scholarly journals Structure and dynamics of pathway activation by the Toll immunoreceptor from the viral mosquito vector Aedes aegypti

2021 ◽  
Author(s):  
Monique Gangloff ◽  
Yoann Saucereau ◽  
Thomas Wilson ◽  
Matthew Tang ◽  
Martin Moncrieffe ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Tissue Regeneration ◽  
Expression Patterns ◽  
Mosquito Vector ◽  
Specific Interactions ◽  
Transcriptional Signature ◽  
Structure And Dynamics ◽  
Pathway Activation ◽  
Receptor Interactions ◽  
Efficient Vector

Abstract A. aegypti has evolved to become an efficient vector for arboviruses such as Dengue but the mechanisms of host-pathogen immune tolerance are unknown. Toll receptors and Spaetzle (Spz) ligands have undergone duplication raising the possibility of neofunctionalization and mutualism to develop between arboviruses and mosquitoes. Here we present cryo-EM structures and biophysical characterisation of low affinity Toll5A-Spz1C complexes that display transient but specific interactions. Binding of the first ligand alters receptor-receptor interactions and promotes asymmetric contacts in the vicinity of the Z-loop in Toll5A. This conformation then restricts binding of a second ligand, while temporarily bridging the C-termini that promote signalling. Increased receptor concentrations promote inactivating head-to-head receptor assemblies. Furthermore, the transcriptional signature of Spz1C differs from other Spz cytokines in the control of genes involved in innate immunity, lipid metabolism and tissue regeneration. Given the remarkable DENV-induced expression patterns of these proteins, our data rationalises how Spz1C upregulation might promote antimicrobial defence in the midgut, and Toll5A upregulation, viral tolerance in the salivary glands.

scholarly journals Viral tolerance in Aedes aegypti relies on the negative cooperativity between Toll5A and the cytokine ligand Spz1C

2021 ◽  
Author(s):  
Yoann Saucereau ◽  
Thomas H Wilson ◽  
Martin C. Moncrieffe ◽  
Steven W Hardwick ◽  
Dimitri Y Chirgadze ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Lipid Metabolism ◽  
Gene Duplication ◽  
Tissue Regeneration ◽  
Expression Patterns ◽  
Negative Cooperativity ◽  
Specific Interactions ◽  
Transcriptional Responses ◽  
Receptor Interactions ◽  
Efficient Vector

A. aegypti has evolved to become an efficient vector of Dengue viruses among other arboviruses despite Toll-regulated infection levels. Interestingly, both Toll and its ligand Spaetzle (Spz) have undergone gene duplication in A. aegypti raising the possibility of neofunctionalization and mutualism to develop between arboviruses and mosquitoes. Here we present cryo-EM structures and biophysical characterisation of low affinity Toll5A-Spz1C complexes that display transient but specific interactions. Binding of the first ligand alters receptor-receptor interactions and promotes asymmetric contacts in the vicinity of the Z-loop in Toll5A. This conformation then restricts binding of a second ligand, while bridging the C termini that promote signalling. In contrast, increased receptor concentrations promote inactivating head-to-head receptor assemblies. We also found that Spz1C differs from orthologous and paralogous cytokines in their transcriptional responses upon A. aegypti Aag2 cell stimulation. Interestingly, Spz1C uniquely controls genes involved in innate immunity, lipid metabolism and tissue regeneration. Given the remarkable DENV-induced expression patterns of these proteins, our data rationalises how Spz1C upregulation might promote innate immunity in the midgut, and Toll5A upregulation, viral tolerance in the salivary glands.

scholarly journals Identification and Functional Analysis of a Lysozyme Gene from Coridius Chinensis (Hemiptera: Dinidoridae)

Biology ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 330
Author(s):  
Hai Huang ◽  
Juan Du ◽  
Shang-Wei Li ◽  
Tao Gong
Keyword(s):  
Innate Immunity ◽  
Fat Body ◽  
Expression Patterns ◽  
Evolutionary Relationship ◽  
Immune Defense ◽  
Amino Acid Residues ◽  
Immune Effector ◽  
Medicinal Value ◽  
Muramidase Activity ◽  
Insect Innate Immunity

