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Globally we have witnessed the increasing emergence of deadly viruses transmitting from animals to humans including the current SARS-CoV-2 pandemic. Accordingly, the need to take a proactive response to better understand emerging viruses and their animal hosts has never been so great.
Bats are an important reservoir of various viruses, including new and emerging viruses such as Ebola and SARS-associated coronaviruses, which are deadly to humans and other mammals but do not cause visible signs of illness in bats. Investigating the unique features of the immune system of bats will shed light on how they tolerate viral infections, potentially informing novel antiviral strategies in humans and other animals.
The broad aims of this project are to further our understanding of the innate immune system of bats, and the characterisation of novel, emerging viruses.
Keep reading to learn more about the following four (4) studies:
L-R: The Australian Black flying fox; Ebola virus; Budding retroviral particles
Aim: Investigate the antiviral activity and mechanism of action of diverse antiviral APOBEC3 proteins from the Black flying fox, an Australian fruit bat, against a retrovirus currently circulating in populations of the black flying fox.
Background: Restriction factors are antiviral proteins at the vanguard of the innate immune response that directly target virus replication to mitigate infections. APOBEC3 proteins are a family of restriction factors which have greatly expanded and diversified in fruit bats, relative to other mammals (Hayward et al., 2018, Mol. Biol. Evo. 35(7)). APOBEC3 proteins function through multiple mechanisms and are well characterized in humans, primarily for their activity against HIV-1. APOBEC3 proteins target a range of viruses, including retroviruses, hepadnaviruses, and parvoviruses. Fruit bat APOBEC3 proteins, including a sub-type not present in other mammals, are functionally capable of restricting HIV-1 in a model system in vitro. However, the activity of fruit bat APOBEC3 proteins against bat viruses and the details of their potentially various and novel mechanisms of action remain unknown.
This study will aim to characterise the activity and function of fruit bat APOBEC3 proteins in vitro, against a the first, recently discovered infectious bat retrovirus, the Hervey pteropid gammaretrovirus (Hayward et al., 2020, PNAS 117(17)). Furthermore, with the recent release of numerous new and diverse bat genomes, there is also scope to uncover and explore the expansion, diversification, and function of APOBEC3 genes in other important bat families.
The APOBEC3 gene loci of several representative mammals. Pteropid bats have the largest, most diverse repertoire of APOBEC3 genes of any mammal reported to date, but little is known about the activity and mechanisms of novel bat APOBEC3 proteins. APOBEC3 genes are colour coded by sub-type: Green, A3Z1; Orange, A3Z2A; Pink, A3Z2B; Blue, A3Z3. Adapted from Hayward et al., 2018, Mol. Biol. Evo. 35(7).
Aim: Investigate the host range and receptor usage of HPG, a newly discovered bat virus.
Background: HPG was recently identified as the first infectious retrovirus to be discovered in any bat. HPG was identified in the Australian black flying fox, and serological evidence of HPG infection was found in numerous individual bats representing multiple fruit bat species across several locations in north-east Australia. Close viral relatives of HPG, such as the koala retrovirus (KoRV) and the gibbon-ape leukemia virus (GALV) infect highly divergent animals in non-overlapping biogeographical regions. Determining if HPG is able to productively replicate in cell lines derived from different animals defining the receptor(s) required for virus attachment and entry is vital for developing an understanding of the potential threat that HPG poses to different species.
This study will involve experimental infection of primary cells and cell lines from different species. Data mining of unreported HPG-related viral sequences present in publicly accessible sequence read archives and genome assemblies will be used to determine the infectious potential of HPG and related viruses. Reverse genetics will be employed to generate infectious molecular clones of HPG and related viruses. Envelope genes from HPG related viruses will be evaluated for their ability to initiate viral entry using retroviral vectors pseudotyped with these envelope proteins. The usage of the mammalian PiT-1 cell receptor will be confirmed and the potential use of the PiT-2 receptor will be investigated.
