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Reviews of "Functional Genomics Screens Reveal a Role for TBC1D24 and SV2B in Antibody-dependent Enhancement of Dengue Virus Infection"

Reviewers: I Rodenhuis-Zybert (University of Groningen) | 📒📒📒◻️◻️ • J Carr (Flinders University) | 📒📒📒◻️◻️

Published onJun 18, 2024
Reviews of "Functional Genomics Screens Reveal a Role for TBC1D24 and SV2B in Antibody-dependent Enhancement of Dengue Virus Infection"
key-enterThis Pub is a Review of
Functional genomics screens reveal a role for TBC1D24 and SV2B in antibody-dependent enhancement of dengue virus infection
Functional genomics screens reveal a role for TBC1D24 and SV2B in antibody-dependent enhancement of dengue virus infection
Description

Abstract Dengue virus (DENV) can hijack non-neutralizing IgG antibodies to facilitate its uptake into target cells expressing Fc gamma receptors (FcgR) - a process known as antibody-dependent enhancement (ADE) of infection. Beyond a requirement for FcgR, host dependency factors for this non-canonical infection route remain unknown. To identify cellular factors exclusively required for ADE, here, we performed CRISPR knockout screens in an in vitro system permissive to infection only in the presence of IgG antibodies. Validating our approach, a top hit was FcgRIIa, which facilitates binding and internalization of IgG-bound DENV but is not required for canonical infection. Additionally, we identified host factors with no previously described role in DENV infection, including TBC1D24 and SV2B, both of which have known functions in regulated secretion. Using genetic knockout and trans-complemented cells, we validated a functional requirement for these host factors in ADE assays performed with monoclonal antibodies and polyclonal sera in multiple cell lines and using all four DENV serotypes. We show that knockout of TBC1D24 or SV2B impaired binding of IgG-DENV complexes to cells without affecting FcgRIIa expression levels. Thus, we identify cellular factors beyond FcgR that are required for ADE of DENV infection. Our findings represent a first step towards advancing fundamental knowledge behind the biology of ADE that can ultimately be exploited to inform vaccination and therapeutic approaches.

To read the original manuscript, click the link above.

Summary of Reviews: Reviewers found the preprint to be potentially informative, with evidence suggesting a role for both TBC1D24 and SV2B in increasing antibody-dependent enhancement (ADE) for Dengue virus (DENV) infection. However, reviewers had certain critiques about the study's experimental design. They highlighted the cell line and antibody used during the CRISPR KO are not the most suitable models for DENV ADE and thus could affect the accuracy of the results. Additionally, they suggested contextualizing the tissue-specific expression levels of the significant genes would help provide further biological significance to the study. Finally, one reviewer suggested providing further validation on the CRISPR KO effectiveness or additional siRNA knockdown as a comparison would strengthen confidence in the role of the highlighted host factors.

Reviewer 1 (Izabela R…) | 📒📒📒 ◻️◻️

Reviewer 2 (Jill C…) | 📒📒📒 ◻️◻️

RR:C19 Strength of Evidence Scale Key

📕 ◻️◻️◻️◻️ = Misleading

📙📙 ◻️◻️◻️ = Not Informative

📒📒📒 ◻️◻️ = Potentially Informative

📗📗📗📗◻️ = Reliable

📘📘📘📘📘 = Strong

To read the reviews, click the links below. 

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