Interferon inducible GBPs restrict Burkholderia thailandensismotility induced cell-cell fusion.

David E Place,Parimal Samir,Geoffrey Neale,Benoit Briard,Jennifer L Peters,Peter Vogel,Sharon Frase,Clifford S Guy,Rajendra Karki,Masahiro Yamamoto,Thirumala-Devi Kanneganti,Anannya Bhattacharya,Dana J Philpott

doi:10.1371/journal.ppat.1008364

David E Place, Parimal Samir + Show 11 more

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https://doi.org/10.1371/journal.ppat.1008364

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Abstract

Innate immunity responds to pathogens by producing alarm signals and activating pathways that make host cells inhospitable for pathogen replication. The intracellular bacterium Burkholderia thailandensis invades the cytosol, hijacks host actin, and induces cell fusion to spread to adjacent cells, forming multinucleated giant cells (MNGCs) which promote bacterial replication. We show that type I interferon (IFN) restricts macrophage MNGC formation during B. thailandensis infection. Guanylate-binding proteins (GBPs) expressed downstream of type I IFN were required to restrict MNGC formation through inhibition of bacterial Arp2/3-dependent actin motility during infection. GTPase activity and the CAAX prenylation domain were required for GBP2 recruitment to B. thailandensis, which restricted bacterial actin polymerization required for MNGC formation. Consistent with the effects in in vitro macrophages, Gbp2−/−, Gbp5−/−, GbpChr3-KO mice were more susceptible to intranasal infection with B. thailandensis than wildtype mice. Our findings reveal that IFN and GBPs play a critical role in restricting cell-cell fusion and bacteria-induced pathology during infection.

Highlights

Interferon (IFN) signaling pathways are critical regulators of host immunity to many viral and bacterial infectious diseases, leading to the expression of a number of IFN-stimulated genes (ISGs) with antiviral, antibacterial, or pathogenic activities [1,2]
The intracellular bacterium Burkholderia thailandensis and its relatives B. pseudomallei and B. mallei each invade host cells and hijack the actin cytoskeleton polymerization machinery to transmit to neighboring cells by cell-cell fusion, a transmission strategy that is unique to this family
In this study we find that guanylate-binding proteins (GBPs) regulated by the type I IFN pathway are required to restrict the formation of multinucleated giant cells (MNGCs) during B. thailandensis infection

Summary

Introduction

Interferon (IFN) signaling pathways are critical regulators of host immunity to many viral and bacterial infectious diseases, leading to the expression of a number of IFN-stimulated genes (ISGs) with antiviral, antibacterial, or pathogenic activities [1,2]. These ISGs include the dynamin-like GTPase myxovirus resistance 1 (Mx1), the IFN-inducible transmembrane (IFITM) proteins, the tripartite-motif family (TRIM) proteins, and the guanylate-binding proteins (GBPs) that are highly upregulated in response to IFN signaling and are important for restricting intracellular infections [2,3,4]. The balance of the beneficial and harmful consequences of inflammasome activation and how Burkholderia-mediated MNGC formation regulates inflammasome activation has not been well studied

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