Global transcriptional regulation of innate immunity in C. elegans

AbstractThe nematode Caenorhabditis elegans has emerged as a genetically tractable animal host in which to study evolutionarily conserved mechanisms of innate immune signaling. We previously showed that the PMK-1 p38 mitogen-activated protein kinase (MAPK) pathway regulates innate immunity of C. elegans through phosphorylation of the CREB/ATF bZIP transcription factor, ATF-7. Here, we have undertaken a genomic analysis of the transcriptional response of C. elegans to infection by Pseudomonas aeruginosa, combining genome-wide expression analysis by RNA-seq with ATF-7 chromatin immunoprecipitation followed by sequencing (ChIP-Seq). We observe that PMK-1-ATF-7 activity regulates a majority of all genes induced by pathogen infection, and observe ATF-7 occupancy in regulatory regions of pathogen-induced genes in a PMK-1-dependent manner. Moreover, functional analysis of a subset of these ATF-7-regulated pathogen-induced target genes supports a direct role for this transcriptional response in host defense. The genome-wide regulation through PMK-1– ATF-7 signaling reveals global control over the innate immune response to infection through a single transcriptional regulator in a simple animal host.Author SummaryInnate immunity is the first line of defense against invading microbes across metazoans. Caenorhabditis elegans lacks adaptive immunity and is therefore particularly dependent on mounting an innate immune response against pathogens. A major component of this response is the conserved PMK-1/p38 MAPK signaling cascade, the activation of which results in phosphorylation of the bZIP transcription factor ATF-7. Signaling via PMK-1 and ATF-7 causes broad transcriptional changes including the induction of many genes that are predicted to have antimicrobial activity including C-type lectins and lysozymes. In this study, we show that ATF-7 directly regulates the majority of innate immune response genes upon pathogen infection of C. elegans, and demonstrate that many ATF-7 targets function to promote pathogen resistance.

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Loss of DNase II function in the gonad is associated with a higher expression of antimicrobial genes in Caenorhabditis elegans

Biochemical Journal ◽

10.1042/bj20150563 ◽

2015 ◽

Vol 470 (1) ◽

pp. 145-154 ◽

Cited By ~ 8

Author(s):

Hsiang Yu ◽

Huey-Jen Lai ◽

Tai-Wei Lin ◽

Chang-Shi Chen ◽

Szecheng J. Lo

Keyword(s):

Immune Response ◽

Innate Immunity ◽

Caenorhabditis Elegans ◽

Innate Immune Response ◽

Innate Immune ◽

Dnase Ii ◽

C Elegans ◽

Elevated Expression

This study uncovered NUC-1 and CRN-7 function in germline apoptosis. Mutations of nuc-1 and crn-7 led to elevated expression of five innate-immunity-related genes and demonstrated that DNase II activity is associated with an innate immune response in C. elegans.

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Identification of genes and molecular pathways involved in a C. elegans model of neuroborreliosis

Proceedings of IMPRS ◽

10.18060/22747 ◽

2018 ◽

Vol 1 (1) ◽

Author(s):

Ruben Prado ◽

Gai-Linn Bessing ◽

Nathaniel Snyder ◽

Gurpalik Singh ◽

Frank Yang ◽

...

Keyword(s):

Immune Response ◽

Innate Immunity ◽

Lyme Disease ◽

Innate Immune Response ◽

Genetic Model ◽

Protein Aggregates ◽

Neuronal Morphology ◽

Innate Immune ◽

Molecular Pathways ◽

C Elegans

Background and Hypothesis: Lyme disease is caused by the spirochaete bacteria from the Borrelia species. Recent studies suggest that Lyme disease may be associated with dementia, brain atrophy, and protein aggregates that may be associated with the development of neurodegenerative diseases such as Parkinson’s disease (PD) and Alzheimers disease (AD). The molecular basis of the Borrelia-associated innate immune response and associated neuropathology is poorly defined. A significant hindrance in dissecting these molecular components is the lack of facile in vivo genetic models to explore the mechanisms involved in the neuropathology. Here we hypothesize that the nematode C. elegans will be a useful model for Borrelia-associated innate immunity and neuropathology. Project Methods: We utilized transcriptional reporters, transgenic animals, neuronal morphology analysis, RNAi, host defense pathways, AD- and PD-associated pathologies, and behavior assays to determine the effect that Borrelia has on C. elegans viability. Results: C. elegans can be infected and survive using Borrelia as a food source, and the bacteria can induce highly conserved innate immune response pathways, and exacerbate PD-associated dopamine neuronal death in human A53T -synuclein-expressing animals. C. elegans models expressing AD-associated human A 1-42 also show significant movement defects and increased protein aggregates when exposed to Borrelia. Conclusions and Potential Impact: This study further characterizes a novel genetic model for Borrelia-associated innate immunity and neuropathology. Incorporating C. elegans genetic screens, this model should allow us to identify mediators of the Borrelia-associated pathologies that should facilitate the identification of molecular pathways and potential therapeutic targets.

