scholarly journals Feeding-induced resistance to acute lethal sepsis is dependent on hepatic BMAL1 and FXR signalling

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sarah S. Geiger ◽  
Javier Traba ◽  
Nathan Richoz ◽  
Taylor K. Farley ◽  
Stephen R. Brooks ◽  
...  
Keyword(s):  
Induced Resistance ◽  
Validation Studies ◽  
Cytokine Production ◽  
Transcriptional Response ◽  
Time Of Day ◽  
Innate Immune ◽  
Farnesoid X Receptor ◽  
Light Cycle ◽  
Feeding Cycle ◽  
Lethal Sepsis

AbstractIn mice, time of day strongly influences lethality in response to LPS, with survival greatest at the beginning compared to the end of the light cycle. Here we show that feeding, rather than light, controls time-of-day dependent LPS sensitivity. Mortality following LPS administration is independent of cytokine production and the clock regulator BMAL1 expressed in myeloid cells. In contrast, deletion of BMAL1 in hepatocytes globally disrupts the transcriptional response to the feeding cycle in the liver and results in constitutively high LPS sensitivity. Using RNAseq and functional validation studies we identify hepatic farnesoid X receptor (FXR) signalling as a BMAL1 and feeding-dependent regulator of LPS susceptibility. These results show that hepatocyte-intrinsic BMAL1 and FXR signalling integrate nutritional cues to regulate survival in response to innate immune stimuli. Understanding hepatic molecular programmes operational in response to these cues could identify novel pathways for targeting to enhance endotoxemia resistance.

scholarly journals Mycobacterium tuberculosisinhibits human innate immune responses via the production of TLR2 antagonist glycolipids

2017 ◽  
Vol 114 (42) ◽  
pp. 11205-11210 ◽  
Author(s):  
Landry Blanc ◽  
Martine Gilleron ◽  
Jacques Prandi ◽  
Ok-ryul Song ◽  
Mi-Seon Jang ◽  
...  
Keyword(s):  
Immune Responses ◽  
Molecular Mechanisms ◽  
Cytokine Production ◽  
Cell Envelope ◽  
Costimulatory Molecule ◽  
Immune Defense ◽  
Innate Immune ◽  
Host Cells ◽  
Innate Immune Responses ◽  
Reporter System

Mycobacterium tuberculosisis a major human pathogen that is able to survive inside host cells and resist immune clearance. Most particularly, it inhibits several arms of the innate immune response, including phagosome maturation or cytokine production. To better understand the molecular mechanisms by whichM. tuberculosiscircumvents host immune defenses, we used a transposon mutant library generated in a virulent clinical isolate ofM. tuberculosisof the W/Beijing family to infect human macrophages, utilizing a cell line derivative of THP-1 cells expressing a reporter system for activation of the transcription factor NF-κB, a key regulator of innate immunity. We identified severalM. tuberculosismutants inducing a NF-κB activation stronger than that of the wild-type strain. One of these mutants was found to be deficient for the synthesis of cell envelope glycolipids, namely sulfoglycolipids, suggesting that the latter can interfere with innate immune responses. Using natural and synthetic molecular variants, we determined that sulfoglycolipids inhibit NF-κB activation and subsequent cytokine production or costimulatory molecule expression by acting as competitive antagonists of Toll-like receptor 2, thereby inhibiting the recognition ofM. tuberculosisby this receptor. Our study reveals that producing glycolipid antagonists of pattern recognition receptors is a strategy used byM. tuberculosisto undermine innate immune defense. Sulfoglycolipids are major and specific lipids ofM. tuberculosis, considered for decades as virulence factors of the bacilli. Our study uncovers a mechanism by which they may contribute toM. tuberculosisvirulence.

scholarly journals CpG Oligodeoxynucleotides Increase the Susceptibility of Normal Mice to Infection by Candida albicans

2005 ◽  
Vol 73 (9) ◽  
pp. 6154-6156 ◽  
Author(s):  
Shuichi Ito ◽  
Joao Pedras-Vasconcelos ◽  
Dennis M. Klinman
Keyword(s):  
Immune Response ◽  
Candida Albicans ◽  
Innate Immune Response ◽  
Host Resistance ◽  
Cytokine Production ◽  
Innate Immune ◽  
Interleukin 12 ◽  
Cpg Oligodeoxynucleotides ◽  
Cpg Motifs ◽  
Resistance To Infection

