The IFN Response in Bats Displays Distinctive IFN-Stimulated Gene Expression Kinetics with Atypical RNASEL Induction

Cruz-Rivera, Pamela C. De La; Kanchwala, Mohammed; Liang, Hanquan; Kumar, Ashwani; Wang, Lin‐Fa; Xing, Chao; Schoggins, John W.

doi:10.4049/jimmunol.1701214

Cited by 73 publications

(82 citation statements)

References 52 publications

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“…ISG transcript expression kinetics have been studied in P. alecto cells. There is a universal rapid induction and subsequent rapid decline in the levels of all ISG transcripts that were studied in type I IFNα treated P. alecto cells (73), which may correlate with quicker control of virus replication and reduced cellular toxicity. In contrast, ISG transcript levels in IFN-treated human cells remained elevated for longer times (73).…”

Section: Interferon Signalingmentioning

confidence: 97%

“…There is a universal rapid induction and subsequent rapid decline in the levels of all ISG transcripts that were studied in type I IFNα treated P. alecto cells (73), which may correlate with quicker control of virus replication and reduced cellular toxicity. In contrast, ISG transcript levels in IFN-treated human cells remained elevated for longer times (73). Transcripts for ISGs in unstimulated bat cells were also higher than in human cells, further corroborating the observation of high levels of basal IFNα in this bat species (15).…”

Section: Interferon Signalingmentioning

confidence: 97%

“…However, these observations have largely been made in primary and immortalized cell lines and the physiological relevance of these responses in in vivo bat model systems remains to be tested. Several unique ISGs and atypical induction of ISGs have been observed in bat cells (73). In human cells, expression of individual ISGs can inhibit virus replication, such as ISG20 that displays remarkable anti-bunyavirus activity (76).…”

Section: Interferon Signalingmentioning

confidence: 99%

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Novel Insights Into Immune Systems of Bats

et al. 2020

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In recent years, viruses similar to those that cause serious disease in humans and other mammals have been detected in apparently healthy bats. These include filoviruses, paramyxoviruses, and coronaviruses that cause severe diseases such as Ebola virus disease, Marburg haemorrhagic fever and severe acute respiratory syndrome (SARS) in humans. The evolution of flight in bats seem to have selected for a unique set of antiviral immune responses that control virus propagation, while limiting self-damaging inflammatory responses. Here, we summarize our current understanding of antiviral immune responses in bats and discuss their ability to co-exist with emerging viruses that cause serious disease in other mammals. We highlight how this knowledge may help us to predict viral spillovers into new hosts and discuss future directions for the field.

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Section: Interferon Signalingmentioning

confidence: 97%

Section: Interferon Signalingmentioning

confidence: 97%

Section: Interferon Signalingmentioning

confidence: 99%

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Novel Insights Into Immune Systems of Bats

et al. 2020

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“…Bats are assumed to host most zoonotic viruses asymptomatically (68). Specific immunological features may allow them to tolerate or enhance the antiviral response to efficiently control viral infection and/or pathogenesis (69)(70)(71)(72)(73), including orthohepadnavirus infections.…”

Section: Orthohepadnavirus-receptor Evolutionary Arms Racementioning

confidence: 99%

Evolution of Hepatitis B Virus Receptor NTCP Reveals Differential Pathogenicities and Species Specificities of Hepadnaviruses in Primates, Rodents, and Bats

Jacquet

Pons

Bernardo

et al. 2019

J Virol

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Human hepatitis B virus (HBV) is a global health problem, affecting more than 250 million people worldwide. HBV-like viruses, named orthohepadnaviruses, also naturally infect nonhuman primates, rodents, and bats, but their pathogenicity and evolutionary history are unclear. Here, we determined the evolutionary history of the HBV receptors NTCP and GPC5 over millions of years of primate, rodent, and bat evolution. We use this as a proxy to understand the pathogenicity of orthohepadnaviruses in mammalian hosts and to determine the implications for species specificity. We found that NTCP, but not GPC5, has evolved under positive selection in primates (27 species), rodents (18 species), and bats (21 species) although at distinct residues. Notably, the positively selected codons map to the HBV-binding sites in primate NTCP, suggesting past genetic "arms races" with pathogenic orthohepadnaviruses. In rodents, the positively selected codons fall outside and within the presumed HBV-binding sites, which may contribute to the restricted circulation of rodent orthohepadnaviruses. In contrast, the presumed HBV-binding motifs in bat NTCP are conserved, and none of the positively selected codons map to this region. This suggests that orthohepadnaviruses may bind to different surfaces in bat NTCP. Alternatively, the patterns may reflect adaptive changes associated with metabolism rather than pathogens. Overall, our findings further point to NTCP as a naturally occurring genetic barrier for cross-species transmissions in primates, which may contribute to the narrow host range of HBV. In contrast, this constraint seems less important in bats, which may correspond to greater orthohepadnavirus circulation and diversity. IMPORTANCE Chronic infection with hepatitis B virus (HBV) is a major cause of liver disease and cancer in humans. Mammalian HBV-like viruses are also found in nonhuman primates, rodents, and bats. As for most viruses, HBV requires a successful interaction with a host receptor for replication. Cellular receptors are thus key determinants of host susceptibility as well as specificity. One hallmark of pathogenic virus-host relationships is the reciprocal evolution of host receptor and viral envelope proteins, as a result of their antagonistic interaction over time. The dynamics of these so-called "evolutionary arms races" can leave signatures of adaptive selection, which in turn reveal the evolutionary history of the virus-host interaction as well as viral pathogenicity and the genetic determinants of species specificity. Here, we show how HBV-like viruses have shaped the evolutionary history of their mammalian host receptor, as a result of their ancient pathogenicity, and decipher the genetic determinants of cross-species transmissions.W ith approximately 257 million cases of chronic infections, human hepatitis B virus (HBV) infection is one of the most common viral infections and the leading cause of liver diseases worldwide. HBV is a member of the family Hepadnaviridae, which are ancient pathogens that naturally inf...

