Poxvirus Decapping Enzymes Enhance Virulence by Preventing the Accumulation of dsRNA and the Induction of Innate Antiviral Responses

Liu, Shin-Wu; Katsafanas, George C.; Liu, Ruikang; Wyatt, Linda S.; Moss, Bernard

doi:10.1016/j.chom.2015.02.002

Cited by 94 publications

(136 citation statements)

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“…The virally encoded decapping enzymes are usually expressed during early and late stages of viral infection to target host mRNAs such that host translation machinery is available almost exclusively for translation of viral RNAs (Liu et al, 2015). However, none of the MdSGHV genes had any significant homologies to known viral decapping enzymes.…”

Section: Discussionmentioning

confidence: 99%

Responses of the Housefly, Musca domestica, to the Hytrosavirus Replication: Impacts on Host's Vitellogenesis and Immunity

Kariithi

et al. 2017

Front. Microbiol.

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Hytrosaviridae family members replicate in the salivary glands (SGs) of their adult dipteran hosts and are transmitted to uninfected hosts via saliva during feeding. Despite inducing similar gross symptoms (SG hypertrophy; SGH), hytrosaviruses (SGHVs) have distinct pathobiologies, including sex-ratio distortions in tsetse flies and refusal of infected housefly females to copulate. Via unknown mechanism(s), SGHV replication in other tissues results in reduced fecundity in tsetse flies and total shutdown of vitellogenesis and sterility in housefly females. We hypothesized that vitellogenesis shutdown was caused by virus-induced modulation of hormonal titers. Here, we used RNA-Seq to investigate virus-induced modulation of host genes/pathways in healthy and virus-infected houseflies, and we validated expression of modulated genes (n = 23) by RT-qPCR. We also evaluated the levels and activities of hemolymph AMPs, levels of endogenous sesquiterpenoids, and impacts of exogenous hormones on ovarian development in viremic females. Of the 973 housefly unigenes that were significantly modulated (padj ≤ 0.01, log2FC ≤ −2.0 or ≥ 2.0), 446 and 527 genes were downregulated and upregulated, respectively. While the most downregulated genes were related to reproduction (embryogenesis/oogenesis), the repertoire of upregulated genes was overrepresented by genes related to non-self recognition, ubiquitin-protease system, cytoskeletal traffic, cellular proliferation, development and movement, and snRNA processing. Overall, the virus, Musca domestica salivary gland hytrosavirus (MdSGHV), induced the upregulation of various components of the siRNA, innate antimicrobial immune, and autophagy pathways. We show that MdSGHV undergo limited morphogenesis in the corpora allata/corpora cardiaca (CA/CC) complex of M. domestica. MdSGHV replication in CA/CC potentially explains the significant reduction of hemolymph sesquiterpenoids levels, the refusal to mate, and the complete shutdown of egg development in viremic females. Notably, hormonal rescue of vitellogenesis did not result in egg production. The mechanism underlying MdSGHV-induced sterility has yet to be resolved.

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Section: Discussionmentioning

confidence: 99%

Responses of the Housefly, Musca domestica, to the Hytrosavirus Replication: Impacts on Host's Vitellogenesis and Immunity

Kariithi

et al. 2017

Front. Microbiol.

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“…Of note, two very recent reports demonstrated that inhibiting the degradation of dsRNA by engineered mutations in VACV decapping genes and reducing expression of the exoribonuclease Xrn1 resulted in accumulation of dsRNA, activation of the PKR and OAS/RNase L pathways, and reduction of viral replication and virulence (47,48). Together with our results, these studies suggest that the rate of production and destruction of RNAs might be finely tuned to enable sufficient viral gene expression to support replication but not so much as to activate host antiviral dsRNA sensors.…”

Section: Discussionmentioning

confidence: 99%

Experimental Evolution Identifies Vaccinia Virus Mutations in A24R and A35R That Antagonize the Protein Kinase R Pathway and Accompany Collapse of an Extragenic Gene Amplification

