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Defining the molecular interface of Influenza-A-virus pathogenicity factor PB1-F2 with human inflammasome NLRP3

Master program titleMaîtrise universitaire (Master) en biologie
Defense date2021
Abstract

Influenza A viruses (IAV) are highly contagious zoonotic pathogens that can give rise to a major epidemic or pandemic and cause acute respiratory infections. In response to IAV infection, the NLRP3 inflammasome is a signaling hub and an intracellular sensor that plays a crucial role in mediating immune inflammatory responses upon its activation, to ensure the protection of the host from any viral invasion. Despite the ability of the host to tackle viral infection by inducing inflammation, IAV evolved tactics to escape the host immune response through its viral proteins. PB1-F2, for instance, is an accessory protein that is encoded by the second ORF of the PB1 segment and is implicated in viral growth, replication and IAV pathogenicity. It was previously shown in our laboratory, that PB1-F2 binds and inhibits NLRP3 to limit fulminant cell death of infected macrophages. In this study, we intended to define the molecular interface between PB1-F2 and human NLRP3 by exchanging a strikingly distinct four amino acid patch located in the C-terminus domain of influenza A/Viet Nam/1203/2004 H5N1 virus (VN/1203) PB1-F2 (binds NLRP3) and A/Puerto Rico/8/1934 (PR/8) H1N1 PB1-F2 (does not bind NLRP3), respectively and to functionally characterize mutant PB1-F2 generated viruses in context of viral infection. Our pull-down results confirm that “TQGS” motif of VN/1203 is required for NLRP3 binding. However, according to our functional data (LDH cytotoxicity assay and ELISA assays for IL1beta secretion), it is inconclusive whether this exact binding motif is sufficient to suppress inflammasome activation.

eng
Citation (ISO format)
HEDHILI, Dalila Sabrine. Defining the molecular interface of Influenza-A-virus pathogenicity factor PB1-F2 with human inflammasome NLRP3. 2021.
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  • PID : unige:150030
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