Dataset Information

Acute experimental infection of bats and ferrets with Hendra virus: insights into the early host response of the reservoir host and susceptible model species

ABSTRACT: Bats are the natural reservoir host for a number of zoonotic viruses, including Hendra virus (HeV) which causes severe clinical disease in humans and other susceptible hosts. Our understanding of the ability of bats to avoid clinical disease following infection with viruses such as HeV has come predominantly from in vitro studies focusing on innate immunity. Information on the early host response to infection in vivo is lacking and there is no comparative data on responses in bats compared with animals that succumb to disease. In this study, we examined the sites of HeV replication and the immune response of infected Australian black flying foxes and ferrets at 12, 36 and 60 hours post exposure (hpe). Viral antigen was detected at 60 hpe in bats and was confined to the lungs whereas in ferrets there was evidence of widespread viral RNA and antigen by 60 hpe. The mRNA expression of IFNs revealed antagonism of type I and III IFNs and a significant increase in the chemokine, CXCL10, in bat lung and spleen following infection. In ferrets, there was an increase in the transcription of IFN in the spleen following infection. Liquid chromatography tandem mass spectrometry (LC-MS/MS) on lung tissue from bats and ferrets was performed at 0 and 60 hpe to obtain a global overview of viral and host protein expression. Gene Ontology (GO) enrichment analysis of immune pathways revealed that six pathways, including a number involved in cell mediated immunity were more likely to be upregulated in bat lung compared to ferrets. GO analysis also revealed enrichment of the type I IFN signaling pathway in bats and ferrets. This study contributes important comparative data on differences in the dissemination of HeV and the first to provide comparative data on the activation of immune pathways in bats and ferrets in vivo following infection.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Pteropus Alecto (black Flying Fox) Mustela Putorius Furo (european Domestic Ferret) (mustela Furo)

TISSUE(S): Lung

SUBMITTER: Nathan Croft

LAB HEAD: Anthony Purcell

PROVIDER: PXD017495 | Pride | 2020-03-03

REPOSITORIES: Pride

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Publications

Acute experimental infection of bats and ferrets with Hendra virus: Insights into the early host response of the reservoir host and susceptible model species.

Woon Amanda P AP Boyd Victoria V Todd Shawn S Smith Ina I Klein Reuben R Woodhouse Isaac B IB Riddell Sarah S Crameri Gary G Bingham John J Wang Lin-Fa LF Purcell Anthony W AW Middleton Deborah D Baker Michelle L ML

PLoS pathogens 20200330 3

Bats are the natural reservoir host for a number of zoonotic viruses, including Hendra virus (HeV) which causes severe clinical disease in humans and other susceptible hosts. Our understanding of the ability of bats to avoid clinical disease following infection with viruses such as HeV has come predominantly from in vitro studies focusing on innate immunity. Information on the early host response to infection in vivo is lacking and there is no comparative data on responses in bats compared with ...[more]

PMID: 32226041

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Project description:Background: Coevolution between pathogens and their hosts decreases host morbidity and mortality. Bats can tolerate viruses which can be lethal to other vertebrate orders, including humans. Bat adaptations to infection include localized immune response, early pathogen sensing, high interferon expression without pathogen stimulation, and regulated inflammatory response. The immune reaction is costly, and bats suppress high-cost metabolism during torpor. In the temperate zone, bats hibernate in winter, utilizing a specific behavioural adaptation to survive detrimental environmental conditions and lack of energy resources. Hibernation torpor involves major physiological changes that pose an additional challenge to bat-pathogen coexistence. Here, we compared bat cellular reaction to viral challenge under conditions simulating hibernation, evaluating the changes between torpor and euthermia. Results: We infected the olfactory nerve-derived cell culture of Myotis myotis with an endemic bat pathogen, European bat lyssavirus 1 (EBLV-1). After infection, the bat cells were cultivated at two different temperatures – 37 ◦ C and 5 ◦ C - to examine the cell response during conditions simulating euthermia and torpor, respectively. The mRNA isolated from the cells was sequenced and analysed for differential gene expression attributable to the temperature and/or infection treatment. In conditions simulating euthermia, infected bat cells produce an excess signalling by multitude of pathways involved in apoptosis and immune regulation influencing proliferation of regulatory cell types which can, in synergy with other produced cytokines, contribute to viral tolerance. We found no up- or downregulated genes expressed in infected cells cultivated at conditions simulating torpor compared to non-infected cells cultivated under the same conditions. When studying the reaction of uninfected cells to the temperature treatment, bat cells show an increased production of heat shock proteins (HSPs) with chaperone activity, improving the bat’s ability to repair molecular structures damaged due to the stress related to the temperature change. Conclusions: The lack of bat cell reaction to infection in conditions simulating hibernation may contribute to the virus tolerance or persistence in bats. Together with the cell damage repair mechanisms induced in response to hibernation, the immune regulation may promote bats’ ability to act as reservoirs of zoonotic viruses such as lyssaviruses.

Project description:Bats are the most important natural reservoirs for a variety of emerging viruses that cause several illnesses in humans and other mammals. Increased viral shedding by bats is thought to be linked to an increased ability of many bat species to tolerate viral infection. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19, is thought to have originated in bats, since viruses with high sequence similarity have been detected in bat feces. However, there is no robust in vitro model for assessing the SARS-CoV-2 infection in the bat GI tract. Here, we established gastrointestinal organoid cultures from Jamaican fruit bats (JFB, Artibeus jamaicensis), which replicated the characteristic morphology of the gastrointestinal epithelium and showed tissue specific gene expression patterns and cell differentiation. To analyze whether JFB intestinal epithelial cells are susceptible to SARS-CoV-2, we performed in vitro infection experiments. Increased SARS-CoV-2 RNA was found in both cell lysates and supernatants from the infected organoids after 48 h, and sgRNA also was detected, indicating that the JFB intestinal epithelium supports limited viral replication. However, no infectious virus was released into the culture media, and no cytopathic effects were observed. Gene expression studies revealed a significant induction of type I interferon and inflammatory cytokine genes in response to active SARS-CoV-2 virus but not to TLR agonist treatment. Untargeted analysis of the organoid proteome using data-independent acquisition mass spectrometry (DIA-MS) revealed a significant increase in proteins and pathways associated with inflammatory signaling, cell turnover and repair, and SARS-CoV-2 infection. Collectively, our data suggest that primary intestinal epithelial cells from JFBs are largely resistant to SARS-CoV-2 infection and cell damage, likely because they are able to mount a strong antiviral interferon and regenerative response upon infection.

Dataset Information

Acute experimental infection of bats and ferrets with Hendra virus: insights into the early host response of the reservoir host and susceptible model species

Publications

Acute experimental infection of bats and ferrets with Hendra virus: Insights into the early host response of the reservoir host and susceptible model species.

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