Broad and Temperature Independent Replication Potential of Filoviruses on Cells Derived From Old and New World Bat Species

Miller, Megan R.; McMinn, Rebekah J; Misra, Vikram; Schountz, Tony; Müller, Marcel A.; Kurth, Andreas; Munster, Vincent J.

doi:10.1093/infdis/jiw199

Cited by 29 publications

(23 citation statements)

References 29 publications

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“…However, sampling bone marrow from M. myotis requires sacrificing a wild animal and therefore this study was limited to one individual euthanized due to an opportunistic event. This is typical of studies employing cell lines derived from wild bat species (Kuhl et al, 2011 ;Miller et al, 2016). Myotis myotis macrophages, of size and shape indistinguishable compared to their murine analogues, were successfully differentiated in medium containing mouse M-CSF, and were responsive to widely used TLR ligands, LPS and Poly(I:C) (Fig.…”

Section: Discussionmentioning

confidence: 80%

A Potent Anti-Inflammatory Response in Bat Macrophages May Be Linked to Extended Longevity and Viral Tolerance

Kacprzyk

Hughes

Pålsson-McDermott

et al. 2017

Acta Chiropterologica

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Bats are unique among mammals given their ability to fly, apparent tolerance of deadly viruses and extraordinary longevity. We propose that these traits are linked and driven by adaptations of the innate immune system. To explore this hypothesis we challenged macrophages from the greater mouse-eared bat, Myotis myotis and the house mouse, Mus musculus with Toll Like Receptors (TLRs) ligands, lipopolysaccharides, LPS and polyinosinic-polycytidylic acid, Poly(I:C). Macrophages from both species presented a high level of mRNA induction of inferon β (INF-β), tumor necrosis factor (TNF) and interleukin-1β (Il-1β). However, in bat macrophages, this antiviral, proinflammatory response was balanced by a sustained high-level transcription of the anti-inflammatory cytokine Il-10, which was not observed in mouse, potentially resulting from adaptive regulation in bats.Additionally, phylogenomic selection tests across the basal divergences in mammals (n = 39) uncovered bat-specific adaptations in six genes involved in antiviral and proinflammatory signalling. Based on this pilot study, we put forward a hypothesis that bats may have evolved unique anti-inflammatory responses to neutralize proinflammatory stimuli resulting from flight. This in turn may drive their extraordinary longevity and viral tolerance by limiting inflammation driven ageing and infection-induced immunopathology. Further data from other individuals and bat species are required to advance this intriguing hypothesis.

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Section: Discussionmentioning

confidence: 80%

A Potent Anti-Inflammatory Response in Bat Macrophages May Be Linked to Extended Longevity and Viral Tolerance

Kacprzyk

Hughes

Pålsson-McDermott

et al. 2017

Acta Chiropterologica

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“…These hypotheses still largely lack functional confirmation, particularly with RNA virus infection. A recent study demonstrated a temperature-independent replication of Filoviruses on bat cells, as opposed to the 'flight as fever' hypothesis 57 . We demonstrate here a dampened NLRP3mediated inflammatory response to three different types of RNA virus in bat immune cells, with no or minimal difference in viral titres.…”

Section: Discussionmentioning

confidence: 95%

Dampened NLRP3-mediated inflammation in bats and implications for a special viral reservoir host

et al. 2019

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ResultsActivation of NLRP3 inflammasome is dampened in bat primary immune cells. Following priming (signal 1) and activation (signal 2), NLRP3 triggers assembly of the diffuse cytosolic apoptosis-associated speck-like protein containing a CARD (ASC) protein to form ASC specks 40 . These then recruit and activate caspase-1 to promote inflammatory cell death via pyroptosis and cleavage/secretion of the potent pro-inflammatory cytokine interleukin-1β (IL-1β) ( Fig. 1a).Bats are special in their ability to host emerging viruses. As the only flying mammal, bats endure high metabolic rates yet exhibit elongated lifespans. It is currently unclear whether these unique features are interlinked. The important inflammasome sensor, NLR family pyrin domain containing 3 (NLRP3), has been linked to both viral-induced and age-related inflammation. Here, we report significantly dampened activation of the NLRP3 inflammasome in bat primary immune cells compared to human or mouse counterparts. Lower induction of apoptosis-associated speck-like protein containing a CARD (ASC) speck formation and secretion of interleukin-1β in response to both 'sterile' stimuli and infection with multiple zoonotic viruses including influenza A virus (−single-stranded (ss) RNA), Melaka virus (PRV3M, double-stranded RNA) andMiddle East respiratory syndrome coronavirus (+ssRNA) was observed. Importantly, this reduction of inflammation had no impact on the overall viral loads. We identified dampened transcriptional priming, a novel splice variant and an altered leucine-rich repeat domain of bat NLRP3 as the cause. Our results elucidate an important mechanism through which bats dampen inflammation with implications for longevity and unique viral reservoir status.

