Novel functions of type I interferons revealed by infection studies with Listeria monocytogenes

Listeria monocytogenes (L. monocytogenes) is a food-borne bacterial pathogen. Innate immunity to L. monocytogenes is profoundly affected by type I interferons (IFN-I). Here we investigated host metabolism in L. monocytogenes-infected mice and its potential control by IFN-I. Accordingly, we used animals lacking either the IFN-I receptor (IFNAR) or IRF9, a subunit of ISGF3, the master regulator of IFN-I-induced genes. Transcriptomes and metabolite profiles showed that L. monocytogenes infection induces metabolic rewiring of the liver. This affects various metabolic pathways including fatty acid (FA) metabolism and oxidative phosphorylation and is partially dependent on IFN-I signaling. Livers and macrophages from Ifnar1-/- mice employ increased glutaminolysis in an IRF9-independent manner, possibly to readjust TCA metabolite levels due to reduced FA oxidation. Moreover, FA oxidation inhibition provides protection from L. monocytogenes infection, explaining part of the protection of Irf9-/- and Ifnar1-/- mice. Our findings define a role of IFN-I in metabolic regulation during L. monocytogenes infection. Metabolic differences between Irf9-/- and Ifnar1-/- mice may underlie the different susceptibility of these mice against lethal infection with L. monocytogenes.

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127 Type I Interferons as Virulence-determining Factors in Listeria Monocytogenes Infections

Cytokine ◽

10.1016/j.cyto.2007.07.132 ◽

2007 ◽

Vol 39 (1) ◽

pp. 35

Author(s):

Benjamin Reutterer ◽

Silvia Stockinger ◽

Andreas Pilz ◽

Didier Soulat ◽

Thomas Rülicke ◽

...

Keyword(s):

Listeria Monocytogenes ◽

Type I Interferons ◽

Type I ◽

Determining Factors

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Hyperinduction of Host Beta Interferon by a Listeria monocytogenes Strain Naturally Overexpressing the Multidrug Efflux Pump MdrT

Infection and Immunity ◽

10.1128/iai.06286-11 ◽

2012 ◽

Vol 80 (4) ◽

pp. 1537-1545 ◽

Cited By ~ 49

Author(s):

Kierstyn T. Schwartz ◽

Joshua D. Carleton ◽

Sarah J. Quillin ◽

Stuart D. Rollins ◽

Daniel A. Portnoy ◽

...

Keyword(s):

Listeria Monocytogenes ◽

Efflux Pump ◽

Type I Interferons ◽

Host Recognition ◽

Type I ◽

Loss Of Function ◽

Multidrug Efflux ◽

Content Type ◽

Beta Interferon ◽

Infected Cells

ABSTRACTMany pathogens regulate or modify their immune-stimulating ligands to avoid detection by their infected hosts.Listeria monocytogenes, a facultative intracellular bacterial pathogen, interacts with multiple components of mammalian innate immunity during its infection cycle. During replication within the cytosol of infected cells,L. monocytogenesutilizes two multidrug efflux pumps, MdrM and MdrT, to secrete the small nucleic acid second messenger cyclic-di-AMP (c-di-AMP). Host recognition of c-di-AMP triggers the production of type I interferons, including beta interferon (IFN-β), which, surprisingly, promoteL. monocytogenesvirulence. In this study, we have examined the capacity of multiple laboratory and clinical isolates ofL. monocytogenesto stimulate host production of IFN-β. We have identified theL. monocytogenesstrain LO28 as able to hyperinduce IFN-β production in infected cells ∼30-fold more than the common laboratory cloneL. monocytogenesstrain 10403S. Genomic analyses determined that LO28 contains a naturally occurring loss-of-function allele of the transcriptional regulator BrtA and correspondingly derepresses expression of MdrT. Surprisingly, while derepression of MdrT resulted in hyperstimulation of IFN-β, it results in significant attenuation in multiple mouse models of infection. While type I interferons may promoteL. monocytogenesvirulence, this study demonstrates that unregulated expression of the c-di-AMP-secreting efflux pump MdrT significantly restricts virulencein vivoby an unknown mechanism.

