scholarly journals Listeria monocytogenes infection rewires host metabolism with regulatory input from type I interferons

2021 ◽  
Vol 17 (7) ◽  
pp. e1009697
Author(s):  
Duygu Demiroz ◽  
Ekaterini Platanitis ◽  
Michael Bryant ◽  
Philipp Fischer ◽  
Michaela Prchal-Murphy ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
Metabolic Regulation ◽  
Bacterial Pathogen ◽  
Type I Interferons ◽  
Type I ◽  
Independent Manner ◽  
Potential Control ◽  
Food Borne ◽  
Regulatory Input ◽  
Host Metabolism

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.

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

2015 ◽  
Vol 83 (6) ◽  
pp. 2358-2368 ◽  
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.

scholarly journals Lymphocytes are detrimental during the early innate immune response against Listeria monocytogenes

2006 ◽  
Vol 203 (4) ◽  
pp. 933-940 ◽  
Author(s):  
Javier A. Carrero ◽  
Boris Calderon ◽  
Emil R. Unanue
Keyword(s):  
Immune Response ◽  
Listeria Monocytogenes ◽  
Innate Immune Response ◽  
Early Stage ◽  
Bacterial Pathogen ◽  
Interleukin 10 ◽  
Innate Immune ◽  
Type I ◽  
Phagocytic Cells ◽  
Immunodeficient Mice

Mice deficient in lymphocytes are more resistant than normal mice to Listeria monocytogenes infection during the early innate immune response. This paradox remains unresolved: lymphocytes are required for sterilizing immunity, but their presence during the early stage of the infection is not an asset and may even be detrimental. We found that lymphocyte-deficient mice, which showed limited apoptosis in infected organs, were resistant during the first four days of infection but became susceptible when engrafted with lymphocytes. Engraftment with lymphocytes from type I interferon receptor–deficient (IFN-αβR−/−) mice, which had reduced apoptosis, did not confer increased susceptibility to infection, even when the phagocytes were IFN-αβR+/+. The attenuation of innate immunity was due, in part, to the production of the antiinflammatory cytokine interleukin 10 by phagocytic cells after the apoptotic phase of the infection. Thus, immunodeficient mice were more resistant relative to normal mice because the latter went through a stage of lymphocyte apoptosis that was detrimental to the innate immune response. This is an example of a bacterial pathogen creating a cascade of events that leads to a permissive infective niche early during infection.

scholarly journals The opportunistic intracellular bacterial pathogen Rhodococcus equi elicits type I interferons by engaging cytosolic DNA sensing in macrophages

2021 ◽  
Author(s):  
Krystal J Vail ◽  
Bibiana Petri da Silveira ◽  
Samantha L Bell ◽  
Angela I Bordin ◽  
Noah D Cohen ◽  
...  
Keyword(s):  
Bacterial Pathogen ◽  
Opportunistic Pathogen ◽  
Rhodococcus Equi ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Dna Sensing ◽  
Interferon Stimulated Genes ◽  
Galectin 3 ◽  
Dna Release

Rhodococcus equi is a major cause of foal pneumonia and an opportunistic pathogen in immunocompromised humans. While alveolar macrophages constitute the primary replicative niche for R. equi, little is known about how intracellular R. equi is sensed by macrophages. Here, we discovered that that in addition to previously characterized pro-inflammatory cytokines (e.g., Tnfa, Il6, Il1b), macrophages infected with R. equi induce a robust type I IFN response, including Ifnb and interferon-stimulated genes (ISGs), similar to the evolutionarily related pathogen, Mycobacterium tuberculosis. Follow up studies using a combination of mammalian and bacterial genetics, demonstrated that induction of this type I IFN expression program is largely dependent on the cGAS/STING/TBK1 axis of the cytosolic DNA surveillance pathway, suggesting that R. equi perturbs the phagosomal membrane and causes DNA release into the cytosol following phagocytosis. Consistent with this we found that a population of ~12% of R. equi phagosomes recruited the galectin-3, -8 and -9 danger receptors. Interesting, neither phagosomal damage nor induction of type I IFN required the R. equi's virulence-associated plasmid. Importantly, R. equi infection of both mice and foals stimulated ISG expression, in organs (mice) and circulating monocytes (foals). By demonstrating that R. equi activates cytosolic DNA sensing in macrophages and elicits type I IFN responses in animal models, our work provides novel insights into how R. equi engages the innate immune system and furthers our understanding how this zoonotic pathogen causes inflammation and disease.

