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Review 1: "Functional Genomics Screens Reveal a Role for TBC1D24 and SV2B in Antibody-dependent Enhancement of Dengue Virus Infection"

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.

Published onJun 18, 2024
Review 1: "Functional Genomics Screens Reveal a Role for TBC1D24 and SV2B in Antibody-dependent Enhancement of Dengue Virus Infection"
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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.

RR:C19 Evidence Scale rating by reviewer:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.

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Review: The study is rigorously conducted and well-written, with a strong rationale and sound methodology. The authors address several limitations of the cell models used; however, they do not sufficiently discuss the implications of these limitations on the overall conclusions of the study.

While human erythroleukemic K562 cells, the primary model used in this research, although often used in DENV research are a standard cell culture model for chronic myeloid leukemia, and  do not naturally represent the primary target cells for direct DENV infection or antibody-dependent enhancement (ADE) of DENV, such as myeloid cells. Myeloid cells are known to be susceptible to both direct infection and ADE in the presence of non-neutralizing antibodies. Addressing this discrepancy is crucial for accurately interpreting the study's findings in the context of natural DENV infection.

Additionally, discussing the tissue/cell-specific expression of TBC1D24 and SV2B, possibly using resources like the Human Protein Atlas, would greatly benefit the scientific community. This information is crucial for translating these potentially significant findings to natural infections, which predominantly occur in immune cells.

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