Abstract

The type I interferon (IFN) signaling pathway has important functions in resistance to viral infection, with the downstream induction of interferon stimulated genes (ISG) protecting the host from virus entry, replication and spread. Listeria monocytogenes (Lm), a facultative intracellular foodborne pathogen, can exploit the type I IFN response as part of their pathogenic strategy, but the molecular mechanisms involved remain unclear. Here we show that type I IFN suppresses the antibacterial activity of phagocytes to promote systemic Lm infection. Mechanistically, type I IFN suppresses phagosome maturation and proteolysis of Lm virulence factors ActA and LLO, thereby promoting phagosome escape and cell-to-cell spread; the antiviral protein, IFN-induced transmembrane protein 3 (IFITM3), is required for this type I IFN-mediated alteration. Ifitm3−/− mice are resistant to systemic infection by Lm, displaying decreased bacterial spread in tissues, and increased immune cell recruitment and pro-inflammatory cytokine signaling. Together, our findings show how an antiviral mechanism in phagocytes can be exploited by bacterial pathogens, and implicate IFITM3 as a potential antimicrobial therapeutic target.

Highlights

  • The type I interferon (IFN) signaling pathway has important functions in resistance to viral infection, with the downstream induction of interferon stimulated genes (ISG) protecting the host from virus entry, replication and spread

  • To determine if type I IFN affects the antimicrobial activity of macrophages, we examined the fate of two different bacteria confined to phagosomes

  • Bone marrow-derived macrophages (BMDMs) from wild-type (WT) C57BL/6 mice were treated with interferon beta (IFNβ) for 20 hours (h) prior to exposure to bacteria

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Summary

Introduction

The type I interferon (IFN) signaling pathway has important functions in resistance to viral infection, with the downstream induction of interferon stimulated genes (ISG) protecting the host from virus entry, replication and spread. The early stages of actin-based motility, a process involving Arp2/ 3-mediated actin polymerization on the bacterial surface, were enhanced by type I IFN by mechanisms that remain unclear. As the type I IFN transcriptional response involves hundreds of genes[21], it is not clear which ISGs promote Lm infection. This led us to examine how type I IFN affects the early stages of bacterial infection in macrophages, an important cellular target of these bacteria during systemic disease. We identify IFITM3 as a downstream target of type I IFN activation that suppresses proteolytic activity in phagocytes, thereby promoting Lm cell-tocell spread in macrophages. Our study has important implications for understanding the role of type I IFN and IFITM3 in innate immunity during bacterial infections

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