

“…Increased abundance of IRF1/3/7 and IFNs at steady state may be responsible for tissue-specific differences between bats and other mammals and/or for differential maturation of immune cell populations (Fig. 1) (120). Furthermore, differential metabolic activity in bats with decreases in reactive oxygen species may alter the potential for NF-B activation (121).…”

Context Is Key: Delineating the Unique Functions of IFNα and IFNβ in Disease

“…Indeed, a recent study compared two different IFNw subtypes from Rousettus aegyptiacus bats and found that IFNw9 displayed more effective antiviral activity against several RNA viruses in vitro compared to IFNw4 (130). Additionally, differences in expression and activity of porcine IFNw subtypes have also been demonstrated, with IFNw7 demonstrating the best antiviral activity in vitro (131).…”

“…Just as there is growing appreciation that expanded IFNα subtypes provide an evolutionary advantage beyond redundancy, it stands to reason that the expansion of IFNω genes likewise imparts a fitness advantage for those species. Indeed, a recent study compared two different IFNω subtypes from Rousettus aegyptiacus bats and found that IFNω9 displayed more effective antiviral activity against several RNA viruses in vitro compared to IFNω4 ( 130 ). Additionally, differences in expression and activity of porcine IFNω subtypes have also been demonstrated, with IFNω7 demonstrating the best antiviral activity in vitro ( 131 ).…”