Coridius chinensis is a valuable medicinal insect resource in China. Previous studies have indicated that the antibacterial and anticancer effects of the C. chinensis extract mainly come from the active polypeptides. Lysozyme is an effective immune effector in insect innate immunity and usually has excellent bactericidal effects. There are two kinds of lysozymes in insects, c-type and i-type, which play an important role in innate immunity and intestinal digestion. Studying lysozyme in C. chinensis will be helpful to further explore the evolutionary relationship and functional differences among lysozymes of various species and to determine whether they have biological activity and medicinal value. In this study, a lysozyme CcLys2 was identified from C. chinensis. CcLys2 contains 223 amino acid residues, and possesses a typical domain of the c-type lysozyme and a putative catalytic site formed by two conserved residues Glu32 and Asp50. Phylogenetic analysis showed that CcLys2 belongs to the H-branch of the c-type lysozyme. The analysis of spatiotemporal expression patterns indicated that CcLys2 was mainly expressed in the fat body of C. chinensis adults and was highly expressed in the second- and fifth-instar nymphs. In addition, CcLys2 was significantly up-regulated after injecting and feeding bacteria. In the bacterial inhibition assay, it was found that CcLys2 had antibacterial activity against Gram-positive bacteria at a low pH. These results indicate that CcLys2 has muramidase activity, involves in the innate immunity of C. chinensis, and is also closely related to the bacterial immune defense or digestive function of the intestine.

scholarly journals ERβ1 Expression Patterns Have Different Effects On EGFR TKIs Treatment Response in EGFR Mutant Lung Adenocarcinomas.

2020 ◽  
Author(s):  
Lijuan Zhang ◽  
Meng Tian ◽  
Jiamao Lin ◽  
Jianbo Zhang ◽  
Haiyong Wang ◽  
...  
Keyword(s):  
Western Blot ◽  
Cell Lines ◽  
Kinase Inhibitors ◽  
Expression Patterns ◽  
Estrogen Therapy ◽  
Growth Factor Receptor ◽  
Treatment Resistance ◽  
Progression Free Survival ◽  
Pathway Activation ◽  
Egfr Tkis

Abstract Background: Estrogen receptor β (ERβ) can regulate cellular signaling through non-genomic mechanisms, potentially promoting resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, the mechanisms underlying the ERβ-mediated resistance to EGFR TKIs remain poorly understood. Methods: qRT-PCR was performed to investigate ERβ1 and ERβ5 expression levels in cell lines. The localization of ERβ and ERβ1 within cells was assessed using immunocytochemistry and immunofluorescence. The effect of estradiol and/or gefitinib on EGFR signaling pathways was determined by western blot. Cell viability and colony formation assays were used to assess gefitinib response for different cell lines. The apoptosis was verified by tunel and western blot. Immunohistochemistry was used to assess the expression of ERβ1 in lung adenocarcinoma tissues. Patient survival was estimated using the Kaplan-Meier method, and comparisons between groups were conducted using log-rank tests. Results: PC9 cell lines stably overexpressing ERβ1 or ERβ1/ERβ5 were established successfully. Immunofluorescence revealed that ERβ5 overexpression partly retained ERβ1 in the cytoplasm. Immunoblotting analyses revealed that EGFR pathway activation levels were higher in PC9/ERβ1/5 cells than those in PC9/ERβ1 or control PC9 cells. In the presence of estradiol, PI3K/AKT/mTOR pathway activation levels were higher in ERβ1/5-expressing cells than those in ERβ1-expressing cells. Additionally, PC9/ERβ1/5 cells were less prone to the cytotoxic and pro-apoptotic effects of gefitinib compared with PC9/ERβ1 or control PC9 cells. Conclusion: Cytoplasmic ERβ1 was associated with poor progression-free survival in lung cancer patients treated with EGFR TKIs. These results suggest that anti-estrogen therapy might reverse EGFR TKI treatment resistance to some extent in selected patients.

Mo1735 Fibrogenesis Is Innate Immunity Driven in Chronic DSS Colitis and Associated With Distinct Gene Expression Patterns

2014 ◽  
Vol 146 (5) ◽  
pp. S-647
Author(s):  
Christine M. Breynaert ◽  
Ingrid Arijs ◽  
Jonathan Cremer ◽  
Leentje Van Lommel ◽  
Frans C. Schuit ◽  
...  
Keyword(s):  
Gene Expression ◽  
Innate Immunity ◽  
Expression Patterns ◽  
Gene Expression Patterns ◽  
Distinct Gene ◽  
Dss Colitis

scholarly journals Inferring malaria parasite population structure from serological networks

