Chikungunya virus entry and infectivity is primarily facilitated through cell line dependent attachment factors in mammalian and mosquito cells

Ballista, Judith Mary Reyes; Miazgowicz, Kerri L.; Acciani, Marissa Danielle; Jimenez, Ariana R; Belloli, Ryan S.; Havranek, Katherine E.; Brindley, Melinda A.

doi:10.3389/fcell.2023.1085913

Cited by 5 publications

(23 citation statements)

References 94 publications

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“…CDC50a knockout cells have higher concentrations of PS on the outer cell membrane relative to wild-type cells. Viruses generated from ΔCDC50a cells have been shown to generate higher concentrations of external PS on viral membranes relative to viral stocks generated from WT cells . To measure whether PS levels would influence the antiviral activity of MXB peptoids, three concentrations of MXB009 were directly incubated with CHIKV stocks generated from either WT HAP1 cells or ΔCDC50a cells and viral titers were quantified after peptoid incubation (Figure A).…”

Section: Resultsmentioning

confidence: 99%

Peptidomimetic Oligomers Targeting Membrane Phosphatidylserine Exhibit Broad Antiviral Activity

Tate,

Mastrodomenico,

Cunha

et al. 2023

ACS Infect. Dis.

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The development of durable new antiviral therapies is challenging, as viruses can evolve rapidly to establish resistance and attenuate therapeutic efficacy. New compounds that selectively target conserved viral features are attractive therapeutic candidates, particularly for combating newly emergent viral threats. The innate immune system features a sustained capability to combat pathogens through production of antimicrobial peptides (AMPs); however, these AMPs have shortcomings that can preclude clinical use. The essential functional features of AMPs have been recapitulated by peptidomimetic oligomers, yielding effective antibacterial and antifungal agents. Here, we show that a family of AMP mimetics, called peptoids, exhibit direct antiviral activity against an array of enveloped viruses, including the key human pathogens Zika, Rift Valley fever, and chikungunya viruses. These data suggest that the activities of peptoids include engagement and disruption of viral membrane constituents. To investigate how these peptoids target lipid membranes, we used liposome leakage assays to measure membrane disruption. We found that liposomes containing phosphatidylserine (PS) were markedly sensitive to peptoid treatment; in contrast, liposomes formed exclusively with phosphatidylcholine (PC) showed no sensitivity. In addition, chikungunya virus containing elevated envelope PS was more susceptible to peptoid-mediated inactivation. These results indicate that peptoids mimicking the physicochemical characteristics of AMPs act through a membrane-specific mechanism, most likely through preferential interactions with PS. We provide the first evidence for the engagement of distinct viral envelope lipid constituents, establishing an avenue for specificity that may enable the development of a new family of therapeutics capable of averting the rapid development of resistance.

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Section: Resultsmentioning

confidence: 99%

Peptidomimetic Oligomers Targeting Membrane Phosphatidylserine Exhibit Broad Antiviral Activity

Tate,

Mastrodomenico,

Cunha

et al. 2023

ACS Infect. Dis.

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“…The ability of CHIKV to counteract this inhibition might result in higher levels of disease spread inside the host's body. However, the significant increase in the production of viral particles from cells lacking TIM-1 and increased infectivity of virions previously observed in ∆CDC50 cells (17) could be employed to maximize particle production during vaccine development. Further studies should characterize the extent to which PS receptors could inhibit the efficient egress of other highly pathogenic enveloped viruses.…”

Section: Discussionmentioning

confidence: 99%

“…TIM plasmids were a gift from Dr. Wendy Maury (18). AXL (BC032229), MXRA8 (BC006213) (17), and L-SIGN (BC038851) plasmids were purchased from Transomic and if necessary, cloned into expression vectors. The following day, cells were infected, and release assays were performed as described above.…”

Section: Virus Release Assays: Transfections and Plasmidsmentioning

confidence: 99%

“…Our group and others showed that CHIKV entry in certain cell lines (i.e., Vero cells) is mainly mediated through attachment to PS receptors, such as T cell immuno-globulin mucin domain-1 (TIM-1) and receptor tyrosine kinase AXL (AXL) (17)(18)(19). Increased levels of PS in CHIKV's outer leaflet enhanced the specific infectivity of particles into Vero cells (17). While PS receptors can aid in virus entry, they can also modulate immune responses and reduce virion release.…”

Section: Introductionmentioning

confidence: 99%

“…Viral envelopes rich in PS can enter cells via apoptotic mimicry, where outer leaflet PS in the viral envelope attaches to PS receptors on the surface of the host cells. Our group and others showed that CHIKV entry in certain cell lines ( i.e., Vero cells) is mainly mediated through attachment to PS receptors, such as T cell immunoglobulin mucin domain-1 (TIM-1) and receptor tyrosine kinase AXL (AXL) (17–19). Increased levels of PS in CHIKV’s outer leaflet enhanced the specific infectivity of particles into Vero cells (17).…”

Section: Introductionmentioning

confidence: 99%

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

Reyes Ballista,

Hoover,

Noble

et al. 2024

Preprint

Self Cite

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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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Chikungunya virus release is reduced by TIM-1 receptors through binding of envelope phosphatidylserine

Reyes Ballista,

Hoover,

Noble

et al. 2024

J Virol

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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-1 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 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. IMPORTANCE Chikungunya virus (CHIKV) is an enveloped alphavirus transmitted by the bites of infectious mosquitoes. Infection with CHIKV results in the development of fever, joint pain, and arthralgia that can become chronic and last for months after infection. Prevention of this disease is still highly focused on vector control strategies. In December 2023, a new live attenuated vaccine against CHIKV was approved by the FDA. We aimed to study the cellular factors involved in CHIKV release, to better understand CHIKV’s ability to efficiently infect and spread among a wide variety of cell lines. We found that TIM-1 receptors can significantly abrogate CHIKV’s ability to efficiently exit infected cells. This information can be beneficial for maximizing viral particle production in laboratory settings and during vaccine manufacturing.

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Chikungunya virus entry and infectivity is primarily facilitated through cell line dependent attachment factors in mammalian and mosquito cells

Cited by 5 publications

References 94 publications

Peptidomimetic Oligomers Targeting Membrane Phosphatidylserine Exhibit Broad Antiviral Activity

Peptidomimetic Oligomers Targeting Membrane Phosphatidylserine Exhibit Broad Antiviral Activity

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

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