Brennan

Kitzman

Shendure

et al. 2015

J Virol

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Most new human infectious diseases emerge from cross-species pathogen transmissions; however, it is not clear how viruses adapt to productively infect new hosts. Host restriction factors represent one species-specific barrier that viruses may initially have little ability to inhibit in new hosts. For example, viral antagonists of protein kinase R (PKR) vary in their ability to block PKR-mediated inhibition of viral replication, in part due to PKR allelic variation between species. We previously reported that amplification of a weak PKR antagonist encoded by rhesus cytomegalovirus, rhtrs1, improved replication of a recombinant poxvirus (VV⌬E⌬K؉RhTRS1) in several resistant primate cells. To test whether amplification increases the opportunity for mutations that improve virus replication with only a single copy of rhtrs1 to evolve, we passaged rhtrs1-amplified viruses in semipermissive primate cells. After passage, we isolated two viruses that contained only a single copy of rhtrs1 yet replicated as well as the amplified virus. Surprisingly, rhtrs1 was not mutated in these viruses; instead, we identified mutations in two vaccinia virus (VACV) genes, A24R and A35R, either of which was sufficient to improve VV⌬E⌬K؉RhTRS1 replication. Neither of these genes has previously been implicated in PKR antagonism. Furthermore, the mutation in A24R, but not A35R, increased resistance to the antipoxviral drug isatin-␤-thiosemicarbazone, suggesting that these mutations employ different mechanisms to evade PKR. This study supports our hypothesis that gene amplification may provide a "molecular foothold," broadly improving replication to facilitate rapid adaptation, while subsequent mutations maintain this efficient replication in the new host without requiring gene amplification. IMPORTANCEUnderstanding how viruses adapt to a new host may help identify viruses poised to cross species barriers before an outbreak occurs. Amplification of rhtrs1, a weak viral antagonist of the host antiviral protein PKR, enabled a recombinant vaccinia virus to replicate in resistant cells from humans and other primates. After serial passage of rhtrs1-amplified viruses, there arose in two vaccinia virus genes mutations that improved viral replication without requiring rhtrs1 amplification. Neither of these genes has previously been associated with inhibition of the PKR pathway. These data suggest that gene amplification can improve viral replication in a resistant host species and facilitate the emergence of novel adaptations that maintain the foothold needed for continued replication and spread in the new host. Of the approximately 1,400 known human pathogens, over 60% are zoonotic (1). Furthermore, during the last 80 years, more than 70% of all new and emerging human infectious diseases were acquired from animal sources (2). These emerging zoonoses are often responsible for severe disease in humans, such as HIV-1 infection/AIDS (3) and the recent Ebola pandemic in West Africa (4). Similarly, pathogen transmission between both wild and domes...

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“…Besides M156 and M029, ancillary MYXV factors may also control eIF2α phosphorylation. In addition to E3 and K3, VACV mRNA decapping enzymes (D9, D10) accelerate mRNA decay, thus limiting dsRNA accumulation, PKR activation, and contributing to virulence in vivo (13,14). Although MYXV encodes D9 and D10 orthologs (15), their contribution to regulating PKR and eIF2α phosphorylation remains unexplored.…”

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confidence: 99%

Evolutionary clash between myxoma virus and rabbit PKR in Australia

Burgess

Mohr

2016

Proc. Natl. Acad. Sci. U.S.A.

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The success of a virus in defeating or evading cellintrinsic immune responses contributes to its virulence, pathogenesis, and host range. A central tenet of virology holds that virus and host coevolve as each adapts to survive. Rarely, however, do we have the chance to observe this principal at play in the real world. The deliberate and repeated release of myxoma virus (MYXV) to control feral European rabbits introduced into Australia provides one such exceptional opportunity. Myxoma is a member of the poxvirus family, though unlike its more famous cousin variola, the agent of small pox, is unable to infect humans and is instead limited to infection of rabbits and hares. Following the release of a MYXV reference strain into the wild that exhibited 99.8% fatality rates in laboratory rabbits, attenuated strains were recovered from the field that had begun to outcompete the virulent parental strain. In addition, the resistance of rabbits to MYXV increased (1). The underlying molecular mechanism of both rabbit resistance and MYXV attenuation, however, remained elusive. Armed with the recently compiled genome sequence of 21 myxoma field isolates, a new study by Peng et al. in PNAS reveals that genetic alterations to the MYXV M156 protein correlate with both MYXV host specificity and changes in virulence observed in the field (2). Remarkably, more than 50% of MYXV field isolates produce an M156 variant that is no longer able to antagonize the rabbit double-stranded RNA (dsRNA)-activated protein kinase PKR, a critical component of IFN-stimulated defenses that controls protein synthesis. This not only provides the first mechanistic explanation for each of these facets of myxoma biology, but also elegantly illustrates the coevolution of host innate defense and viral virulence factors since the first release of MYXV in 1950.In response to virus infection, a key arm of antiviral host defenses acts to cripple the infected cell's capacity to produce the polypeptides required for virus replication and spread. This is achieved by globally inhibiting the initiation of mRNA translation and is triggered by accumulation of dsRNA, a pathogenassociated molecular pattern produced by many different viruses during their replication cycle. Upon sensing dsRNA, host PKR, which resides in uninfected cells as an inactive, unphosphorylated monomer, becomes activated as a phosphorylated dimer bound to dsRNA (Fig. 1). The ensuing site-specific phosphorylation of the eukaryotic translation initiation factor eIF2 α-subunit prevents methionine-initiator tRNA charging of 40S small ribosome subunits, inhibiting the initiation of protein synthesis and effectively preventing virus replication (3). The extraordinary efforts and diverse molecular tactics many different viruses rely upon to counteract PKR and preserve the activity of the critical initiation factor eIF2 underscore the significant role PKR plays in host defense.To safeguard eIF2 function and effectively contain PKR, viruses frequently enlist multiple molecular strategies. MYXV is no excep...

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Poxvirus Decapping Enzymes Enhance Virulence by Preventing the Accumulation of dsRNA and the Induction of Innate Antiviral Responses

Cited by 94 publications

References 58 publications

Responses of the Housefly, Musca domestica, to the Hytrosavirus Replication: Impacts on Host's Vitellogenesis and Immunity

Responses of the Housefly, Musca domestica, to the Hytrosavirus Replication: Impacts on Host's Vitellogenesis and Immunity

Experimental Evolution Identifies Vaccinia Virus Mutations in A24R and A35R That Antagonize the Protein Kinase R Pathway and Accompany Collapse of an Extragenic Gene Amplification

Evolutionary clash between myxoma virus and rabbit PKR in Australia

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