Fake it to break it: mimicking superinfection exclusion disrupts alphavirus infection and transmission in the yellow fever mosquito <i>Aedes aegypti</i>

Reitmayer, Christine M; Levitt, Emily; Basu, Subhash; Atkinson, Barry; Merits, Andres; Lumley, Sarah; Larner, Will; Díaz, Adriana V.; Rooney, Sara; Thomas, Callum J. E.; Wyschetzki, Katharina von; Rausalu, Kai; Alphey, Luke

doi:10.1101/2022.09.20.508686

Cited by 3 publications

(4 citation statements)

References 53 publications

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“…While infection also reduced surface proteins AXL and transferrin, surface TIM levels were more significantly depleted. nsP2 shuts off cellular transcription and has been suggested to be one of the main factors behind superinfection exclusion in alphaviruses by interfering with the formation of replication complexes of incoming viruses (37–39). Therefore, the CHIKV-induced receptor decrease may not be specific, but might disproportionally affect surface proteins with shorter half-lives such as TIM (half-life <2hrs) (31).…”

Section: Discussionmentioning

confidence: 99%

Chikungunya Virus Release is Reduced by TIM-1 Receptors Through Binding of Envelope Phosphatidylserine

Reyes Ballista,

Hoover,

Noble

et al. 2024

Preprint

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T-cell immunoglobin and mucin domain protein-1 (TIM-1) mediates entry of Chikungunya virus (CHIKV) into some mammalian cells through the interaction with envelope phospholipids. While this interaction enhances entry, TIM has been shown to tether newly formed HIV and Ebola virus particles, limiting their efficient release. In this study, we investigate the ability of surface receptors such as TIM-1 to sequester newly budded virions on the surface of infected cells. We established a luminescence reporter system to produce Chikungunya viral particles that integrate nano-luciferase and easily quantify viral particles. We found that TIM-1 on the surface of host cells significantly reduced CHIKV release efficiency in comparison to other entry factors. Removal of cell surface TIM-1 through direct cellular knock-out or altering the cellular lipid distribution enhanced CHIKV release. Over the course of infection, CHIKV was able to counteract the tethering effect by gradually decreasing the surface levels of TIM-1 in a process that appears to be mediated by the nonstructural protein 2. This study highlights the importance of phosphatidylserine receptors in mediating not only the entry of CHIKV but also its release and could aid in developing cell lines capable of enhanced vaccine production.

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Section: Discussionmentioning

confidence: 99%

Chikungunya Virus Release is Reduced by TIM-1 Receptors Through Binding of Envelope Phosphatidylserine

Reyes Ballista,

Hoover,

Noble

et al. 2024

Preprint

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“…aegypti, then functional modification drives in this species will also require the development of disease-refractory systems, as have been developed for some pathogens in Ae. aegypti [36][37][38][39] . With transgenic manipulation of Cx.…”

Section: Discussionmentioning

confidence: 99%

CRISPR-based gene drives generate super-Mendelian inheritance in the disease vectorCulex quinquefasciatus

Harvey-Samuel,

Feng,

Okamoto

et al. 2023

Preprint

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Culexmosquitoes pose a significant public health threat as vectors for a variety of diseases including West Nile virus and lymphatic filariasis, and transmit pathogens threatening livestock, companion animals, and endangered birds. Rampant insecticide resistance makes controlling these mosquitoes challenging and necessitates the development of new control strategies. Gene drive technologies have made significant progress in other mosquito species, although similar advances have been lagging inCulex. Here we test the first CRISPR-based homing gene drive forCulex quinquefasciatus, demonstrating the possibility of using this technology to controlCulexmosquitoes. Our results show that the inheritance of two split-gene-drive transgenes, targeting different loci, are biased in the presence of a Cas9-expressing transgene although with modest efficiencies. Our findings extend the list of disease vectors where engineered homing gene drives have been demonstrated to includeCulexalongsideAnophelesandAedes, and pave the way for future development of these technologies to controlCulexmosquitoes.

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“…One of these hypotheses attributes SIE to a block in negative strand RNA synthesis of the superinfecting virus by premature proteolytic cleavage of the non-structural polyprotein by the viral nsP2 protease of the rst, incoming alphavirus. This is supported by ndings that mutations in the arthritogenic chikungunya virus (CHIKV), Semliki Forest virus (SFV), and Sindbis virus (SINV) nsP2 increased co-replication of another alphavirus in the same cell 12,27,28 . However, this may not be the only molecular mechanism as other studies contradict the universal role of nsP2 in SIE 8,26 .…”

Section: Introductionmentioning

confidence: 93%

“…Discovery of SIE induced by arboviruses, which are viruses transmitted by arthropod vectors that cause disease in vertebrates, raised the question whether SIE can be utilized to limit virus dispersal by mosquitoes in a similar cross-protective manner as in plants [8][9][10][11][12] .…”

Section: Introductionmentioning

confidence: 99%

Venezuelan equine encephalitis virus non-structural protein 3 dictates superinfection exclusion in mammalian cells

Hick,

Zotler,

Bosveld

et al. 2024

Preprint

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Superinfection exclusion (SIE) is a well-known phenomenon induced by a broad spectrum of viruses to hinder a virus from the same virus family to establish a secondary infection in an already infected cell. Despite many years of study, the molecular mechanism(s) of alphavirus SIE remain enigmatic. Alphaviruses are arthropod-borne viruses that cause arthritogenic or encephalitic diseases in vertebrates, depending on the viral species. Several arthritogenic alphaviruses are known to block RNA replication of a superinfecting alphavirus via early proteolytic cleavage by non-structural protein 2 (nsP2). Here, we explore for the first time the SIE mechanism of an encephalitic alphavirus, Venezuelan equine encephalitis virus (VEEV). Using single-cell imaging techniques and encapsidated VEEV replicons encoding green or red fluorescent proteins, we observed immediate onset of VEEV interference, which increases to nearly full SIE capacity in three hours. In a series of experiments, we observed that transient expression of VEEV nsP3, but not nsP2, reduced alphavirus replication in the same mammalian cell, suggesting a key role for VEEV nsP3 in the mechanism of SIE. In particular, the VEEV nsP3 C-terminal hypervariable domain (HVD) was found to be required and sufficient for SIE of VEEV and the more distantly related Sindbis virus. As the nsP3 HVD is known to bind multiple host proteins to form RNA replication complexes and modulate the cellular stress response, we propose that sequestering of essential host protein(s) by VEEV nsP3 interferes with RNA replication of the superinfecting alphavirus.

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Fake it to break it: mimicking superinfection exclusion disrupts alphavirus infection and transmission in the yellow fever mosquito Aedes aegypti

Cited by 3 publications

References 53 publications

Chikungunya Virus Release is Reduced by TIM-1 Receptors Through Binding of Envelope Phosphatidylserine

Chikungunya Virus Release is Reduced by TIM-1 Receptors Through Binding of Envelope Phosphatidylserine

CRISPR-based gene drives generate super-Mendelian inheritance in the disease vectorCulex quinquefasciatus

Venezuelan equine encephalitis virus non-structural protein 3 dictates superinfection exclusion in mammalian cells

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