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Mitochondrial UPR negatively regulates wounding-induced innate immune response in C. elegans epidermis

10.1101/2021.09.19.460990 ◽

2021 ◽

Author(s):

Jianzhi Zhao ◽

Hongying Fu ◽

Hengda Zhou ◽

Xuecong Ren ◽

Yuanyuan Wang ◽

...

Keyword(s):

Immune Response ◽

Signaling Pathways ◽

Innate Immune Response ◽

Tissue Damage ◽

P38 Map Kinase ◽

Innate Immune ◽

Loss Of Function ◽

C Elegans ◽

Unfolded Protein ◽

Protein Response

Tissue damage elicits a rapid innate immune response that is essential for efficient wound healing and survival of metazoans. It is well known that p38 MAPK kinase, TGF-β, and hemidesmosome signaling pathways have been involved in wounding-induced innate immunity in C. elegans. Here, we find that loss of function of ATFS-1 increased innate immune response while an elevated level of mitochondrial unfolded protein response (mitoUPR) inhibits the innate immune response upon epidermal wounding. Epidermal wounding triggers the nucleus export of ATFS-1 and inhibits themitoUPR in C. elegans epidermis. Moreover, genetic analysis suggests that ATFS-1 functions upstream of the p38 MAP kinase, TGF-β, and DAF-16 signaling pathways in regulating AMPs induction. Thus, our results suggest that the mitoUPR function as an intracellular signal required to fine-tune innate immune response after tissue damage.

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RNA sensors as a mechanism of innate immune evasion among SARS-CoV2, HIV and Nipah viruses

Current Protein and Peptide Science ◽

10.2174/1389203722666210322142725 ◽

2021 ◽

Vol 22 ◽

Author(s):

Dalia Cicily Kattiparambil Dixon ◽

Chameli Ratan ◽

Bhagyalakshmi Nair ◽

Sabitha Mangalath ◽

Rachy Abraham ◽

...

Keyword(s):

Immune Response ◽

Innate Immunity ◽

Innate Immune Response ◽

Vaccine Development ◽

Innate Immune ◽

Interferon Response ◽

Host Immune System ◽

Type I ◽

Adaptive Responses ◽

Rna Sensors

: Innate immunity is the first line of defence elicited by the host immune system to fight against invading pathogens such as viruses and bacteria. From this elementary immune response, the more complex antigen-specific adaptive responses are recruited to provide a long-lasting memory against the pathogens. Innate immunity gets activated when the host cell utilizes a diverse set of receptors known as pattern recognition receptors (PRR) to recognize the viruses that have penetrated the host and respond with cellular processes like complement system, phagocytosis, cytokine release and inflammation and destruction of NK cells. Viral RNA or DNA or viral intermediate products are recognized by receptors like toll-like receptors(TLRs), nucleotide oligomerization domain(NOD)-like receptors (NLRs) and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) thereby, inducing type I interferon response (IFN) and other proinflammatory cytokines in infected cells or other immune cells. But certain viruses can evade the host innate immune response to replicate efficiently, triggering the spread of the viral infection. The present review describes the similarity in the mechanism chosen by viruses from different families -HIV, SARS-CoV2 and Nipah viruses to evade the innate immune response and how efficiently they establish the infection in the host. The review also addresses the stages of developments of various vaccines against these viral diseases and the challenges encountered by the researchers during vaccine development.

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The Hypoxia-Inducible Transcription Factor ZNF395 Is Controlled by IĸB Kinase-Signaling and Activates Genes Involved in the Innate Immune Response and Cancer

PLoS ONE ◽

10.1371/journal.pone.0074911 ◽

2013 ◽

Vol 8 (9) ◽

pp. e74911 ◽

Cited By ~ 17

Author(s):

Darko Jordanovski ◽

Christine Herwartz ◽

Anna Pawlowski ◽

Stefanie Taute ◽

Peter Frommolt ◽

...