Left: The evolutionary family tree of HPG and HPG-related viruses. Closely related gammaretroviruses are capable of infecting diverse and distantly related mammalian hosts. It is highly likely that many members of the HPG-related virus family remain to be discovered and many other species are likely to be susceptible to infection. Silhouettes represent the host species: top left, mice; right (in descending order), pteropid bats, koalas, woolly monkeys, microbats, and gibbons.
Right: An electron micrograph of mature HPG viral particles produced in human cells. Understanding the molecular mechanisms of cellular entry are critical for effectively combating viral infections. Adapted from Hayward et al., 2020, PNAS 117(17).
Aims: Determine the functional activity of diverse fruit bat restriction factors against the fruit bat retrovirus, HPG, and other mammalian retroviruses.
Background: Bats are infamous reservoirs of zoonotic viruses and retroviruses, which include HIV. Retroviruses are one of the most significant virus families to have jumped from animals into humans. However, whether bat retroviruses pose a threat to humans remains unknown. Understanding the immunological interface between viruses and their hosts will enable proactive responses in the event of viral spillover. Homologues of most human restriction factors have been discovered in fruit bats (Hayward, 2016, Doctoral thesis). The best understood antiviral restriction factors are those with reported activity against retroviruses. We have reported that two key antiretroviral restriction factors, APOBEC3 and tetherin, have expanded and diversified in bats, supporting the hypotheses that (i) bats have an important and ongoing relationship with mammalian retroviruses, and (ii) that bat antiviral proteins have undergone differential evolution relative to other mammals (Hayward et al., 2022, J Virol, epub; Hayward et al., 2018, Mol. Biol. Evo. 35(7)).
Other fruit bat restriction factors, e.g., TRIM, Mx1-2, and OAS, have been observed to possess interesting features not seen in other mammals, but their antiviral functions have not been reported, or remain to be explored in depth. Furthermore, with the recent release of numerous new and diverse bat genomes and transcriptomes, there is also scope to uncover and explore the expansion, diversification, and function of restriction factors in other important bat families. Exploring the functional activity of bat restriction factors against bat and other mammalian retroviruses and advancing our understanding of the evolutionary diversification of bat restriction factors will provide key insights that will arm us against future potential zoonotic viral spillover events.
The fruit bat restriction factor, tetherin, is functionally capable of inhibiting the release of retroviral HIV (left) and filoviral Ebola (right) virus-like particles from cells, demonstrating the ability of tetherin to inhibit viral infectivity. Different forms of tetherin have differential activity against different viruses, suggesting that tetherin has broad activity against enveloped viruses. Adapted from Hayward et al., 2022, J Virol, ePub.
Aim: Characterize and determine the potential antiviral activity of the marsupial protein, APOBEC5.
Background: Koalas in Australia are in the middle of an epidemic of the Koala retrovirus, which is a close relative of the bat retrovirus, HPG. APOBEC3 proteins are an important part of the anti-retroviral immune response in non-marsupial mammals. Marsupials do not possess APOBEC3 proteins, but analyses of their genomes suggest that they have a similar antiviral protein that is exclusive to marsupials, APOBEC5. Determining whether APOBEC5 has anti-retroviral activity homologous to APOBEC3 proteins against HPG, the Koala retrovirus, and other mammalian retroviruses, will be a significant advancement in our understanding of the antiviral defences of the Australian koala and other marsupials.
The potential antiviral activity of the marsupial protein APOBEC5 in Australian koala and other marsupials will be determined through a combination of laboratory-based experimental analysis of APOBEC5 function and computational paleovirological analysis of ancient retroviral infections.
Left: Koalas are under major threat from the koala retrovirus.
Right: Paleovirological methods, such as hypermutation analysis of genetic remnants of retroviruses present in mammalian genomes, can reveal the activity of APOBEC-family proteins against ancient retroviral infections. Adapted from Hayward et al., 2018, Mol. Biol. Evo. 35(7).
For any general enquiries relating to this project, please contact:
Senior Research Officer
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VIC, 3004, Australia
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