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Functional genomics screens reveal a role for TBC1D24 and SV2B in antibody-dependent enhancement of dengue virus infection.

ABSTRACT: Functional genomics screens reveal a role for TBC1D24 and SV2B in antibody-dependent enhancement of dengue virus infection.

PROVIDER: PRJNA1103674 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28779013.fastq.gz	Fastqsanger.gz
	SRR28779014.fastq.gz	Fastqsanger.gz
	SRR28779015.fastq.gz	Fastqsanger.gz
	SRR28779016.fastq.gz	Fastqsanger.gz
	SRR28779017.fastq.gz	Fastqsanger.gz

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Functional genomics screens reveal a role for TBC1D24 and SV2B in antibody-dependent enhancement of dengue virus infection.

Project description: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 TBC1D24 and SV2B promote 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.

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Human primary macrophages infected with dengue virus serotype 2, strain 16681, and antibody-dependent enhancement of infection

Project description:Human primary monocytes were differentiated for 6days in the presence of M-CSF. The resulting macrophages were infected with dengue virus serotype 2, strain 16681 under the following conditions: Mock, Multiplicity of infection (MOI) 1 without antibodies, MOI 1 with 40ng/mL of irrelevant human antibody, MOI 1 with infection enhancing antibody (40ng/mL of a human monoclonal antibody against dengue), and either MOI 5 or MOI 2.5. Total cell RNA was isolated at 2h post infection or 24h post infection.

2014-12-30 | E-MTAB-3138 | biostudies-arrayexpress

Functional genomics screens reveal a role for TBC1D24 and SV2B in antibody-dependent enhancement of dengue virus infection.

Project description: Not available

| S-EPMC11578089 | biostudies-literature

Functional genomics screens reveal a role for TBC1D24 and SV2B in antibody-dependent enhancement of dengue virus infection.

Project description: Not available

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Immune metabolic interplay drives the protective antibody response pre-vaccination with Dengue virus Vaccine

Project description:Protective immunity to dengue virus (DENV) requires antibody response to all four serotypes. Systems vaccinology identified pre-vaccination mechanisms predictive of broad antibody responses after immunization with a tetravalent live-attenuated DENV vaccine candidate (Butantan-DV/TV003). Anti-inflammatory pathways including TGF-b signaling expressed by CD68low monocytes and the metabolokines phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were positively correlated with broadly neutralizing Ab responses against DENV. In contrast expression of pro-inflammatory pathways and cytokines (IFN, IL-1) in CD68hi monocytes and primary and secondary bile acids negatively correlated with broad DENVDENV specific Ab responses. Induction of TGF-b and IFNs respectively by PC/PE and bile acids in CD68low and CD68hi monocytes and their impact on viral sensing was confirmed in vitro. We show that the balance between metabolites and pro- or anti-inflammatory innate immune cells drives broad and protective B cell response to the live-attenuated dengue vaccine.

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