Lloviu virus disrupts human innate immune signaling pathways, just like Ebola
The filoviruses Ebola virus (EBOV) and Marburg virus (MARV) are zoonotic pathogens that are highly lethal in humans. Until recently, filoviruses were only known to circulate in Africa or the Philippines. Therefore, it was surprising when the sequence of a new filovirus, Lloviu Virus (LLOV), was discovered by Negredo et al. in dead Schreiber’s bats (Miniopterus schreibersii) in Spain. Although infectious virus was not isolated from the bat carcasses, the near complete genomic sequence demonstrated the presence of homologues to all of the EBOV and MARV proteins, including proteins that block interferon response pathways in human cells. We demonstrate that the innate immune antagonist proteins VP35 and VP24 from either EBOV or the recently identified LLOV block type I interferon production and type I interferon-induced signaling in both human and bat cells. This suggests that both viruses can effectively counteract innate immune signaling in either species.
The lethality of EBOV and MARV in humans is likely due in part to their ability to effectively suppress host innate immune responses, especially the type I interferon response. Therefore, it was of interest to determine if LLOV encodes proteins with the same capability. At the same time, bats have been implicated as filovirus reservoir hosts, and studies suggest that EBOV and MARV are not particularly pathogenic in bats. The effect of LLOV infection on bats remains uncertain. Therefore, it is also of interest to determine whether these viruses effectively block innate immunity in bat cells. Our data indicates that like EBOV, LLOV VP35 and VP24 disrupt human innate immune signaling pathways. Therefore, these pathways are unlikely to serve as a block to LLOV disease in humans. Furthermore, because EBOV and LLOV proteins effectively function to suppress innate immune signaling in bat cells, these functions are unlikely to explain the absence of disease in EBOV-infected bats.
For this work, there was a question as to what bat cells to use. Bats are a highly diverse group of mammals that comprise roughly one-fifth of all mammalian species. In the end, we chose to use an Epomops buettikoferi cell line as representative bat cells for several reasons including their availability, reasonable transfection efficiency, and potential for infection by filoviruses, particularly EBOV. It will now be interesting to determine whether our findings apply to other bat species as well.
LLOV VP35 and VP24 proteins antagonize the type I interferon (IFN) production and interferon-induced signaling pathways in both human and bat cells. LLOV VP35 inhibits the phosphorylation of interferon regulatory factor 3 (IRF3) and downstream IFN-β promoter activity, in both human and bat cells, which suggests an impairment of the RIG-I signaling pathway comparable to EBOV VP35. Suppression of RIG-I signaling has been connected to EBOV VP35 interaction with dsRNA and with the cellular protein PACT. LLOV VP24, similar to EBOV VP24, impairs type I IFN signaling by preventing phosphorylated STAT1 translocation from the cytoplasm to the nucleus, in human and bat cells, where it activates genes involved in the antiviral response. EBOV VP24 and VP35 proteins also function as antagonists in bat cells.
About the author
Alicia Feagins is a Postdoctoral Fellow in the Department of Microbiology at the Icahn School of Medicine at Mount Sinai in New York, New York, USA.