scholarly journals STING: a master regulator in the cancer-immunity cycle

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Yuanyuan Zhu ◽  
Xiang An ◽  
Xiao Zhang ◽  
Yu Qiao ◽  
Tongsen Zheng ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune Responses ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Negative Effects ◽  
Independent Manner ◽  
Adaptive Immune ◽  
Cancer Immunity

Abstract The aberrant appearance of DNA in the cytoplasm triggers the activation of cGAS-cGAMP-STING signaling and induces the production of type I interferons, which play critical roles in activating both innate and adaptive immune responses. Recently, numerous studies have shown that the activation of STING and the stimulation of type I IFN production are critical for the anticancer immune response. However, emerging evidence suggests that STING also regulates anticancer immunity in a type I IFN-independent manner. For instance, STING has been shown to induce cell death and facilitate the release of cancer cell antigens. Moreover, STING activation has been demonstrated to enhance cancer antigen presentation, contribute to the priming and activation of T cells, facilitate the trafficking and infiltration of T cells into tumors and promote the recognition and killing of cancer cells by T cells. In this review, we focus on STING and the cancer immune response, with particular attention to the roles of STING activation in the cancer-immunity cycle. Additionally, the negative effects of STING activation on the cancer immune response and non-immune roles of STING in cancer have also been discussed.

scholarly journals Route of Infection Determines the Impact of Type I Interferons on Innate Immunity to Listeria monocytogenes

PLoS ONE ◽  
2013 ◽  
Vol 8 (6) ◽  
pp. e65007 ◽  
Author(s):  
Elisabeth Kernbauer ◽  
Verena Maier ◽  
Isabella Rauch ◽  
Mathias Müller ◽  
Thomas Decker
Keyword(s):  
Innate Immunity ◽  
Listeria Monocytogenes ◽  
Type I Interferons ◽  
Type I ◽  
Route Of Infection ◽  
The Impact

scholarly journals prfA-Like Transcription Factor Genelmo0753Contributes to l-Rhamnose Utilization in Listeria monocytogenes Strains Associated with Human Food-Borne Infections

2013 ◽  
Vol 79 (18) ◽  
pp. 5584-5592 ◽  
Author(s):  
Joelle K. Salazar ◽  
Zhuchun Wu ◽  
P. David McMullen ◽  
Qin Luo ◽  
Nancy E. Freitag ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Listeria Monocytogenes ◽  
Bacterial Pathogen ◽  
Phenol Red ◽  
Flagellar Motility ◽  
Content Type ◽  
Genetic Lineages ◽  
Functional Roles ◽  
Food Borne ◽  
Virulence Regulator

ABSTRACTListeria monocytogenesis a food-borne bacterial pathogen and the causative agent of human and animal listeriosis. Among the three major genetic lineages ofL. monocytogenes(i.e., LI, LII, and LIII), LI and LII are predominantly associated with food-borne listeriosis outbreaks, whereas LIII is rarely implicated in human infections. In a previous study, we identified a Crp/Fnr family transcription factor gene,lmo0753, that was highly specific to outbreak-associated LI and LII but absent from LIII. Lmo0753 shares two conserved functional domains, including a DNA binding domain, with the well-characterized master virulence regulator PrfA inL. monocytogenes. In this study, we constructedlmo0753deletion and complementation mutants in two fully sequencedL. monocytogenesLII strains, 10403S and EGDe, and compared the flagellar motility, phospholipase C production, hemolysis, and intracellular growth of the mutants and their respective wild types. Our results suggested thatlmo0753plays a role in hemolytic activity in both EGDe and 10403S. More interestingly, we found that deletion oflmo0753led to the loss ofl-rhamnose utilization in EGDe, but not in 10403S. RNA-seq analysis of EGDe Δ0753incubated in phenol red medium containingl-rhamnose as the sole carbon source revealed that 126 (4.5%) and 546 (19.5%) out of 2,798 genes in the EGDe genome were up- and downregulated more than 2-fold, respectively, compared to the wild-type strain. Genes related to biotin biosynthesis, general stress response, and rhamnose metabolism were shown to be differentially regulated. Findings from this study collectively suggested varied functional roles oflmo0753in different LIIL. monocytogenesstrain backgrounds associated with human listeriosis outbreaks.

