Abstract
Bats of different species play a major role in the emergence and transmission of highly pathogenic viruses including Ebola virus, SARS-like coronavirus and the henipaviruses. These viruses require proteolytic activation of surface envelope glycoproteins needed for entry, and cellular cathepsins have been shown to be involved in proteolysis of glycoproteins from these distinct virus families. Very little is currently known about the available proteases in bats. To determine whether the utilization of cathepsins by bat-borne viruses is related to the nature of proteases in their natural hosts, we examined proteolytic processing of several viral fusion proteins in cells derived from two fruit bat species, Pteropus alecto and Rousettus aegyptiacus. Our work shows that fruit bat cells have homologs of cathepsin and furin proteases capable of cleaving and activating both the cathepsin-dependent Hendra virus F and the furin-dependent parainfluenza virus 5 F proteins. Sequence analysis comparing Pteropus alecto furin and cathepsin L to proteases from other mammalian species showed a high degree of conservation; however significant amino acid variation occurs at the C-terminus of Pteropus alecto furin. Further analysis of furin-like proteases from fruit bats revealed that these proteases are catalytically active and resemble other mammalian furins in their response to a potent furin inhibitor. However, kinetic analysis suggests that differences may exist in the cellular localization of furin between different species. Collectively, these results indicate that the unusual role of cathepsin proteases in the life cycle of bat-borne viruses is not due to the lack of active furin-like proteases in these natural reservoir species; however, differences may exist between furin proteases present in fruit bats compared to furins in other mammalian species, and these differences may impact protease usage for viral glycoprotein processing.
Highlights
IntroductionIn the past twenty years, bats of different species have been recognized as important hosts of viruses from different families including rhabdoviruses [1,2,3], coronaviruses [4,5,6,7,8,9], filoviruses [10,11,12], flaviviruses [13,14], orthomyxoviruses [15,16,17], paramyxoviruses [18,19] and others [20,21]
To assess the ability of pteropus host cell proteases to proteolytically process viral fusion proteins, we examined the proteolytic processing of the cathepsin-dependent Hendra virus F protein and the furin-dependent parainfluenza virus 5 (PIV5) F protein in P. alecto kidney cells (PaKi) and R. aegyptiacus cells obtained from body tissues (R06E)
To address the ability of bat cells to proteolytically process viral fusion proteins, we examined the proteolytic processing of the PIV5 F protein, normally cleaved by furin, and the Hendra virus F protein, normally cleaved by cathepsin L, in cells derived from two species of bats of the Pteropodidae family
Summary
In the past twenty years, bats of different species have been recognized as important hosts of viruses from different families including rhabdoviruses [1,2,3], coronaviruses [4,5,6,7,8,9], filoviruses [10,11,12], flaviviruses [13,14], orthomyxoviruses [15,16,17], paramyxoviruses [18,19] and others [20,21]. Hendra virus first emerged in 1994 in Australia in an outbreak that occurred in horses [30], and more than thirty subsequent outbreaks have occurred, with a total of four human deaths associated with the virus infection [31,32] Another closely related virus, Nipah virus was identified in Malaysia in 1999 causing an outbreak of viral encephalitis [33]; with additional outbreaks showing high mortality rates that reached 70%. A novel henipavirus that does not seem to cause clinical disease in several animals which are known to be susceptible to Hendra and Nipah viruses, was identified recently and has Pteropus bats as its natural reservoir [37]. Despite the important role of bats in the emergence of henipaviruses and other highly pathogenic viruses, very little is known about the viral life cycle or virus-host interactions in this natural reservoir
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