2008 ◽  
Vol 276 (1656) ◽  
pp. 477-485 ◽  
Author(s):  
Caroline O Buckee ◽  
Peter C Bull ◽  
Sunetra Gupta
Keyword(s):  
Population Structure ◽  
Malaria Parasite ◽  
Expression Patterns ◽  
Immune Selection ◽  
Structure And Dynamics ◽  
Control Programmes ◽  
Population Structures ◽  
Population Structure And Dynamics ◽  
Serological Data ◽  
Different Levels

The malaria parasite Plasmodium falciparum is characterized by high levels of genetic diversity at antigenic loci involved in virulence and immune evasion. Knowledge of the population structure and dynamics of these genes is important for designing control programmes and understanding the acquisition of immunity to malaria; however, high rates of homologous and non-homologous recombination as well as complex patterns of expression within hosts have hindered attempts to elucidate these structures experimentally. Here, we analyse serological data from Kenya using a novel network technique to deconstruct the relationships between patients' immune responses to different parasite isolates. We show that particular population structures and expression patterns produce distinctive signatures within serological networks of parasite recognition, which can be used to discriminate between competing hypotheses regarding the organization of these genes. Our analysis suggests that different levels of immune selection occur within different groups of the same multigene family leading to mixed population structures.

scholarly journals Mayaro Virus Infec6on Elicits an Innate Immune Response and Represses Autophagy in Anopheles stephensi

2020 ◽  
Author(s):  
Cory A. Henderson ◽  
Marco Brustolin ◽  
Shivanand Hegde ◽  
Grant L. Hughes ◽  
Jason L. Rasgon
Keyword(s):  
Immune Response ◽  
South America ◽  
Small Rna ◽  
Anopheles Stephensi ◽  
Expression Patterns ◽  
Molecular Response ◽  
Mosquito Vector ◽  
The Caribbean ◽  
Infection Response ◽  
Mayaro Virus

ABSTRACTMayaro virus (MAYV) is an arboviral pathogen in the genus Alphavirus that is circulating in South America with potential to spread to naïve regions. MAYV is also one of the few viruses with the ability to be transmitted by mosquitoes in the genus Anopheles, as well as the typical arboviral transmitting mosquitoes in the genera Aedes and Haemagogus. Few studies have investigated the infection response of Anopheles mosquitoes. In this study we detail the transcriptomic and small RNA responses of An. stephensi to infection with MAYV via infectious bloodmeal at 2, 7, and 14 days post infection (dpi). 361 unique transcripts were significantly regulated and 79 novel miRNAs were identified. Gene ontology analysis of transcripts regulated at each timepoint suggested activation of the Toll pathway at 2 and 7 dpi and repression of pathways related to autophagy at 14 dpi. These findings provide a basic understanding of the infection response of An. stephensi to MAYV and help to identify host factors which might be useful to target to inhibit viral replication in Anopheles mosquitoes.AUTHOR SUMMARYMayaro virus (MAYV) is a mosquito-borne Alphavirus responsible for outbreaks in South America and the Caribbean. In this study we infected Anopheles stephensi with MAYV and sequenced mRNA and small RNA to understand how MAYV infection impacts gene transcription and the expression of small RNAs in the mosquito vector. Genes involved with innate immunity and autophagy are regulated in response to MAYV infection of An. stephensi. We also discovered novel miRNAs and described their expression patterns following bloodmeal ingestion. These results suggest that MAYV does induce a molecular response to infection in its mosquito vector species and that MAYV may have mechanisms to evade the vector immune response.

scholarly journals Innate immunity mediator STING modulates nascent DNA metabolism at stalled forks in human cells

2021 ◽  
Author(s):  
Vy N. Nguyen ◽  
Salomé Brunon ◽  
Maria N. Pavlova ◽  
Pavlo Lazarchuk ◽  
Roya D. Sharifian ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Replication Forks ◽  
Wild Type ◽  
Feedback Connection ◽  
Pathway Activation ◽  
Foreign Dna ◽  
Sting Pathway