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The Human P-Glycoprotein Transporter Enhances the Type I Interferon Response to Listeria monocytogenes Infection

Infection and Immunity ◽

10.1128/iai.00380-15 ◽

2015 ◽

Vol 83 (6) ◽

pp. 2358-2368 ◽

Cited By ~ 8

Author(s):

Nadejda Sigal ◽

Millie Kaplan Zeevi ◽

Shiri Weinstein ◽

Dan Peer ◽

Anat A. Herskovits

Keyword(s):

Listeria Monocytogenes ◽

Type I Interferon ◽

Bacterial Pathogen ◽

Type I Interferons ◽

Interferon Response ◽

Type I ◽

Monocytic Cell ◽

Monocytic Cell Line ◽

Content Type ◽

P Glycoprotein

Human multidrug efflux transporters are known for their ability to extrude antibiotics and toxic compounds out of cells, yet accumulating data indicate they have additional functions in diverse physiological processes not related to drug efflux. Here, we show that the human multidrug transporter P-glycoprotein (P-gp) (also named MDR1 and ABCB1) is transcriptionally induced in the monocytic cell line THP-1 upon infection with the human intracellular bacterial pathogenListeria monocytogenes. Notably, we found that P-gp is important for full activation of the type I interferon response elicited againstL. monocytogenesbacteria. Both inhibition of P-gp function by verapamil and inhibition of its transcription using mRNA silencing led to a reduction in the magnitude of the type I response in infected cells. This function of P-gp was specific to type I interferon cytokines elicited against cytosolic replicating bacteria and was not observed in response to cyclic di-AMP (c-di-AMP), a molecule that was shown to be secreted byL. monocytogenesduring infection and to trigger type I interferons. Moreover, P-gp was not involved in activation of other proinflammatory cytokines, such as those triggered by vacuolar-restrictedL. monocytogenesor lipopolysaccharide (LPS). Taken together, these findings demonstrate a role for P-gp in proper development of an innate immune response against intracellular pathogens, highlighting the complexity in employing therapeutic strategies that involve inhibition of multidrug resistance (MDR) efflux pumps.

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Type I Interferon Production Enhances Susceptibility to Listeria monocytogenes Infection

Journal of Experimental Medicine ◽

10.1084/jem.20040712 ◽

2004 ◽

Vol 200 (4) ◽

pp. 437-445 ◽

Cited By ~ 363

Author(s):

Ryan M. O'Connell ◽

Supriya K. Saha ◽

Sagar A. Vaidya ◽

Kevin W. Bruhn ◽

Gustavo A. Miranda ◽

...

Keyword(s):

Listeria Monocytogenes ◽

Host Defense ◽

Viral Infections ◽

Type I Interferons ◽

Type I ◽

Innate Response ◽

Type I Ifns ◽

Listeria Monocytogenes Infection ◽

Resistance To Infection ◽

Deficient Mice

Numerous bacterial products such as lipopolysaccharide potently induce type I interferons (IFNs); however, the contribution of this innate response to host defense against bacterial infection remains unclear. Although mice deficient in either IFN regulatory factor (IRF)3 or the type I IFN receptor (IFNAR)1 are highly susceptible to viral infection, we show that these mice exhibit a profound resistance to infection caused by the Gram-positive intracellular bacterium Listeria monocytogenes compared with wild-type controls. Furthermore, this enhanced bacterial clearance is accompanied by a block in L. monocytogenes–induced splenic apoptosis in IRF3- and IFNAR1-deficient mice. Thus, our results highlight the disparate roles of type I IFNs during bacterial versus viral infections and stress the importance of proper IFN modulation in host defense.

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