Immune System Modulation and Viral Persistence in Bats: Understanding Viral Spillover

Subudhi, Sonu; Rapin, Noreen; Misra, Vikram

doi:10.3390/v11020192

Cited by 128 publications

(158 citation statements)

References 68 publications

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“…There is mounting evidence to suggest that bats are major zoonotic reservoir hosts, as they can tolerate and survive viral infections (e.g. Ebola and MERs), potentially due to adaptations in their immune response 84 , consistent with our findings of selection in immune-related genes (e.g. INAVA ) and expansions of the viral-restricting APOBEC3 gene cluster.…”

Section: Introductionsupporting

confidence: 89%

Six new reference-quality bat genomes illuminate the molecular basis and evolution of bat adaptations

Jebb

Huang

Pippel

et al. 2019

Preprint

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42 43 ^Joint first authors 44 *joint senior/corresponding authors emails 45 Michael Hiller: hiller@mpi-cbg.de 46 Sonja Vernes: sonja.vernes@mpi.nl 47 Eugene Myers: gene@mpi-cbg.de 48 Emma C. Teeling: emma.teeling@ucd.ie 49 2 Abstract: Bats account for ~20% of all extant mammal species and are considered exceptional 50given their extraordinary adaptations, including biosonar, true flight, extreme longevity, and 51 unparalleled immune systems. To understand these adaptations, we generated reference-quality 52 genomes of six species representing the key divergent lineages. We assembled these genomes 53 with a novel pipeline incorporating state-of-the-art long-read and long-range sequencing and 54 assembly techniques. The genomes were annotated using a maximal evidence approach, de 55 novo predictions, protein/mRNA alignments, Iso-seq long read and RNA-seq short read 56 transcripts, and gene projections from our new TOGA pipeline, retrieving virtually all (>99%) 57 mammalian BUSCO genes. Phylogenetic analyses of 12,931 protein coding-genes and 10,857 58 conserved non-coding elements identified across 48 mammalian genomes helped to resolve 59 bats' closest extant relatives within Laurasiatheria, supporting a basal position for bats within 60 Scrotifera. Genome-wide screens along the bat ancestral branch revealed (a) selection on 61 hearing-involved genes (e.g LRP2, SERPINB6, TJP2), which suggest that laryngeal 62 echolocation is a shared ancestral trait of bats; (b) selection (e.g INAVA, CXCL13, NPSR1) and 63 loss of immunity related proteins (e.g. LRRC70, IL36G), including pro-inflammatory NF-kB 64 signalling; and (c) expansion of the APOBEC family, associated with restricting viral infection, 65 transposon activity and interferon signalling. We also identified unique integrated viruses, 66 indicating that bats have a history of tolerating viral pathogens, lethal to other mammal species. 67Non-coding RNA analyses identified variant and novel microRNAs, revealing regulatory 68 relationships that may contribute to phenotypic diversity in bats. Together, our reference-69 quality genomes, high-quality annotations, genome-wide screens and in-vitro tests revealed 70 previously unknown genomic adaptations in bats that may explain their extraordinary traits. 71 72

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Section: Introductionsupporting

confidence: 89%

Six new reference-quality bat genomes illuminate the molecular basis and evolution of bat adaptations

Jebb

Huang

Pippel

et al. 2019

Preprint

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mentioning

confidence: 83%

“…The authors observed that persistent infection is disrupted by immunologically stressful events, such as a secondary fungal infection with the white-nose syndrome causing fungus, Pseudogymnoascus destructans leading to an increase in virus replication 26 . Persistence of viruses in bats and increase in virus shedding during 'stressful' events has also been observed with Henipavirus infections 27,28 .Members of the coronavirus family possess high levels of genetic variability, especially in coding sequences for their accessory proteins, but not in the conserved viral polymerase 18 . Accessory proteins are dispensable for virus replication but provide vital functions within the context of infection in a particular host.…”

mentioning

confidence: 95%

Selection of viral variants during persistent infection of insectivorous bat cells with Middle East respiratory syndrome coronavirus

