NF-κB Links CO2 Sensing to Innate Immunity and Inflammation in Mammalian Cells

ABSTRACTThe bacterial second messenger cyclic di-GMP (c-di-GMP) stimulates inflammation by initiating innate immune cell recruitment and triggering the release of proinflammatory cytokines and chemokines. These properties make c-di-GMP a promising candidate for use as a vaccine adjuvant, and numerous studies have demonstrated that administration of purified c-di-GMP with different antigens increases protection against infection in animal models. Here, we have developed a novel approach to produce c-di-GMP inside host cells as an adjuvant to exploit a host-pathogen interaction and initiate an innate immune response. We have demonstrated that c-di-GMP can be synthesizedin vivoby transducing a diguanylate cyclase (DGC) gene into mammalian cells using an adenovirus serotype 5 (Ad5) vector. Expression of DGC led to the production of c-di-GMPin vitroandin vivo, and this was able to alter proinflammatory gene expression in murine tissues and increase the secretion of numerous cytokines and chemokines when administered to animals. Furthermore, coexpression of DGC modestly increased T-cell responses to aClostridium difficileantigen expressed from an adenovirus vaccine, although no significant differences in antibody titers were observed. This adenovirus c-di-GMP delivery system offers a novel method to administer c-di-GMP as an adjuvant to stimulate innate immunity during vaccination.

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Induction of Nitric Oxide Synthase in Anopheles stephensi by Plasmodium falciparum: Mechanism of Signaling and the Role of Parasite Glycosylphosphatidylinositols

Infection and Immunity ◽

10.1128/iai.73.5.2778-2789.2005 ◽

2005 ◽

Vol 73 (5) ◽

pp. 2778-2789 ◽

Cited By ~ 88

Author(s):

Junghwa Lim ◽

D. Channe Gowda ◽

Gowdahalli Krishnegowda ◽

Shirley Luckhart

Keyword(s):

Nitric Oxide ◽

Innate Immunity ◽

Protein Kinase ◽

Nitric Oxide Synthase ◽

Insulin Signaling ◽

Mammalian Cells ◽

Anopheles Stephensi ◽

Midgut Epithelium ◽

Parasite Development ◽

Oxide Synthase

ABSTRACT Malaria parasite (Plasmodium spp.) infection in the mosquito Anopheles stephensi induces significant expression of A. stephensi nitric oxide synthase (AsNOS) in the midgut epithelium as early as 6 h postinfection and intermittently thereafter. This induction results in the synthesis of inflammatory levels of nitric oxide (NO) in the blood-filled midgut that adversely impact parasite development. In mammals, P. falciparum glycosylphosphatidylinositols (PfGPIs) can induce NOS expression in immune and endothelial cells and are sufficient to reproduce the major effects of parasite infection. These effects are mediated in part by mimicry of insulin signaling by PfGPIs. In this study, we demonstrate that PfGPIs can induce AsNOS expression in A. stephensi cells in vitro and in the midgut epithelium in vivo. Signaling by P. falciparum merozoites and PfGPIs is mediated through A. stephensi Akt/protein kinase B and a pathway involving DSOR1, a mitogen-activated protein kinase kinase, and an extracellular signal-regulated kinase. However, despite the involvement of kinases that are also associated with insulin signaling in A. stephensi cells, signaling by P. falciparum and by PfGPIs is distinctively different from signaling by insulin. Therefore, although mimicry of insulin by PfGPIs appears to be restricted to mammalian hosts of P. falciparum, the conservation of PfGPIs as a prominent parasite-derived signal of innate immunity can now be extended to include Anopheles mosquitoes, indicating that parasite signaling of innate immunity is conserved in mosquito and mammalian cells.

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Control of Innate Immunity by Sialic Acids in the Nervous Tissue

International Journal of Molecular Sciences ◽

10.3390/ijms21155494 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5494 ◽

Cited By ~ 3

Author(s):

Huan Liao ◽

Christine Klaus ◽

Harald Neumann

Keyword(s):