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“…While these important studies have begun to untangle the complexity of signaling mechanisms within the interferon response, and even led to the discovery of specific ISG subsets with antiviral activity, we are only starting to grasp that the interferon response also has a temporal gene expression component. Using novel transcriptional profiling techniques, several recent studies reveal that genes downstream of interferon signaling can be classified into qualitatively distinct modules with different temporal expression dynamics post-interferon (12–14). Such differences cannot be explained by the action of ISGF3 alone, suggesting non-canonical mechanisms at work (Fig.…”

Section: Introductionmentioning

confidence: 99%

The regulatory factor ELF1 triggers a critical wave of transcription in the antiviral response to type I interferon

Seifert

Ballentine

et al. 2019

Preprint

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31 32 Keywords: ETS transcription factor, interferon, RNA virus, DNA virus, innate immunity 33 34 35 Seifert and Si et al., page 3 36 ABSTRACT 37The transcription of interferon-stimulated genes (ISGs) is classically triggered via 38 activation of the JAK-STAT pathway, and together, ISGs raise a multifaceted antiviral 39 barrier. An increasing body of evidence reports the existence of additional, non-canonical 40 pathways and transcription factors that coordinate ISG expression. Detailed knowledge 41 of how heterogenous mechanisms regulate ISG expression is crucial for the rational 42 design of drugs targeting the type I interferon response. Here, we characterize the first 43 ETS transcription factor family member as a regulator of non-canonical ISG expression:44 E74-like ETS transcription factor 1 (ELF1). Using high-content microscopy to quantify viral 45 infection over time, we found that ELF1, itself an ISG, inhibits eight diverse RNA and DNA 46 viruses uniquely at multi-cycle replication. ELF1 did not regulate expression of type I or II 47 interferons, and ELF1's antiviral effect was not abolished by the absence of STAT1 or by 48 inhibition of JAK phosphorylation. Accordingly, comparative expression analyses by 49 RNAseq revealed that the ELF1 transcriptional program is distinct from, and delayed with 50 respect to, the immediate interferon response. Finally, knockdown experiments 51 demonstrated that ELF1 is a critical component of the antiviral interferon response in vitro 52 and in vivo. Our findings reveal a previously overlooked mechanism of non-canonical ISG 53 regulation that both amplifies and prolongs the initial interferon response by expressing 54 broadly antiviral restriction factors. 55 Seifert and Si et al., page 456 AUTHOR SUMMARY 57 Over 60 years after their discovery, we still struggle to understand exactly how interferons 58 inhibit viruses. Our gap in knowledge stems, on one hand, from the sheer number of 59 interferon-stimulated effector genes, of which only few have been characterized in 60 mechanistic detail. On the other hand, our knowledge of interferon-regulated gene 61 transcription is constantly evolving. We know that different regulatory mechanisms greatly 62 influence the quality, magnitude, and timing of interferon-stimulated gene expression, all 63 of which may contribute to the antiviral mechanism of interferons. Deciphering these 64 regulatory mechanisms is indispensable for understanding this critical first line of host 65 defense, and for harnessing the power of interferons in novel antiviral therapies. Here, 66 we report a novel mechanism of interferon-induced gene regulation by an interferon-67 stimulated gene, which, paradoxically, inhibits viruses in the absence of additional 68 interferon signaling: E74-like ETS transcription factor 1 (ELF1) raises an unusually 69 delayed antiviral program that potently restricts propagation of all viruses tested in our 70 study. Reduced levels of ELF1 significantly diminished interferon-mediated host defenses 71 against influenza A viru...

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The IFN Response in Bats Displays Distinctive IFN-Stimulated Gene Expression Kinetics with Atypical RNASEL Induction

Cited by 73 publications

References 52 publications

Novel Insights Into Immune Systems of Bats

Novel Insights Into Immune Systems of Bats

Evolution of Hepatitis B Virus Receptor NTCP Reveals Differential Pathogenicities and Species Specificities of Hepadnaviruses in Primates, Rodents, and Bats

The regulatory factor ELF1 triggers a critical wave of transcription in the antiviral response to type I interferon

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