Alphavirus Virulence Determinants

Rangel, Margarita V.; Stapleford, Kenneth A.

doi:10.3390/pathogens10080981

Cited by 7 publications

(4 citation statements)

References 133 publications

(163 reference statements)

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“…This mechanism of immune evasion unique to EEEV and WEEV and the examples above emphasize the significance of small differences in sequences that may be overlooked in potential srRNA vectors that would otherwise be missed from in vitro experimentation. A recent in-depth review covered numerous known virulence determinants in the coding and non-coding regions of alphaviruses [ 44 ].…”

Section: Srrna Vector–host Cell Interactionsmentioning

confidence: 99%

Next generation self-replicating RNA vectors for vaccines and immunotherapies

Aliahmad¹,

Miyake-Stoner²,

Geall³

et al. 2022

Cancer Gene Ther

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RNA technology has recently come to the forefront of innovative medicines and is being explored for a wide range of therapies, including prophylactic and therapeutic vaccines, biotherapeutic protein expression and gene therapy. In addition to conventional mRNA platforms now approved for prophylactic SARS-CoV2 vaccines, synthetic self-replicating RNA vaccines are currently being evaluated in the clinic for infectious disease and oncology. The prototypical srRNA vectors in clinical development are derived from alphaviruses, specifically Venezuelan Equine Encephalitis Virus (VEEV). While non-VEEV alphaviral strains have been explored as single cycle viral particles, their use as synthetic vectors largely remains under-utilized in clinical applications. Here we describe the potential commonalities and differences in synthetic alphaviral srRNA vectors in host cell interactions, immunogenicity, cellular delivery, and cargo expression. Thus, unlike the current thinking that VEEV-based srRNA is a one-size-fits-all platform, we argue that a new drug development approach leveraging panels of customizable, synthetic srRNA vectors will be required for clinical success.

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Section: Srrna Vector–host Cell Interactionsmentioning

confidence: 99%

Next generation self-replicating RNA vectors for vaccines and immunotherapies

Aliahmad¹,

Miyake-Stoner²,

Geall³

et al. 2022

Cancer Gene Ther

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“…For New World alphaviruses, such as VEEV and EEEV, the capsid protein is associated with IFN antagonism [11,132]. In EEEV, a region of the capsid between 55 and 75 amino acids is associated with inhibition of host gene expression and interferon sensitivity, whereas WEEV has a nucleocapsid arrangement targeting the PRR pathways downstream of IRF3 [133,134]. In contrast, a study on VEEV and SINV has shown that the suppression of IFN-β and ISG mRNA production in neuron cells is associated with structural protein of VEEV but nonstructural protein of SINV [135].…”

Section: Alphaviral Antagonism Of the Type I Ifn Systemmentioning

confidence: 99%

Host Immune Responses to Arthritogenic Alphavirus Infection, with Emphasis on Type I IFN Responses

Tang

Liu

2022

Zoonoses

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Arthritogenic alphaviruses, such as Ross River virus, chikungunya virus and O’nyong-nyong virus, cause endemic disease globally and are a major public health concern. The hallmarks of arthritogenic alphavirus disease are debilitating pain, and potentially chronic inflammation of the muscles, thus influencing quality of life. The type I IFN response is a major component of the innate immune response against arthritogenic alphaviruses, and is essential in inhibiting viral replication and dissemination. Type I IFNs are induced during early stages of infection and are essential for the activation of the antiviral innate immune response. They also link the innate immune response and the activation of adaptive immunity. This review focuses on the host immune response, particularly that involving type I IFN, in arthritogenic alphavirus disease.

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“…Importantly, CHIKV continues to emerge with a significant increase in CHIKV cases in South America in 2023, emphasizing the importance of further studying the mechanisms, transmission, and spread of CHIKV (9) (10). The alphavirus genome consists of two open reading frames, the first encoding 4 nonstructural proteins (nsP1-nsP4) and the latter encoding the structural proteins, including capsid, E3, 6K/TF, and the class II fusion glycoproteins E1 and E2 (11). Embedded in the virion membrane, the CHIKV E1 and E2 glycoproteins are essential in the early stages of receptor-mediated endocytosis.…”

Section: Introductionmentioning

confidence: 99%

The chikungunya virus E1 glycoprotein fusion loop and hinge alter glycoprotein dynamics leading to cell and host specific changes in infectivity

Thannickal,

Battini,

Spector

et al. 2023

Preprint

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Alphaviruses infect both mammals and insects, yet the distinct mechanisms that alphaviruses use to infect different hosts are not well defined. In this study, we characterize CHIKV E1 variants in the fusion loop (E1-M88L) and hinge region (E1-N20Y)in vitroandin vivoto understand how these regions of the E1 glycoprotein contribute to host-specific infection. Through cell culture assays, we found that CHIKV E1-N20Y enhanced infectivity in mosquito cells while the CHIKV E1-M88L variant enhanced virus binding and infectivity in both BHK-21 and C6/36 cells, and led to changes in the virus cholesterol-dependence in BHK-21 cells. Given thesein vitroresults and that residue E1-M88L is in a defined Mxra8 interacting domain, we hypothesized that this residue may be important for receptor usage. However, while the CHIKV E1-M88L variant increased replication in Mxra8-deficient mice compared to WT CHIKV, it was attenuatedin vitroin mouse fibroblasts, suggesting that residue E1-M88 may function in a cell-type dependent manner to alter entry. Finally, using molecular dynamics to understand how potential changes in the E1 glycoprotein may impact the CHIKV glycoprotein E1-E2 complex, we found that E1-M88L and other E1 domain II variants lead to changes in both E1 and E2 dynamics. Taken together, these studies show that key residues in the CHIKV E1 fusion loop and hinge region function through changes in E1-E2 dynamics to facilitate cell- and host-dependent entry.ImportanceArthropod-borne viruses (arboviruses) are significant global public health threats, and their continued emergence around the world highlights the need to understand how these viruses replicate at the molecular level. The alphavirus class II glycoproteins are critical for virus entry in mosquitoes and mammals, yet how these proteins function is not completely understood. Therefore, to address these gaps in our knowledge, it is critical to dissect how distinct glycoprotein domains functionin vitroandin vivo. Here, we show that changes in the CHIKV E1 fusion loop and hinge contribute to host-specific entry and E1-E2 dynamics, furthering our knowledge of how alphaviruses infect mammals and insects.

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Alphavirus Virulence Determinants

Cited by 7 publications

References 133 publications

Next generation self-replicating RNA vectors for vaccines and immunotherapies

Next generation self-replicating RNA vectors for vaccines and immunotherapies

Host Immune Responses to Arthritogenic Alphavirus Infection, with Emphasis on Type I IFN Responses

The chikungunya virus E1 glycoprotein fusion loop and hinge alter glycoprotein dynamics leading to cell and host specific changes in infectivity

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