Innate Immunity ◽

Sialic Acid ◽

Mammalian Cells ◽

Nervous Tissue ◽

Neurological Diseases ◽

Sialic Acids ◽

Factor H ◽

Complement Factor ◽

Sialidase Activity ◽

Microglial Phagocytosis

Sialic acids (Sias) are the most abundant terminal sugar residues of glycoproteins and glycolipids on the surface of mammalian cells. The nervous tissue is the organ with the highest expression level of Sias. The ‘sialylation’ of glycoconjugates is performed via sialyltransferases, whereas ‘desialylation’ is done by sialidases or is a possible consequence of oxidative damage. Sialic acid residues on the neural cell surfaces inhibit complement and microglial activation, as well as phagocytosis of the underlying structures, via binding to (i) complement factor H (CFH) or (ii) sialic acid-binding immunoglobulin-like lectin (SIGLEC) receptors. In contrast, activated microglial cells show sialidase activity that desialylates both microglia and neurons, and further stimulates innate immunity via microglia and complement activation. The desialylation conveys neurons to become susceptible to phagocytosis, as well as triggers a microglial phagocytosis-associated oxidative burst and inflammation. Dysfunctions of the ‘Sia–SIGLEC’ and/or ‘Sia–complement’ axes often lead to neurological diseases. Thus, Sias on glycoconjugates of the intact glycocalyx and its desialylation are major regulators of neuroinflammation.

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The Regulatory Network of Cyclic GMP-AMP Synthase-Stimulator of Interferon Genes Pathway in Viral Evasion

Frontiers in Microbiology ◽

10.3389/fmicb.2021.790714 ◽

2021 ◽

Vol 12 ◽

Author(s):

Tongyu Hu ◽

Mingyu Pan ◽

Yue Yin ◽

Chen Wang ◽

Ye Cui ◽

...

Keyword(s):

Innate Immunity ◽

Cyclic Gmp ◽

Mammalian Cells ◽

Type I Interferon ◽

Viral Proteins ◽

Current Status ◽

Type I ◽

Non Coding Rnas ◽

Sting Pathway ◽

Viral Evasion

Virus infection has been consistently threatening public health. The cyclic GMP-AMP synthase (cGAS)-Stimulator of Interferon Genes (STING) pathway is a critical defender to sense various pathogens and trigger innate immunity of mammalian cells. cGAS recognizes the pathogenic DNA in the cytosol and then synthesizes 2′3′-cyclic GMP-AMP (2′3′cGAMP). As the second messenger, cGAMP activates STING and induces the following cascade to produce type I interferon (IFN-I) to protect against infections. However, viruses have evolved numerous strategies to hinder the cGAS-STING signal transduction, promoting their immune evasion. Here we outline the current status of the viral evasion mechanism underlying the regulation of the cGAS-STING pathway, focusing on how post-transcriptional modifications, viral proteins, and non-coding RNAs involve innate immunity during viral infection, attempting to inspire new targets discovery and uncover potential clinical antiviral treatments.

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The Mitochondrial Outer Membrane Protein Tom70-Mediator in Protein Traffic, Membrane Contact Sites and Innate Immunity

International Journal of Molecular Sciences ◽

10.3390/ijms21197262 ◽

2020 ◽

Vol 21 (19) ◽

pp. 7262

Author(s):

Sebastian Kreimendahl ◽

Joachim Rassow

Keyword(s):

Innate Immunity ◽

Outer Membrane ◽

Mammalian Cells ◽

Tertiary Structure ◽

Viral Infections ◽

Adaptor Protein ◽

Type I Interferons ◽

Mitochondrial Outer Membrane ◽

Type I ◽

Membrane Contact Sites

Tom70 is a versatile adaptor protein of 70 kDa anchored in the outer membrane of mitochondria in metazoa, fungi and amoeba. The tertiary structure was resolved for the Tom70 of yeast, showing 26 α-helices, most of them participating in the formation of 11 tetratricopeptide repeat (TPR) motifs. Tom70 serves as a docking site for cytosolic chaperone proteins and co-chaperones and is thereby involved in the uptake of newly synthesized chaperone-bound proteins in mitochondrial biogenesis. In yeast, Tom70 additionally mediates ER-mitochondria contacts via binding to sterol transporter Lam6/Ltc1. In mammalian cells, TOM70 promotes endoplasmic reticulum (ER) to mitochondria Ca2+ transfer by association with the inositol-1,4,5-triphosphate receptor type 3 (IP3R3). TOM70 is specifically targeted by the Bcl-2-related protein MCL-1 that acts as an anti-apoptotic protein in macrophages infected by intracellular pathogens, but also in many cancer cells. By participating in the recruitment of PINK1 and the E3 ubiquitin ligase Parkin, TOM70 can be implicated in the development of Parkinson’s disease. TOM70 acts as receptor of the mitochondrial antiviral-signaling protein (MAVS) and thereby participates in the corresponding system of innate immunity against viral infections. The protein encoded by Orf9b in the genome of SARS-CoV-2 binds to TOM70, probably compromising the synthesis of type I interferons.

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