Banerjee

Subudhi

Rapin

et al. 2020

Sci Rep

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coronaviruses that cause severe acute respiratory syndrome (SARS) and Middle east respiratory syndrome (MeRS) are speculated to have originated in bats. the mechanisms by which these viruses are maintained in individuals or populations of reservoir bats remain an enigma. Mathematical models have predicted long-term persistent infection with low levels of periodic shedding as a likely route for virus maintenance and spillover from bats. In this study, we tested the hypothesis that bat cells and MERS coronavirus (coV) can co-exist in vitro. To test our hypothesis, we established a long-term coronavirus infection model of bat cells that are persistently infected with MeRS-coV. We infected cells from Eptesicus fuscus with MERS-CoV and maintained them in culture for at least 126 days. We characterized the persistently infected cells by detecting virus particles, protein and transcripts. Basal levels of type I interferon in the long-term infected bat cells were higher, relative to uninfected cells, and disrupting the interferon response in persistently infected bat cells increased virus replication. By sequencing the whole genome of MERS-CoV from persistently infected bat cells, we identified that bat cells repeatedly selected for viral variants that contained mutations in the viral open reading frame 5 (ORF5) protein. Furthermore, bat cells that were persistently infected with ΔORF5 MERS-CoV were resistant to superinfection by wildtype virus, likely due to reduced levels of the virus receptor, dipeptidyl peptidase 4 (DPP4) and higher basal levels of interferon in these cells. In summary, our study provides evidence for a model of coronavirus persistence in bats, along with the establishment of a unique persistently infected cell culture model to study MeRS-coV-bat interactions.On rare occasions, viruses spill over from reservoir species to other animals, including humans 1 . Establishment of infection in the new host requires viruses to adapt to the efficient use of entry receptors and circumvent innate antiviral defense mechanisms that are unique to each host species 2 . The elaborate mechanisms underlying such changes that govern new virus-host dynamics are not well known. Bats are speculated to be reservoirs of several emerging viruses, including coronaviruses (CoVs) that cause severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) in humans, and porcine epidemic diarrhea (PED) and swine acute diarrhoea syndrome (SADS) in pigs 3-6 . Although bats harbor SARS-and MERS-like coronaviruses, overt signs of disease in bats that are naturally or experimentally infected are often undetectable 7 . In contrast, infections in spillover species, such as humans and pigs lead to diseases with high morbidity and mortality 7-13 .MERS-CoV is an on-going concern as it causes periodic outbreaks in the Middle East with a mortality rate of about thirty-five percent 14,15 . Human-to-human transmission of the virus occurs through aerosol or close contact. Camels are the known reservoirs of MERS-CoV 16,17 and...

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“…As more insights are gained into the immune systems of these mammals, especially bats, a very disturbing picture emerges. Bats, many researchers postulate, may be an ideal reservoir for these viruses 12,13,14,15 . There is a possibility that they allow these viruses to persist in their bodies for a long time, therefore giving them ample opportunity to learn from and adapt themselves to the innate immune defence mechanisms of mammals 13 .…”

Section: A Quick Review Of the Innate Immune Systemmentioning

confidence: 99%

Covid-19: Immunological Lessons from Bats, Pangolins and Old Coronaviruses; And How We Can Apply Them in a Timely Way for a Better Outcome

Dua¹,

Yadav²,

Jetley³

et al. 2020

Preprint

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Introduction: The COVID-19 pandemic is a global crisis, the number of cases and deaths are on a steep incline. This article reviews the possible immunological mechanisms which underlie the disease pathogenesis by looking at the behaviour of previous coronaviruses not only in humans but also other mammals which possibly act as reservoir hosts. Observations: A key aspect of this coronavirus as well as the previous SARS CoV seems to be the importance of host immune response in the pathology and clinical severity of illness caused by them. A hyperactive innate immune state in combination with an exhausted adaptive immune response are possible determinants of severe illness. Conclusion: There is a possibility that the current SARS CoV 2 has immune evasive tactics similar to SARS CoV in its repertoire, since they share a 76% homology. These might have been learnt behaviour from long periods of persistence in their reservoir hosts and they may be the reason behind the dysregulated immune response evoked in humans. That in turn is highly likely to be one of the factors which govern disease severity. With this in mind we want to bring the medical community’s attention to a ‘hit early, hit hard’ intervention as a possible strategy to modify the course of the disease and bring down the numbers of severe sufferers.

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Immune System Modulation and Viral Persistence in Bats: Understanding Viral Spillover

Cited by 128 publications

References 68 publications

Six new reference-quality bat genomes illuminate the molecular basis and evolution of bat adaptations

Six new reference-quality bat genomes illuminate the molecular basis and evolution of bat adaptations

Selection of viral variants during persistent infection of insectivorous bat cells with Middle East respiratory syndrome coronavirus

Covid-19: Immunological Lessons from Bats, Pangolins and Old Coronaviruses; And How We Can Apply Them in a Timely Way for a Better Outcome

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