Keyword(s):

Immune Response ◽

Transcription Factor ◽

Innate Immune Response ◽

Innate Immune ◽

Kinase Signaling

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Lifespan Extension in C. elegans Caused by Bacterial Colonization of the Intestine and Subsequent Activation of an Innate Immune Response

Developmental Cell ◽

10.1016/j.devcel.2019.03.010 ◽

2019 ◽

Vol 49 (1) ◽

pp. 100-117.e6 ◽

Cited By ~ 26

Author(s):

Sandeep Kumar ◽

Brian M. Egan ◽

Zuzana Kocsisova ◽

Daniel L. Schneider ◽

John T. Murphy ◽

...

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Bacterial Colonization ◽

Innate Immune ◽

Lifespan Extension ◽

C Elegans ◽

Subsequent Activation

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The transcription factor NRF2 enhances melanoma malignancy by blocking differentiation and inducing COX2 expression

Oncogene ◽

10.1038/s41388-020-01477-8 ◽

2020 ◽

Vol 39 (44) ◽

pp. 6841-6855 ◽

Cited By ~ 3

Author(s):

Christina Jessen ◽

Julia K. C. Kreß ◽

Apoorva Baluapuri ◽

Anita Hufnagel ◽

Werner Schmitz ◽

...

Keyword(s):

Oxidative Stress ◽

Immune Response ◽

Transcription Factor ◽

Prostaglandin E2 ◽

Innate Immune Response ◽

Stress Responses ◽

Melanoma Cells ◽

Innate Immune ◽

Dependent Manner

AbstractThe transcription factor NRF2 is the major mediator of oxidative stress responses and is closely connected to therapy resistance in tumors harboring activating mutations in the NRF2 pathway. In melanoma, such mutations are rare, and it is unclear to what extent melanomas rely on NRF2. Here we show that NRF2 suppresses the activity of the melanocyte lineage marker MITF in melanoma, thereby reducing the expression of pigmentation markers. Intriguingly, we furthermore identified NRF2 as key regulator of immune-modulating genes, linking oxidative stress with the induction of cyclooxygenase 2 (COX2) in an ATF4-dependent manner. COX2 is critical for the secretion of prostaglandin E2 and was strongly induced by H2O2 or TNFα only in presence of NRF2. Induction of MITF and depletion of COX2 and PGE2 were also observed in NRF2-deleted melanoma cells in vivo. Furthermore, genes corresponding to the innate immune response such as RSAD2 and IFIH1 were strongly elevated in absence of NRF2 and coincided with immune evasion parameters in human melanoma datasets. Even in vitro, NRF2 activation or prostaglandin E2 supplementation blunted the induction of the innate immune response in melanoma cells. Transcriptome analyses from lung adenocarcinomas indicate that the observed link between NRF2 and the innate immune response is not restricted to melanoma.

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Determination of the Role and Active Sites of PKC-Delta-Like from Lamprey in Innate Immunity

International Journal of Molecular Sciences ◽

10.3390/ijms20133357 ◽

2019 ◽

Vol 20 (13) ◽

pp. 3357

Author(s):

Yang Xu ◽

Huan Zhao ◽

Yang Tian ◽

Kaixia Ren ◽

Nan Zheng ◽

...

Keyword(s):

Immune Response ◽

Innate Immunity ◽

Immune System ◽

Innate Immune Response ◽

Active Sites ◽

Innate Immune ◽

Pkc Delta ◽

Kinase C ◽

Catalytic Fragment

Protein kinase C-δ (PKC-δ) is an important protein in the immune system of higher vertebrates. Lampreys, as the most primitive vertebrates, have a uniquevariable lymphocyte receptor (VLR) immune system. PKC-δ-like is a crucial functional gene in lampreys and is highly expressed in their immune organs. In this study, lampreys were stimulated with different immunogens, and lipopolysaccharide (LPS) was found to increase the expression of PKC-δ-like. Overexpression of PKC-δ-like could also effectively activate the innate immune response. We further demonstrated that PKC-δ-like-CF, a catalytic fragment of PKC-δ-like, is responsible for activating the innate immune response, and Thr-211, which is Thr-419 of PKC-δ-like, was confirmed to be the key site affecting PKC-δ-like-CF activity. These results indicated that PKC-δ-like from lamprey may have an important role in the innate immune response.

