Listeria exploits IFITM3 to suppress antibacterial activity in phagocytes

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.

Evaluation of Host Protein Biomarkers by ELISA From Whole Lysed Peripheral Blood for Development of Diagnostic Tests for Active Tuberculosis

“…IFIT3 functions to inhibit the function of TLR3 (65), which is involved in recognition of cytoplasmic PAMPS like 'foreign' double stranded RNA (66). IFITM3 is a key mediator of the early innate cellular response, however it functions to inhibit phagocytosis, which is beneficial in viral infections, but not with intracellular bacterial pathogens like Listeria which have evolved strategies to exploit its function to avoid phagocyte killing (67). Therefore, upregulation of IFITM3 may inhibit bacterial uptake, but upregulation of GBP1 and parallel downregulation of IFIT3, may lead to GBP-mediated bacterial killing mechanisms and an increase in TLR3-directed immune responses.…”

IFITM proteins: Understanding their diverse roles in viral infection, cancer, and immunity

“…In the same study, IFITMdel mice developed spontaneous chronic colitis from an early age. Interestingly, a more recent study has also found that Ifitm3 -deficient mice infected with Listeria monocytogenes exhibit enhanced production of both IL-12, a Th1-promoting cytokine, and IL-4, a Th2-promoting cytokine ( 81 ); however, Th cell subsets were not analyzed in detail. The enhanced immune priming in Ifitm3 -deficient mice explained improved pathogen clearance in this model, thus providing the first in vivo evidence for the importance of immune regulation by IFITMs in a nonviral infection modality.…”

Impact of STING Inflammatory Signaling during Intracellular Bacterial Infections

“…Using the cell surface-bound virulence protein (ActA), L. monocytogenes polarizes, driving bacterial motility in the cytosol. Type I IFN promoted polarization and the suppressed phagosome proteolysis of ActA, increasing actin-based motility and bacterial dissemination to perpetuate infection [ 103 , 104 ]. Recently, two bacterial products that facilitate L. monocytogenes infection, by directly inducing type I IFN signaling, were described.…”