scholarly journals The Polybasic Cleavage Site in SARS-CoV-2 Spike Modulates Viral Sensitivity to Type I Interferon and IFITM2

2021 ◽  
Vol 95 (9) ◽  
Author(s):  
Helena Winstone ◽  
Maria Jose Lista ◽  
Alisha C. Reid ◽  
Clement Bouton ◽  
Suzanne Pickering ◽  
...  
Keyword(s):  
Viral Entry ◽  
Cleavage Site ◽  
Type I Interferons ◽  
Spike Protein ◽  
Type I ◽  
Furin Cleavage ◽  
Independent Manner ◽  
Type I Ifns ◽  
Furin Cleavage Site ◽  
Potent Inhibition

ABSTRACT The cellular entry of severe acute respiratory syndrome-associated coronaviruses types 1 and 2 (SARS-CoV-1 and -2) requires sequential protease processing of the viral spike glycoprotein. The presence of a polybasic cleavage site in SARS-CoV-2 spike at the S1/S2 boundary has been suggested to be a factor in the increased transmissibility of SARS-CoV-2 compared to SARS-CoV-1 by facilitating maturation of the spike precursor by furin-like proteases in the producer cells rather than endosomal cathepsins in the target. We investigate the relevance of the polybasic cleavage site in the route of entry of SARS-CoV-2 and the consequences this has for sensitivity to interferons (IFNs) and, more specifically, the IFN-induced transmembrane (IFITM) protein family that inhibit entry of diverse enveloped viruses. We found that SARS-CoV-2 is restricted predominantly by IFITM2, rather than IFITM3, and the degree of this restriction is governed by route of viral entry. Importantly, removal of the cleavage site in the spike protein renders SARS-CoV-2 entry highly pH and cathepsin dependent in late endosomes, where, like SARS-CoV-1 spike, it is more sensitive to IFITM2 restriction. Furthermore, we found that potent inhibition of SARS-CoV-2 replication by type I but not type II IFNs is alleviated by targeted depletion of IFITM2 expression. We propose that the polybasic cleavage site allows SARS-CoV-2 to mediate viral entry in a pH-independent manner, in part to mitigate against IFITM-mediated restriction and promote replication and transmission. This suggests that therapeutic strategies that target furin-mediated cleavage of SARS-CoV-2 spike may reduce viral replication through the activity of type I IFNs. IMPORTANCE The furin cleavage site in the spike protein is a distinguishing feature of SARS-CoV-2 and has been proposed to be a determinant for the higher transmissibility between individuals, compared to SARS-CoV-1. One explanation for this is that it permits more efficient activation of fusion at or near the cell surface rather than requiring processing in the endosome of the target cell. Here, we show that SARS-CoV-2 is inhibited by antiviral membrane protein IFITM2 and that the sensitivity is exacerbated by deletion of the furin cleavage site, which restricts viral entry to low pH compartments. Furthermore, we find that IFITM2 is a significant effector of the antiviral activity of type I interferons against SARS-CoV-2 replication. We suggest that one role of the furin cleavage site is to reduce SARS-CoV-2 sensitivity to innate immune restriction, and thus, it may represent a potential therapeutic target for COVID-19 treatment development.

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

Cytokine ◽  
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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