ABSTRACT Synthetic oligodeoxynucleotides containing CpG motifs trigger an innate immune response that typically increases host resistance to infection. Yet CpG treatment reduces the resistance of normal mice to Candida albicans infection. This effect is mediated by CpG-induced interleukin-12, indicating that CpG-dependent cytokine production may have adverse consequences for the host.

scholarly journals Evidence of Immunostimulating Lipoprotein Existing in the Natural Lipoteichoic Acid Fraction

2007 ◽  
Vol 75 (4) ◽  
pp. 1926-1932 ◽  
Author(s):  
Masahito Hashimoto ◽  
Maiko Furuyashiki ◽  
Ryoko Kaseya ◽  
Yuka Fukada ◽  
Mai Akimaru ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Cytokine Production ◽  
Lipoteichoic Acid ◽  
Inhibitory Effect ◽  
Innate Immune ◽  
Enterococcus Hirae ◽  
Inhibitory Effects ◽  
Active Structure ◽  
Gram Positive Bacteria ◽  
A Cell

ABSTRACT Lipoteichoic acid (LTA) is a cell surface glycoconjugate of gram-positive bacteria and is reported to activate the innate immune system. We previously reported that purified LTA obtained from Enterococcus hirae has no immunostimulating activity, but a subfraction (Eh-AF) in an LTA fraction possesses activity. In this study, we established a mouse monoclonal antibody neutralizing the activity of Eh-AF and investigated its inhibitory effects. Monoclonal antibody (MAbEh1) was established by the immunization of BALB/c mice with Eh-AF, followed by hybridoma screening based on its inhibitory effect for the production of interleukin-6 (IL-6) induced by Eh-AF. MAbEh1 neutralized the production of IL-6 by LTA fraction from not only E. hirae but also Staphylococcus aureus, while it failed to block that of lipopolysaccharide, suggesting that the antibody recognized a common active structure(s) in LTA fractions. Synthetic glycolipids in these LTAs did not induce cytokine production, at least in our system. Interestingly, the antibody was found to inhibit the activity of immunostimulating synthetic lipopeptides, Pam3CSK4 and FSL-1. These results suggest that MAbEh1 neutralizes the activity of lipoprotein-like compounds which is responsible for the activity of the LTA fraction of E. hirae and S. aureus.

scholarly journals Dectin-3 recognizes cryptococcal glucuronoxylomannan to initiate host defense against cryptococcosis

2018 ◽  
Author(s):  
Hua-Rong Huang ◽  
Fan Li ◽  
Hua Han ◽  
Quan-Zhen Lv ◽  
Xia Xu ◽  
...  
Keyword(s):  
Cytokine Production ◽  
Adaptor Protein ◽  
Innate Immune ◽  
Inflammatory Cytokine Production ◽  
Lectin Receptor ◽  
Structural Differences ◽  
Life Threatening ◽  
Serotype B ◽  
Deficient Mice ◽  
Macrophage Accumulation

AbstractCryptococcus neoformansandCryptococcus gattiicause life-threatening meningoencephalitis and pneumonia in immunosuppressed and immunocompetent individuals. Given the structural differences of major polysaccharide glucuronoxylomannan (GXM) betweenC. neoformansandC. gattii, it remains unclear that how innate immune system recognizes GXM. Here, we report that C-type lectin receptor Dectin-3 (MCL encoded by Clec4d) is a direct receptor for GXMs fromC. neoformansserotype AD (C.n-AD) andC. gattiiserotype B (C.g-B). GXMs fromC.n-AD andC.g-B activated both NF-κB and ERK pathways to induce the pro-inflammatory cytokine production, whereas it was completely abolished due to deficiency of Dectin-3 or its downstream adaptor protein CARD9. Upon pulmonaryC.n-AD andC.g-B infection, Dectin-3- and CARD9-deficient mice were highly susceptible and showed augmented lung injury due to impairment of alveolar macrophage accumulation and killing activities. These results demonstrate that Dectin-3 contributes to host immunity againstCryptococcusinfection through selectively recognizingGXM.

