A Reverse Genetics Approach for the Design of Methyltransferase-Defective Live Attenuated Avian Metapneumovirus Vaccines

Sun, Jing; Wei, Yongwei; Lǐ, Jiànróng

doi:10.1007/978-1-4939-3389-1_7

Cited by 9 publications

(4 citation statements)

References 29 publications

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“…In this study, we showed that the well-known MTase inhibitor sinefungin possesses inhibitory activity on GAV nsp16. Although it appears unlikely to produce efficient and cost-effective antiviral drugs against shrimp viruses, debilitation of GAV 2=-O-MTase may be used as a strategy to generate live attenuated ronivirus vaccines, like that used to produce coronavirus and flavivirus vaccines (9)(10)(11)(12).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, viral 2=-MTase represents a potential target for antiviral drug development. Generation of 2=-O-MTase-deficient viruses has been used as a strategy to develop effective live attenuated vaccines (9)(10)(11)(12). Chemical and polypeptide inhibitors targeting viral 2=-O-MTase have been shown to function as antivirals (13)(14)(15).…”

Section: Methylation Of the 5=-cap Structure Of Viral Rnas Plays Impomentioning

confidence: 99%

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Identification and Characterization of a Ribose 2′- O -Methyltransferase Encoded by the Ronivirus Branch of Nidovirales

Zeng

Wang

et al. 2016

J Virol

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The order Nidovirales currently comprises four virus families: Arteriviridae, Coronaviridae (divided into the subfamilies Coronavirinae and Torovirinae), Roniviridae, and the recently recognized Mesoniviridae. RNA cap formation and methylation have been best studied for coronaviruses, with emphasis on the identification and characterization of two virus-encoded methyltransferases (MTases) involved in RNA capping, a guanine-N7-MTase and a ribose-2=-O-MTase. Although bioinformatics analyses suggest that these MTases may also be encoded by other nidoviruses with large genomes, such as toroviruses and roniviruses, no experimental evidence has been reported thus far. In this study, we show that a ronivirus, gill-associated virus (GAV), encodes the 2=-O-MTase activity, although we could not detect 2=-O-MTase activity for the homologous protein of a torovirus, equine torovirus, which is more closely related to coronaviruses. Like the coronavirus 2=-O-MTase, the roniviral 2=-O-MTase harbors a catalytic K-D-K-E tetrad that is conserved among 2=-O-MTases and can target only the N7-methylated cap structure of adenylate-primed RNA substrates. However, in contrast with the coronavirus protein, roniviral 2=-O-MTase does not require a protein cofactor for stimulation of its activity and differs in its preference for several biochemical parameters, such as reaction temperature and pH. Furthermore, the ronivirus 2=-O-MTase can be targeted by MTase inhibitors. These results extend our current understanding of nidovirus RNA cap formation and methylation beyond the coronavirus family. IMPORTANCEMethylation of the 5=-cap structure of viral RNAs plays important roles in genome replication and evasion of innate recognition of viral RNAs by cellular sensors. It is known that coronavirus nsp14 acts as an N7-(guanine)-methyltransferase (MTase) and nsp16 as a 2=-O-MTase, which are involved in the modification of RNA cap structure. However, these enzymatic activities have not been shown for any other nidoviruses beyond coronaviruses in the order Nidovirales. In this study, we identified a 2=-Omethyltransferase encoded by ronivirus that shows common and unique features in comparison with that of coronaviruses. Ronivirus 2=-O-MTase does not need a protein cofactor for MTase activity, whereas coronavirus nsp16 needs the stimulating factor nsp10 for its full activity. The conserved K-D-K-E catalytic tetrad is identified in ronivirus 2=-O-MTase. These results extend our understanding of nidovirus RNA capping and methylation beyond coronaviruses and also strengthen the evolutionary and functional links between roniviruses and coronaviruses.

