scholarly journals Interferon-induced guanylate-binding proteins: Guardians of host defense in health and disease

2019 ◽  
Vol 216 (3) ◽  
pp. 482-500 ◽  
Author(s):  
Kyle Tretina ◽  
Eui-Soon Park ◽  
Agnieszka Maminska ◽  
John D. MacMicking
Keyword(s):  
Innate Immunity ◽  
Bacterial Infection ◽  
Host Defense ◽  
Tissue Damage ◽  
Binding Proteins ◽  
Wide Spectrum ◽  
Cell Types ◽  
Microbial Pathogens ◽  
Health And Disease ◽  
Basic Biology

Guanylate-binding proteins (GBPs) have recently emerged as central orchestrators of immunity to infection, inflammation, and neoplastic diseases. Within numerous host cell types, these IFN-induced GTPases assemble into large nanomachines that execute distinct host defense activities against a wide variety of microbial pathogens. In addition, GBPs customize inflammasome responses to bacterial infection and sepsis, where they act as critical rheostats to amplify innate immunity and regulate tissue damage. Similar functions are becoming evident for metabolic inflammatory syndromes and cancer, further underscoring the importance of GBPs within infectious as well as altered homeostatic settings. A better understanding of the basic biology of these IFN-induced GTPases could thus benefit clinical approaches to a wide spectrum of important human diseases.

scholarly journals Pregnane X Receptor Regulates Pathogen-Induced Inflammation and Host Defense against an Intracellular Bacterial Infection through Toll-like Receptor 4

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Zhijuan Qiu ◽  
Jorge L. Cervantes ◽  
Basak B. Cicek ◽  
Subhajit Mukherjee ◽  
Madhukumar Venkatesh ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Bacterial Infection ◽  
Host Defense ◽  
Negative Impact ◽  
Pregnane X Receptor ◽  
Negative Regulator ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Chemokine Production ◽  
Inflammatory Monocytes

Abstract The nuclear pregnane X receptor (PXR) plays a central role in regulating xenobiotic metabolism. We now report a novel role for PXR as a critical negative regulator of innate immunity after infection. Pxr −/− mice exhibited remarkably elevated pro-inflammatory cytokine and chemokine production following infection with Listeria monocytogenes (Lm). Despite the more robust innate immune response, Pxr −/− mice were highly susceptible to Lm infection. Surprisingly, disruption of the Toll-like receptor 4 (TLR4) but not TLR2 signaling restored the inflammation to normal levels and the ability to clear Lm in Pxr −/− mice. Mechanistically, the heightened inflammation in Pxr −/− mice resulted in the death of inflammatory monocytes that led to the enhanced susceptibility to Lm infection. These data demonstrated that PXR regulated pathogen-induced inflammation and host defense against Lm infection through modulating the TLR4 pathway. In summary, we discovered an apical role for PXR in regulating innate immunity. In addition, we uncovered a remarkable negative impact of the TLR4 pathway in controlling the quality of the inflammatory response and host defense against a gram-positive bacterial infection.

scholarly journals The CXC Chemokines Gamma Interferon (IFN-γ)-Inducible Protein 10 and Monokine Induced by IFN-γ Are Released during Severe Melioidosis

2000 ◽  
Vol 68 (7) ◽  
pp. 3888-3893 ◽  
Author(s):  
Fanny N. Lauw ◽  
Andrew J. H. Simpson ◽  
Jan M. Prins ◽  
Sander J. H. van Deventer ◽  
Wipada Chaowagul ◽  
...  
Keyword(s):  
Bacterial Infection ◽  
Host Defense ◽  
Cell Types ◽  
Gamma Interferon ◽  
Interleukin 12 ◽  
Necrosis Factor Alpha ◽  
Activated T Lymphocytes ◽  
Ifn Γ ◽  
Inducible Protein

