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Characterization of the hypersensitive response-like cell death phenomenon induced by targeting antiviral lectin griffithsin to the secretory pathway.

ABSTRACT: Griffithsin (GRFT) is an antiviral lectin, originally derived from a red alga, which is currently being investigated as a topical microbicide to prevent transmission of human immunodeficiency virus (HIV). Targeting GRFT to the apoplast for production in Nicotiana benthamiana resulted in necrotic symptoms associated with a hypersensitive response (HR)-like cell death, accompanied by H₂ O₂ generation and increased PR1 expression. Mannose-binding lectins surfactant protein D (SP-D), cyanovirin-N (CV-N) and human mannose-binding lectin (hMBL) also induce salicylic acid (SA)-dependent HR-like cell death in N. benthamiana, and this effect is mediated by the lectin's glycan binding activity. We found that secreted GRFT interacts with an endogenous glycoprotein, α-xylosidase (XYL1), which is involved in cell wall organization. The necrotic effect could be mitigated by overexpression of Arabidopsis XYL1, and by co-expression of SA-degrading enzyme NahG, providing strategies for enhancing expression of oligomannose-binding lectins in plants.

SUBMITTER: Kim BM

PROVIDER: S-EPMC6131415 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Characterization of the hypersensitive response-like cell death phenomenon induced by targeting antiviral lectin griffithsin to the secretory pathway.

Kim Bo Min BM Lotter-Stark Hester Catharina Therese HCT Rybicki Edward P EP Chikwamba Rachel K RK Palmer Kenneth E KE

Plant biotechnology journal 20180502 10

Griffithsin (GRFT) is an antiviral lectin, originally derived from a red alga, which is currently being investigated as a topical microbicide to prevent transmission of human immunodeficiency virus (HIV). Targeting GRFT to the apoplast for production in Nicotiana benthamiana resulted in necrotic symptoms associated with a hypersensitive response (HR)-like cell death, accompanied by H<sub>2</sub> O<sub>2</sub> generation and increased PR1 expression. Mannose-binding lectins surfactant protein D ( ...[more]

PMID: 29509998

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Project description:Although COVID-19 transmission has been reduced by the advent of vaccinations and a variety of rapid monitoring techniques, the SARS-CoV-2 virus itself has shown a remarkable ability to mutate and persist. With this long track record of immune escape, researchers are still exploring prophylactic treatments to curtail future SARS-CoV-2 variants. Specifically, much focus has been placed on the antiviral lectin Griffithsin in preventing spike protein-mediated infection via the hACE2 receptor (direct infection). However, an oft-overlooked aspect of SARS-CoV-2 infection is viral capture by attachment receptors such as DC-SIGN, which is thought to facilitate the initial stages of COVID-19 infection in the lung tissue (called trans-infection). In addition, while immune escape is dictated by mutations in the spike protein, coronaviral virions also incorporate M, N, and E structural proteins within the particle. In this paper, we explored how several structural facets of both the SARS-CoV-2 virion and the antiviral lectin Griffithsin can affect and attenuate the infectivity of SARS-CoV-2 pseudovirus. We found that Griffithsin was a better inhibitor of hACE2-mediated direct infection when the coronaviral M protein is present compared to when it is absent (possibly providing an explanation regarding why Griffithsin shows better inhibition against authentic SARS-CoV-2 as opposed to pseudotyped viruses, which generally do not contain M) and that Griffithsin was not an effective inhibitor of DC-SIGN-mediated trans-infection. Furthermore, we found that DC-SIGN appeared to mediate trans-infection exclusively via binding to the SARS-CoV-2 spike protein, with no significant effect observed when other viral proteins (M, N, and/or E) were present. These results provide etiological data that may help to direct the development of novel antiviral treatments, either by leveraging Griffithsin binding to the M protein as a novel strategy to prevent SARS-CoV-2 infection or by narrowing efforts to inhibit trans-infection to focus on DC-SIGN binding to SARS-CoV-2 spike protein.

Dataset Information

Characterization of the hypersensitive response-like cell death phenomenon induced by targeting antiviral lectin griffithsin to the secretory pathway.

Publications

Characterization of the hypersensitive response-like cell death phenomenon induced by targeting antiviral lectin griffithsin to the secretory pathway.

Similar Datasets

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