A Novel Live-Attenuated Vaccine Candidate for Mayaro Fever

Weise, W.; Hermance, Meghan E.; Forrester, Naomi L.; Adams, Alexandra; Langsjoen, Rose M.; Gorchakov, Rodion; Wang, Eryu; Alcorn, Maria D. H.; Tsetsarkin, Konstantin A.; Weaver, Scott C.

doi:10.1371/journal.pntd.0002969

Cited by 57 publications

(64 citation statements)

References 50 publications

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“…CHIKV 181/clone 25 (77), CHIKV 15561 (77), and MAYV IQU3056 (78) infectious clones were kindly provided by Dr. Scott Weaver. Low-passage AURV BeAr93375 (P2, C6/36) and SINV CGLT599 (P2, suckling mouse) isolates were provided by the World Reference Center for Emerging Viruses and Arboviruses (WRCEVA; Galveston, TX).…”

Section: Methodsmentioning

confidence: 99%

Differential alphavirus defective RNA diversity between intracellular and encapsidated compartments is driven by subgenomic recombination events

Langsjoen

Muruato

Kunkel

et al. 2020

Preprint

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Alphaviruses are positive-sense RNA arboviruses that can cause either a chronic arthritis or a 24 potentially lethal encephalitis. Like other RNA viruses, alphaviruses produce truncated, defective 25 genomes featuring large deletions during replication. Defective RNAs (D-RNAs) have primarily been 26 isolated from virions after high-multiplicity of infection passaging. Here, we aimed to characterize both 27 intracellular and packaged viral D-RNA populations during early passage infections under the 28 hypothesis that D-RNAs arise de novo intracellularly that may not be packaged and thus have remained 29 undetected. To this end, we generated NGS libraries using RNA derived from passage 1 (P1) stock 30 chikungunya virus (CHIKV) 181/clone 25, intracellular virus, and encapsidated P2 virus and analyzed 31 samples for D-RNA expression, followed by diversity and differential expression analyses. We found 32 that the diversity of D-RNA species is significantly higher for intracellular D-RNA populations than 33 encapsidated and specific populations of D-RNAs are differentially expressed between intracellular and 34 encapsidated compartments. Importantly, these trends were likewise observed in a murine model of 35 CHIKV 15561 infection, as well as in vitro studies using related Mayaro, Sindbis, and Aura viruses. 36Additionally, we identified a novel subtype of subgenomic D-RNA that are conserved across 37 arthritogenic alphaviruses. D-RNAs specific to intracellular populations were defined by recombination 38 events specifically in the subgenomic region, which was confirmed by direct RNA nanopore sequencing 39 of intracellular CHIKV RNAs. Together, these studies show that only a portion of D-RNAs generated 40 intracellularly are packaged and D-RNAs readily arise de novo in the absence of transmitted template. 41 3 IMPORTANCE 42 Our understanding of viral defective RNAs (D-RNAs), or truncated viral genomes, comes largely from 43 passaging studies in tissue culture under artificial conditions and/or packaged viral RNAs. Here, we 44 show that specific populations of alphavirus D-RNAs arise de novo and that they are not packaged into 45 virions, thus imposing a transmission bottleneck and impeding their prior detection. This raises 46 important questions about the roles of D-RNAs, both in nature and in tissue culture, during viral infection 47 and whether their influence is constrained by packaging requirements. Further, during the course of 48 these studies, we found a novel type of alphavirus D-RNA that is enriched intracellularly; dubbed 49 subgenomic D-RNAs (sgD-RNAs), they are defined by deletion boundaries between capsid/E3 and 50 E1/3'UTR regions and are common to chikungunya, Mayaro, Sindbis, and Aura viruses. These sgD-51 RNAs are enriched intracellularly and do not appear to be selectively packaged, and additionally may 52 exist as subgenome-derived transcripts. 53 Although D-RNAs have been considered an epi-phenomenon of cell-culturing practices, emerging deep 79 sequencing technologies have enabled researchers t...