ABSTRACT Gamma interferon (IFN-γ)-inducible protein 10 (IP-10) and monokine induced by IFN-γ (Mig) are related CXC chemokines which bind to the CXCR3 receptor and specifically target activated T lymphocytes and natural killer (NK) cells. The production of IP-10 and Mig by various cell types in vitro is strongly dependent on IFN-γ. To determine whether IP-10 and Mig are released during bacterial infection in humans, we measured plasma levels of IP-10 and Mig in patients with melioidosis, a severe gram-negative infection caused byBurkholderia pseudomallei. IP-10 and Mig were markedly elevated in patients with melioidosis on admission, particularly in blood culture-positive patients, and remained elevated during the 72-h study period. Levels of IP-10 and Mig showed a positive correlation with IFN-γ concentrations and also correlated with clinical outcome. In whole blood stimulated with heat-killed B. pseudomallei, neutralization of IFN-γ and tumor necrosis factor alpha (TNF-α) partly attenuated IP-10 and Mig release, while anti-interleukin-12 (IL-12) and anti-IL-18 had a synergistic effect. Stimulation with other bacteria or endotoxin also induced strong secretion of IP-10 and Mig. These data suggest that IP-10 and Mig are part of the innate immune response to bacterial infection. IP-10 and Mig may contribute to host defense in Th1-mediated host defense during infections by attracting CXCR3+ Th1 cells to the site of inflammation.

scholarly journals Mitofusin-2 boosts innate immunity through the maintenance of aerobic glycolysis and activation of xenophagy in mice

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Prashanta Silwal ◽  
Jin Kyung Kim ◽  
Sang Min Jeon ◽  
June-Young Lee ◽  
Young Jae Kim ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Bacterial Infection ◽  
Host Defense ◽  
Inflammatory Responses ◽  
Aerobic Glycolysis ◽  
Hypoxia Inducible Factor ◽  
Chain Complex ◽  
Mitochondrial Respiratory Chain ◽  
Mitofusin 2 ◽  
Mitochondrial Respiratory Chain Complex

AbstractMitochondrial function and innate immunity are intimately linked; however, the mechanisms how mitochondrion-shaping proteins regulate innate host defense remains largely unknown. Herein we show that mitofusin-2 (MFN2), a mitochondrial fusion protein, promotes innate host defense through the maintenance of aerobic glycolysis and xenophagy via hypoxia-inducible factor (HIF)-1α during intracellular bacterial infection. Myeloid-specific MFN2 deficiency in mice impaired the antimicrobial and inflammatory responses against mycobacterial and listerial infection. Mechanistically, MFN2 was required for the enhancement of inflammatory signaling through optimal induction of aerobic glycolysis via HIF-1α, which is activated by mitochondrial respiratory chain complex I and reactive oxygen species, in macrophages. MFN2 did not impact mitophagy during infection; however, it promoted xenophagy activation through HIF-1α. In addition, MFN2 interacted with the late endosomal protein Rab7, to facilitate xenophagy during mycobacterial infection. Our findings reveal the mechanistic regulations by which MFN2 tailors the innate host defense through coordinated control of immunometabolism and xenophagy via HIF-1α during bacterial infection.

scholarly journals Resistin, a Novel Host Defense Peptide of Innate Immunity

2021 ◽  
Vol 12 ◽  
Author(s):  
Yanran Li ◽  
Qiyuan Yang ◽  
Dongjie Cai ◽  
Hongrui Guo ◽  
Jing Fang ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Host Defense ◽  
Metabolic Diseases ◽  
Defense Mechanism ◽  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Wide Spectrum ◽  
Biological Properties ◽  
Obesity And Diabetes ◽  
Host Defense Peptide

Resistin, a cysteine-rich protein, expressed in adipocytes, was initially proposed as a link between obesity and diabetes in mice. In humans, resistin is considered to be a pro-inflammatory molecule expressed in immune cells, which plays a regulatory role in many chronic inflammatory diseases, metabolic diseases, infectious diseases, and cancers. However, increasing evidence shows that resistin functions as a host defense peptide of innate immunity, in terms of its wide-spectrum anti-microbial activity, modulation of immunity, and limitation of microbial product-induced inflammation. To date, the understanding of resistin participating in host defense mechanism is still limited. The review aims to summarize current knowledge about the biological properties, functions, and related mechanisms of resistin in host defense, which provides new insights into the pleiotropic biological function of resistin and yields promising strategies for developing new antimicrobial therapeutic agents.

scholarly journals TOR functions as a molecular switch connecting an iron cue with host innate defense against bacterial infection