scholarly journals Response of Pseudomonas aeruginosa to the innate immune system-derived oxidants hypochlorous acid and hypothiocyanous acid

2020 ◽  
Author(s):  
Katie V. Farrant ◽  
Livia Spiga ◽  
Jane C. Davies ◽  
Huw D. Williams
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Type Iii Secretion ◽  
Hypochlorous Acid ◽  
Efflux Pump ◽  
Transcriptional Response ◽  
Innate Immune ◽  
Taurine Transport ◽  
Genes Encoding ◽  
Transposon Mutants ◽  
Lung Infections

ABSTRACTPseudomonas aeruginosa is a significant nosocomial pathogen and associated with lung infections in cystic fibrosis (CF). Once established, P. aeruginosa infections persist and are rarely eradicated despite the host immune cells producing antimicrobial oxidants, including hypochlorous acid (HOCl) and hypothiocyanous acid (HOSCN). There is limited knowledge as to how P. aeruginosa senses, responds to, and survives attack from HOCl and HOSCN, and the contribution of such responses to its success as a CF pathogen. We investigated the P. aeruginosa response to these oxidants by screening 707 transposon mutants, with mutations in regulatory genes, for altered growth following HOCl exposure. We identified regulators involved in antibiotic resistance, methionine biosynthesis and catabolite repression, and PA14_07340, the homologue of the Escherichia coli HOCl-sensor RclR (30% identical), that were required for HOCl survival. We have shown that RclR (PA14_07340) protects specifically against HOCl and HOSCN stress, and responds to both oxidants by upregulating expression of a putative peroxiredoxin, rclX (PA14_07355). While there was specificity in the transcriptional response to HOCl (231 genes upregulated) and HOSCN (105 genes upregulated) there was considerable overlap, with 74 genes upregulated by both oxidants. These included genes encoding the type III secretion system (T3SS), sulphur and taurine transport, and the MexEF-OprN efflux pump. RclR coordinated the transcriptional response to HOCl and HOSCN, including upregulation of pyocyanin biosynthesis genes, and in response to HOSCN alone RclR downregulated chaperone genes. These data indicate that the P. aeruginosa response to HOCl and HOSCN is multifaceted, with RclR playing an essential role.

scholarly journals Upper airway gene expression differentiates COVID-19 from other acute respiratory illnesses and reveals suppression of innate immune responses by SARS-CoV-2

2020 ◽  
Author(s):  
Eran Mick ◽  
Jack Kamm ◽  
Angela Oliveira Pisco ◽  
Kalani Ratnasiri ◽  
Jennifer M Babik ◽  
...  
Keyword(s):  
Gene Expression ◽  
Direct Detection ◽  
Transcriptional Response ◽  
Upper Airway ◽  
Innate Immune ◽  
Lymphoid Cells ◽  
Metagenomic Sequencing ◽  
Respiratory Illnesses ◽  
Expression Of Genes ◽  
Neutrophil Degranulation

We studied the host transcriptional response to SARS-CoV-2 by performing metagenomic sequencing of upper airway samples in 238 patients with COVID-19, other viral or non-viral acute respiratory illnesses (ARIs). Compared to other viral ARIs, COVID-19 was characterized by a diminished innate immune response, with reduced expression of genes involved in toll-like receptor and interleukin signaling, chemokine binding, neutrophil degranulation and interactions with lymphoid cells. Patients with COVID-19 also exhibited significantly reduced proportions of neutrophils and macrophages, and increased proportions of goblet, dendritic and B-cells, compared to other viral ARIs. Using machine learning, we built 26-, 10- and 3-gene classifiers that differentiated COVID-19 from other acute respiratory illnesses with AUCs of 0.980, 0.950 and 0.871, respectively. Classifier performance was stable at low viral loads, suggesting utility in settings where direct detection of viral nucleic acid may be unsuccessful. Taken together, our results illuminate unique aspects of the host transcriptional response to SARS-CoV-2 in comparison to other respiratory viruses and demonstrate the feasibility of COVID-19 diagnostics based on patient gene expression.

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