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Innate Immune Response against Hepatitis C Virus: Targets for Vaccine Adjuvants

Vaccines ◽

10.3390/vaccines8020313 ◽

2020 ◽

Vol 8 (2) ◽

pp. 313

Author(s):

Daniel Sepulveda-Crespo ◽

Salvador Resino ◽

Isidoro Martinez

Keyword(s):

Immune Response ◽

Innate Immunity ◽

Hepatitis C Virus ◽

Hepatitis C ◽

Innate Immune Response ◽

Vaccine Development ◽

Innate Immune ◽

World Health ◽

Cell Immune Response ◽

Vaccine Adjuvants

Despite successful treatments, hepatitis C virus (HCV) infections continue to be a significant world health problem. High treatment costs, the high number of undiagnosed individuals, and the difficulty to access to treatment, particularly in marginalized susceptible populations, make it improbable to achieve the global control of the virus in the absence of an effective preventive vaccine. Current vaccine development is mostly focused on weakly immunogenic subunits, such as surface glycoproteins or non-structural proteins, in the case of HCV. Adjuvants are critical components of vaccine formulations that increase immunogenic performance. As we learn more information about how adjuvants work, it is becoming clear that proper stimulation of innate immunity is crucial to achieving a successful immunization. Several hepatic cell types participate in the early innate immune response and the subsequent inflammation and activation of the adaptive response, principally hepatocytes, and antigen-presenting cells (Kupffer cells, and dendritic cells). Innate pattern recognition receptors on these cells, mainly toll-like receptors, are targets for new promising adjuvants. Moreover, complex adjuvants that stimulate different components of the innate immunity are showing encouraging results and are being incorporated in current vaccines. Recent studies on HCV-vaccine adjuvants have shown that the induction of a strong T- and B-cell immune response might be enhanced by choosing the right adjuvant.

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A newly established in vitro culture using transgenic Drosophila reveals functional coupling between the phospholipase A2-generated fatty acid cascade and lipopolysaccharide-dependent activation of the immune deficiency (imd) pathway in insect immunity

Biochemical Journal ◽

10.1042/bj20021603 ◽

2003 ◽

Vol 371 (1) ◽

pp. 205-210 ◽

Cited By ~ 69

Author(s):

Masashi YAJIMA ◽

Masatoshi TAKADA ◽

Nahoko TAKAHASHI ◽

Haruhisa KIKUCHI ◽

Shunji NATORI ◽

...

Keyword(s):

Immune Deficiency ◽

Immune Response ◽

Innate Immunity ◽

Arachidonic Acid ◽

Fatty Acid ◽

Innate Immune Response ◽

Innate Immune ◽

Insect Immunity ◽

Imd Pathway

Innate immunity is the first line of defence against infectious micro-organisms, and the basic mechanisms of pathogen recognition and response activation are evolutionarily conserved. In mammals, the innate immune response in combination with antigen-specific recognition is required for the activation of adaptive immunity. Therefore, innate immunity is a pharmaceutical target for the development of immune regulators. Here, for the purpose of pharmaceutical screening, we established an in vitro culture based on the innate immune response of Drosophila. The in vitro system is capable of measuring lipopolysaccharide (LPS)-dependent activation of the immune deficiency (imd) pathway, which is similar to the tumour necrosis factor signalling pathway in mammals. Screening revealed that well-known inhibitors of phospholipase A2 (PLA2), dexamethasone (Dex) and p-bromophenacyl bromide (BPB) inhibit LPS-dependent activation of the imd pathway. The inhibitory effects of Dex and BPB were suppressed by the addition of an excess of three (arachidonic acid, eicosapentaenoic acid and γ-linolenic acid) of the fatty acids so far tested. Arachidonic acid, however, did not activate the imd pathway when used as the sole agonist. These findings indicate that PLA2 participates in LPS-dependent activation of the imd pathway via the generation of arachidonic acid and other mediators, but requires additional signalling from LPS stimulation. Moreover, PLA2 was activated in response to bacterial infection in Sarcophaga. These results suggest a functional link between the PLA2-generated fatty acid cascade and the LPS-stimulated imd pathway in insect immunity.

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