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“…Thus, Nunes-Correia et al (1999) reported that the binding affinity of AIV H1N1 to canine kidney cells increased by over 10-fold from 4°C to 37°C. In the case of filovirus infectivity, Miller et al (2016) demonstrated that at 72 h, titres of Ebola virus Makona and Marburg virus Angola were 1000-fold and 100-fold higher, respectively, at 41°C than at 37°C in Rousettus aegyptiacus cell lines (although they were both similar at the 96 h end point). This is not consistent with a negative ΔH a_receptor for GP binding to Cr and indeed suggests a positive ΔH a_receptor as in entropy-driven binding (Fig.…”

Section: To Identify Mechanisms By Which the Effect Of Temperature Onmentioning

confidence: 99%

Towards a thermodynamic mechanistic model for the effect of temperature on arthropod vector competence for transmission of arboviruses

Gale¹

2019

Microbial Risk Analysis

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A B S T R A C TArboviruses such as West Nile virus (WNV), bluetongue virus (BTV), dengue virus (DENV) and chikungunya virus (CHIKV) infect their arthropod vectors over a range of average temperatures depending on the ambient temperature. How the transmission efficiency of an arbovirus (i.e. vector competence) varies with temperature influences not only the short term risk of arbovirus outbreaks in humans and livestock but also the long term impact of climate change on the geographical range of the virus. The strength of the interaction between viral surface (glyco)protein (GP) and the host cell receptor (Cr) on binding of virus to host cell is defined by the thermodynamic dissociation constant K d_receptor which is assumed to equal 10 −3 M (at 37°C) for binding of a sialic acid (SA) on the arthropod midgut epithelial cell surface to a SA-binding site on the surface of BTV, for example. Here virus binding affinity is modelled with increasing number of GP/Cr contacts at temperatures from 10°C to 35°C taking into account the change in entropy on immobilization of the whole virus on binding (ΔS a_immob ). Based on published data, three thermodynamic GP/Cr binding scenarios, namely enthalpy-driven, entropy-assisted and entropy-driven, are shown to affect the temperature sensitivity of virus binding in different ways. Thus for enthalpy-driven GP/Cr binding, viruses bind host cells much more strongly at 10°C than 35°C. A mechanistic model is developed for the number of arthropod midgut cells with bound virus and by building in a kinetic component for the rate of arbovirus replication and subsequent spread to the arthropod salivary glands, a model for the effect of temperature on vector competence is developed. The model separates the opposing effects of temperature on midgut cell binding affinity from the kinetic component of virogenesis. It successfully accommodates both increases in vector competence with temperature as for DENV and WNV in mosquitoes and decreases as for the CHIKV 2010-1909 strain in various populations of Aedes albopictus mosquitoes. Enhanced cell binding at lower temperatures through enthalpy-driven GP/Cr binding compensates for the lower replication rate to some degree such that some transmission can still occur at lower temperatures. In contrast, the strength of entropy-driven GP/Cr binding diminishes at low temperatures although there is no minimum temperature threshold for transmission efficiency. The magnitude of ΔS a_immob is an important data gap. It is concluded that thermodynamic and kinetic data obtained at the molecular level will prove important in modelling vector competence with temperature.Abbreviations: AIV, avian influenza virus; BBF, brush border fragments from midgut; C free , number of midgut epithelial cells which can bind virus with no virus bound; CHIKV, chikungunya virus; Cr, host cell receptor; C total_midgut , number of midgut epithelial cells which can bind virus; C.V T , number of arthropod midgut cells with bound arbovirus at temperature T; DENV, dengue fever virus; E A ...

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Broad and Temperature Independent Replication Potential of Filoviruses on Cells Derived From Old and New World Bat Species

Cited by 29 publications

References 29 publications

A Potent Anti-Inflammatory Response in Bat Macrophages May Be Linked to Extended Longevity and Viral Tolerance

A Potent Anti-Inflammatory Response in Bat Macrophages May Be Linked to Extended Longevity and Viral Tolerance

Dampened NLRP3-mediated inflammation in bats and implications for a special viral reservoir host

Towards a thermodynamic mechanistic model for the effect of temperature on arthropod vector competence for transmission of arboviruses

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