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Section: Methodsmentioning

confidence: 99%

Differential alphavirus defective RNA diversity between intracellular and encapsidated compartments is driven by subgenomic recombination events

Langsjoen

Muruato

Kunkel

et al. 2020

Preprint

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“…However, unpublished data described by Ziegler in a 2008 report suggest that subcutaneously infected newborn and 14-day-old ICR mice present skeletal muscle and connective tissue changes similar to those described for CHIKV and RRV (Ziegler et al, 2008). A recent study used A129 mice, which lack functional type-I IFN receptors, to assess the level of attenuation of MAYV vaccines (Weise et al, 2014). Five 8-week-old mice were inoculated intradermally in the left footpad with 10 4 p.f.u.…”

Section: Mayaro Virusmentioning

confidence: 97%

Mouse models of alphavirus-induced inflammatory disease

Taylor

Herrero

Rudd

et al. 2015

Journal of General Virology

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Part of the Togaviridae family, alphaviruses are arthropod-borne viruses that are widely distributed throughout the globe. Alphaviruses are able to infect a variety of vertebrate hosts, but in humans, infection can result in extensive morbidity and mortality. Symptomatic infection can manifest as fever, an erythematous rash and/or significant inflammatory pathologies such as arthritis and encephalitis. Recent overwhelming outbreaks of alphaviral disease have highlighted the void in our understanding of alphavirus pathogenesis and the re-emergence of alphaviruses has given new impetus to anti-alphaviral drug design. In this review, the development of viable mouse models of Old Word and New World alphaviruses is examined. How mouse models that best replicate human disease have been used to elucidate the immunopathology of alphavirus pathogenesis and trial novel therapeutic discoveries is also discussed.

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“…Given the close genetic relationship with CHIKV , it is plausible that MAYV could also evolve to become more infectious to humans or anthropophilic mosquitoes, and experience similarly high levels of outbreaks. Fortunately, there is a promising vaccine candidate under development , and while it may take some time to become commercially available, this may eventuate before MAYV ever becomes a serious threat. Nonetheless, the potential impact of MAYV is not something that should be dismissed out of hand, and further research and surveillance are essential to ensure that it does not become the next Zika.…”

Section: Obscure Arboviruses With Global Epidemiological Potentialmentioning

confidence: 99%

“…Wolbachia could be used to combat obscure arboviral diseases The repertoire of vector control techniques is expanding Over the past 50 years, a great deal of research has focused on developing vaccines or drugs to combat arboviral disease. While this has unfortunately proven to be more difficult than predicted, the near future will likely bring greater success as there are many promising vaccine candidates under development [83,109,110]. But, what the continued outbreaks of YFV and JEV tell us is that even with a widely available and effective vaccine, it is difficult to control a vector-borne disease using a single technique in isolation.…”

Section: O'nyong-nyong Virus Is a Chikv-like Virus Endemic To Africamentioning

confidence: 99%

The re‐emerging arboviral threat: Hidden enemies

Dutra¹,

Caragata²,

Moreira³

2016

BioEssays

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Mayaro, Oropouche, and O'Nyong-Nyong share many traits with more prominent arboviruses, like dengue and yellow fever, chikungunya, and Zika. These include severe clinical symptoms, multiple animal hosts, and widespread vector species living in close proximity to human habitats, all of which constitute significant risk factors for more frequent outbreaks in the future, greatly increasing the potential of these hidden enemies to follow Zika and become the next wave of global arboviral threats. Critically, the current dearth of knowledge on these arboviruses might impede the success of future control efforts, including the potential application of Wolbachia pipientis. This bacterium inherently possesses broad anti-pathogen properties and a means of genetic drive that allows it to eliminate or replace target vector populations. We conclude that control of obscure arboviruses with Wolbachia might be possible, but successful implementation will be critically dependent on the ability to transinfect key vector species.

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A Novel Live-Attenuated Vaccine Candidate for Mayaro Fever

Cited by 57 publications

References 50 publications

Differential alphavirus defective RNA diversity between intracellular and encapsidated compartments is driven by subgenomic recombination events

Differential alphavirus defective RNA diversity between intracellular and encapsidated compartments is driven by subgenomic recombination events

Mouse models of alphavirus-induced inflammatory disease

The re‐emerging arboviral threat: Hidden enemies

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