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Section: Discussionmentioning

confidence: 99%

Section: Methylation Of the 5=-cap Structure Of Viral Rnas Plays Impomentioning

confidence: 99%

Identification and Characterization of a Ribose 2′- O -Methyltransferase Encoded by the Ronivirus Branch of Nidovirales

Zeng

Wang

et al. 2016

J Virol

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“…Accordingly, new methyltransferasedefective live attenuated aMPV vaccines have been developed to reduce the viral return to virulence and stop the emergence of field strains that may disturb the vaccine immunity (Y. Zhang et al, 2016).…”

Section: Vaccinationmentioning

confidence: 99%

Avian Metapneumovirus Infection in Poultry Flocks: A Review of Current Knowledge

A. Abd El-Ghany

2023

JTAS

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Avian metapneumovirus (aMPV) is one of the respiratory viruses that cause global economic losses in poultry production systems. Therefore, it was important to design a comprehensive review article that gives more information about aMPV infection regarding the distribution, susceptibility, transmission, pathogenesis, pathology, diagnosis, and prevention. The aMPV infection is characterized by respiratory and reproductive disorders in turkeys and chickens. The disease condition is turkey rhinotracheitis in turkeys and swollen head syndrome in chickens. Infection with aMPV is associated with worldwide economic losses, especially in complications with other infections or poor environmental conditions. The genus Metapneumovirus is a single-stranded enveloped RNA virus and contains A, B, C, and D subtypes. Meat and egg-type birds are susceptible to aMPV infection. The virus can transmit through aerosol, direct contact, mechanical, and vertical routes. The disease condition is characterized by respiratory manifestations, a decrease in egg production, growth retardation, increasing morbidity rate, and sometimes nervous signs and a high mortality rate, particularly in concurrent infections. Definitive diagnosis of aMPV is based mainly on isolation and identification methods, detection of the viral DNA, as well as seroconversion. Prevention of aMPV infection depends on adopting biosecurity measures and vaccination using inactivated, live attenuated, and recombinant or DNA vaccines.

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“…Vero E6 cells. hMPV and hMPV-GFP were generated by a reverse genetics system based on the NL/1/00 strain, a prototypic A1 strain, utilizing a previously described system [34]. The hMPV 02-202 (B1) strain was kindly provided to us by Dr. John Williams (University of Pittsburgh).…”

Section: Cell Culture Transfections and Transductionsmentioning

confidence: 99%

Opposing roles of endosomal innate immunity proteins IFITM3 and TLR7 in human metapneumovirus infection

McMichael

Kenney

Zhang

et al. 2018

Preprint

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Human metapneumovirus (hMPV) utilizes a bifurcated cellular entry strategy, fusing either with the plasma membrane or, after endocytosis, with the endosome membrane. Whether cellular factors restrict or enhance either entry pathway is largely unknown. We found that the interferon-induced transmembrane protein 3 (IFITM3) inhibits hMPV infection to an extent similar to endocytosis-inhibiting drugs, and an IFITM3 variant that accumulates at the plasma membrane in addition to its endosome localization provided increased virus restriction. Mechanistically, IFITM3 blocks hMPV F protein-mediated membrane fusion, and inhibition of infection was reversed by the membrane destabilizing drug amphotericin B. Conversely, we unexpectedly found that infection by some hMPV strains is enhanced by Toll-like receptor 7 (TLR7), an endosomal protein, suggesting that cellular entry via endocytosis may be particularly advantageous for hMPV despite eventual restriction of this pathway upon induction of IFITM3. Overall, our results identify IFITM3 and TLR7 as endosomal factors differentially regulating hMPV infection.

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A Reverse Genetics Approach for the Design of Methyltransferase-Defective Live Attenuated Avian Metapneumovirus Vaccines

Cited by 9 publications

References 29 publications

Identification and Characterization of a Ribose 2′- O -Methyltransferase Encoded by the Ronivirus Branch of Nidovirales

Identification and Characterization of a Ribose 2′- O -Methyltransferase Encoded by the Ronivirus Branch of Nidovirales

Avian Metapneumovirus Infection in Poultry Flocks: A Review of Current Knowledge

Opposing roles of endosomal innate immunity proteins IFITM3 and TLR7 in human metapneumovirus infection

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