The cGAS/STING pathway, part of the innate immune response to foreign DNA, is known to be activated by cell's own DNA arising from the processing of the genome, including the excision of nascent DNA at arrested replication forks. We found STING activation to affect nascent DNA processing, suggesting a novel, unexpected feedback connection between the two events. Depletion of STING suppressed and re-expression of the protein in STING-deficient cells upregulated degradation of nascent DNA. Fork arrest was accompanied by the STING pathway activation, and a STING mutant that does not activate the pathway failed to upregulate nascent strand degradation. Consistent with this, cells expressing the STING mutant had a reduced level of RPA on parental and nascent DNA of arrested forks as well as a reduced CHK1 activation compared to the cells with wild type STING. Together our findings reveal a novel connection between replication stress and innate immunity.

scholarly journals NHR-49/PPAR-α and HLH-30/TFEB promote C. elegans host defense via a flavin-containing monooxygenase

2020 ◽  
Author(s):  
Khursheed A. Wani ◽  
Debanjan Goswamy ◽  
Stefan Taubert ◽  
Ramesh Ratnappan ◽  
Arjumand Ghazi ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Host Defense ◽  
Bacterial Infections ◽  
Model Organism ◽  
Defense Responses ◽  
Cellular Level ◽  
Nuclear Hormone Receptor ◽  
Multiple Infection ◽  
C Elegans ◽  
Transcriptional Signature

SUMMARYDuring bacterial infection, the host is confronted with multiple overlapping signals that are integrated at the organismal level to produce defensive host responses. How multiple infection signals are sensed by the host and how they elicit the transcription of host defense genes is much less understood at the whole-animal level than at the cellular level. The model organism Caenorhabditis elegans is known to mount transcriptional defense responses against intestinal bacterial infections that elicit overlapping starvation and infection responses, but the regulation of such responses is not well understood. Direct comparison of C. elegans that were starved or infected with Staphylococcus aureus revealed a large infection-specific transcriptional signature. This signature was almost completely abrogated by deletion of transcription factor hlh-30/TFEB, except for six genes including a flavin-containing monooxygenase (FMO) gene, fmo-2/FMO5. Deletion of fmo-2/FMO5 severely compromised infection survival, thus identifying the first FMO with innate immunity functions in animals. Moreover, the mechanism of fmo-2/FMO5 induction required the nuclear hormone receptor, NHR-49/PPAR-α, which induced fmo-2/FMO5 and host defense cell non-autonomously. These findings for the first time reveal an infection-specific host response to S. aureus, identify HLH-30/TFEB as its main regulator, reveal that FMOs are important innate immunity effectors in animals, and identify the mechanism of FMO regulation through NHR-49/PPAR-α in C. elegans, with important implications for innate host defense in higher organisms.

scholarly journals Glucose transporter Glut1 influences Plasmodium berghei infection in Anopheles stephensi

2020 ◽  
Author(s):  
Mengfei Wang ◽  
Jingwen Wang
Keyword(s):  
Transcriptome Analysis ◽  
Plasmodium Berghei ◽  
Serine Proteases ◽  
Anopheles Stephensi ◽  
Glucose Transporter ◽  
Vector Competence ◽  
Expression Patterns ◽  
Mosquito Vector ◽  
Temporal Expression ◽  
Expression Of Genes

Abstract Background Sugar feeding provides energy for mosquito. Facilitated glucose transporters (GLUT) are responsible for cellular uptake of glucose. However, the knowledge of GLUT function in Anopheles mosquito is limited. Methods Phylogenetic analysis of GLUTs in Anopheles stephensi (AsteGlut) was performed by the maximum likelihood and Bayesian method. The spatial and temporal expression patterns of three Astegluts were analyzed by qPCR. The function of AsteGlut1 was examined using a dsRNA-mediated RNA interference method. Transcriptome analysis was used to understand the influence of AsteGlut1 on mosquito vector competence. Results We identified 3 glut genes, Asteglut1 , Asteglutx and Asteglut3 in An. stephensi . Asteglut1 and Asteglut3 were mainly localized in the midgut. The expression of all three Astegluts were strongly induced after blood meal. All three genes were knocked down successfully, but only abrogation of Asteglut1 significantly increased the susceptibility of An. stephensi to Plasmodium berghei infection. Our transcriptome analysis revealed that knockdown of Asteglut1 differentially regulated expression of genes associated with the functional clusters including detoxification, serine proteases, and immunity. The dysregulation of multiple pathways might contribute to the increased P. berghei infection. Conclusions Our study shows that Asteglut1 plays a role in defense against P. berghei in An. stephensi . The regulation of Asteglut1 on vector competence might through modulating multiple biological processes, including detoxification and immunity.

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