PLoS Genetics ◽  
2021 ◽  
Vol 17 (3) ◽  
pp. e1009383
Author(s):  
Yi-Cheng Ma ◽  
Li-Li Dai ◽  
Bei-Bei Qiu ◽  
Ying Zhou ◽  
Yu-Qiang Zhao ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Bacterial Infection ◽  
Host Defense ◽  
Bacterial Infections ◽  
Iron Availability ◽  
Innate Defense ◽  
Iron Sequestration ◽  
Serovar Typhimurium ◽  
Important Regulator ◽  
Host Innate Immunity

As both host and pathogen require iron for survival, iron is an important regulator of host-pathogen interactions. However, the molecular mechanism by which how the availability of iron modulates host innate immunity against bacterial infections remains largely unknown. Using the metazoan Caenorhabditis elegans as a model, we demonstrate that infection with a pathogenic bacterium Salmonella enterica serovar Typhimurium induces autophagy by inactivating the target of rapamycin (TOR). Although the transcripts of ftn-1 and ftn-2 encoding two H-ferritin subunits are upregulated upon S. Typhimurium infection, the ferritin protein is kept at a low level due to its degradation mediated by autophagy. Autophagy, but not ferritin, is required for defense against S. Typhimurium infection under normal circumstances. Increased abundance of iron suppresses autophagy by activating TOR, leading to an increase in the ferritin protein level. Iron sequestration, but not autophagy, becomes pivotal to protect the host from S. Typhimurium infection in the presence of exogenous iron. Our results show that TOR acts as a regulator linking iron availability with host defense against bacterial infection.

scholarly journals Neural Stem Cells: What Happens When They Go Viral?

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1468
Author(s):  
Yashika S. Kamte ◽  
Manisha N. Chandwani ◽  
Alexa C. Michaels ◽  
Lauren A. O’Donnell
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Viral Infections ◽  
Wide Spectrum ◽  
Cell Types ◽  
Developmental Abnormalities ◽  
Multipotent Progenitor Cells ◽  
The Central Nervous System ◽  
Simplex Virus ◽  
The Brain

Viruses that infect the central nervous system (CNS) are associated with developmental abnormalities as well as neuropsychiatric and degenerative conditions. Many of these viruses such as Zika virus (ZIKV), cytomegalovirus (CMV), and herpes simplex virus (HSV) demonstrate tropism for neural stem cells (NSCs). NSCs are the multipotent progenitor cells of the brain that have the ability to form neurons, astrocytes, and oligodendrocytes. Viral infections often alter the function of NSCs, with profound impacts on the growth and repair of the brain. There are a wide spectrum of effects on NSCs, which differ by the type of virus, the model system, the cell types studied, and the age of the host. Thus, it is a challenge to predict and define the consequences of interactions between viruses and NSCs. The purpose of this review is to dissect the mechanisms by which viruses can affect survival, proliferation, and differentiation of NSCs. This review also sheds light on the contribution of key antiviral cytokines in the impairment of NSC activity during a viral infection, revealing a complex interplay between NSCs, viruses, and the immune system.

scholarly journals Effectors Targeting the Unfolded Protein Response during Intracellular Bacterial Infection

2021 ◽  
Vol 9 (4) ◽  
pp. 705
Author(s):  
Manal H. Alshareef ◽  
Elizabeth L. Hartland ◽  
Kathleen McCaffrey
Keyword(s):  
Bacterial Infection ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Host Defense ◽  
Effector Proteins ◽  
Dual Nature ◽  
Unfolded Protein ◽  
Bacterial Replication ◽  
The Unfolded Protein Response ◽  
Protein Response

The unfolded protein response (UPR) is a homeostatic response to endoplasmic reticulum (ER) stress within eukaryotic cells. The UPR initiates transcriptional and post-transcriptional programs to resolve ER stress; or, if ER stress is severe or prolonged, initiates apoptosis. ER stress is a common feature of bacterial infection although the role of the UPR in host defense is only beginning to be understood. While the UPR is important for host defense against pore-forming toxins produced by some bacteria, other bacterial effector proteins hijack the UPR through the activity of translocated effector proteins that facilitate intracellular survival and proliferation. UPR-mediated apoptosis can limit bacterial replication but also often contributes to tissue damage and disease. Here, we discuss the dual nature of the UPR during infection and the implications of UPR activation or inhibition for inflammation and immunity as illustrated by different bacterial pathogens.

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