Retroviruses and restriction factors of bats

Bats have attracted significant attention in recent years as reservoirs of emerging viruses deadly to humans and other mammals, including the Ebola, Hendra, and SARS-Coronaviruses. These infections are typically nonpathogenic in bats raising questions about the innate immune differences that might exist between bats and other mammals. Retroviruses infect a wide range of species including bats which are adept at transmitting retroviral infections to other mammals. Retroviral infections including the global HIV epidemic, have had a profound impact on humans. These epidemics have their origins as zoonotic infections transmitted to humans from other species. To improve our understanding of the role of bats in the transmission of retroviruses to other mammals, this study investigated the presence of Betaretroviruses in the genomes and transcriptomes of bats. To gain new insights into differences that exist between the antiviral immune system of bats and other mammals that might account for distinct responses of bats to infection with deadly viruses, this study assessed the restriction factor (RF) class of antiviral effector proteins of bats for evidence of unique or novel evolutionary adaptions. A diverse range of complete betaretroviral fossils were discovered in bat genomes, with evidence that they are being actively transcribed, including the first identified intact endogenous retrovirus in a bat. It was determined that bat betaretroviruses can be classified into eight distinct sub-groups with evidence of cross-species transmissions, and that bats have contended with betaretroviral infections for over 30 million years. Bats were found to possess an RF repertoire that is broadly homologous to human RFs, with several important exceptions. The anti-retroviral APOBEC3 family of RFs in bats were found to be subjected to extensive expansion and diversification relative to other mammals. This includes the discovery that bats possess a greater number of APOBEC3 genes than any mammal reported to date and the identification of an additional sub-type of APOBEC3 in bats that is not present in other mammals. Bat APOBEC3 proteins were found to be functionally potent with evidence that they have been involved in antiviral activities against ancient bat retroviruses. Furthermore, the expansion of the APOBEC3 gene repertoire in bats was found to be coincident with the extinction of LINE-1 retroelements in bats. Tetherin is an RF that targets diverse viruses including retroviruses, filoviruses, and paramyxoviruses. Bats were found to express multiple structurally unique forms of tetherin that include isoforms lacking protein features identified as important for the function of human tetherin. These novel forms of tetherin were functional, restricting the release of viral particles derived from multiple viruses including HIV, Ebola, and Hendra viruses. The revelation of a diverse range of endogenous betaretroviruses with the ability to transcribe active viral elements in a major animal reservoir for viral pathogens has potential implications for public health. The identification of RFs that have undergone genetic expansion and diversification in bats relative to other mammals supports the hypothesis of differential antiviral gene evolution in bats.