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Immunology
Involvement of H-Ras in the adaptive immunity of Nile tilapia by regulating lymphocyte activation.
Apr 16, 2019   Fish & Shellfish Immunology
Wei X, Zhao T, Zhang Y, Ai K, Li H, Yang J
Involvement of H-Ras in the adaptive immunity of Nile tilapia by regulating lymphocyte activation.
Apr 16, 2019
Fish & Shellfish Immunology
H-Ras is a guanosine triphosphatase (GTPase), which acts as a molecular switch and controls multiple important cellular processes including lymphocyte activation and function. However, regulatory mechanism of adaptive immune response by H-Ras remains unclear in non-mammalian animals. In the present study, we investigated the involvement of H-Ras in lymphocyte activation with a teleost model Oreochromis niloticus. H-Ras from O. niloticus (On-H-Ras) is highly conserved with those from other vertebrates. The mRNA of On-H-Ras showed a wide expression pattern in the lymphoid-tissues and with the highest level in liver. After Aeromonas hydrophila infection, transcription of On-H-Ras was significantly induced on day 8 but came back to basal level on day 16, suggesting that On-H-Ras potentially participated in primary response during the adaptive immunity. Furthermore, On-H-Ras mRNA was obviously up-regulated when leukocytes were activated by T lymphocyte mitogen PHA in vitro. Meanwhile, protein level of H-Ras was also augmented once leukocytes were stimulated with lymphocyte receptor signaling agonist PMA and ionomycin. More importantly, once Ras activity was inhibited by specific inhibitor, the up-regulation of lymphocyte activation marker CD122 was obviously impaired during lymphocyte activation process. Therefore, On-H-Ras regulated lymphocyte activation through both mRNA and protein level. Altogether, our results illustrated the involvement of H-Ras in teleost adaptive immunity via controlling lymphocyte activation, and thus provided a novel perspective to understand evolution of the lymphocyte-mediated adaptive immunity.
Early signalling mechanisms underlying receptor kinase-mediated immunity in plants.
Apr 12, 2019   Philosophical Transactions Of The Royal Society Of London. Series B, Biological Sciences
Zhou Z, Zhao Y, Bi G, Liang X, Zhou JM
Early signalling mechanisms underlying receptor kinase-mediated immunity in plants.
Apr 12, 2019
Philosophical Transactions Of The Royal Society Of London. Series B, Biological Sciences
Pattern-recognition receptors (PRRs), which are single transmembrane proteins belonging to the receptor-like kinase (RLK) and receptor-like protein (RLP) super families, sense microbe- and host-derived molecular patterns to activate immune responses in plants. PRRs associate with co-receptors, scaffold proteins and receptor-like cytoplasmic kinases (RLCKs) to form immune receptor complexes at the cell surface, allowing activation of cellular responses upon perception of extracellular ligands. Recent advances have uncovered new mechanisms by which these immune receptor complexes are regulated at the levels of composition, stability and activity. It has become clear that RLCKs are central components directly linking PRRs to multiple downstream signalling modules. Furthermore, new studies have provided important insights into the regulation of reactive oxygen species, mitogen-activated protein (MAP) kinase cascades and heterotrimeric G proteins, which has not only deepened our understanding of immunity, but also expanded our view of transmembrane signalling in general. This article is part of the theme issue 'Biotic signalling sheds light on smart pest management'.
Cathelicidin is a "fire alarm", generating protective NLRP3-dependent airway epithelial cell inflammatory responses during infection with Pseudomonas aeruginosa.
Apr 12, 2019   PLoS Pathogens
McHugh BJ, Wang R, Li HN, Beaumont PE, Kells R, Stevens H, Young L, Rossi AG, Gray RD, Dorin JR, Gwyer Findlay EL, Brough D, Davidson DJ
Cathelicidin is a "fire alarm", generating protective NLRP3-dependent airway epithelial cell inflammatory responses during infection with Pseudomonas aeruginosa.
Apr 12, 2019
PLoS Pathogens
Pulmonary infections are a major global cause of morbidity, exacerbated by an increasing threat from antibiotic-resistant pathogens. In this context, therapeutic interventions aimed at protectively modulating host responses, to enhance defence against infection, take on ever greater significance. Pseudomonas aeruginosa is an important multidrug-resistant, opportunistic respiratory pathogen, the clearance of which can be enhanced in vivo by the innate immune modulatory properties of antimicrobial host defence peptides from the cathelicidin family, including human LL-37. Initially described primarily as bactericidal agents, cathelicidins are now recognised as multifunctional antimicrobial immunomodulators, modifying host responses to pathogens, but the key mechanisms involved in these protective functions are not yet defined. We demonstrate that P. aeruginosa infection of airway epithelial cells promotes extensive infected cell internalisation of LL-37, in a manner that is dependent upon epithelial cell interaction with live bacteria, but does not require bacterial Type 3 Secretion System (T3SS). Internalised LL-37 acts as a second signal to induce inflammasome activation in airway epithelial cells, which, in contrast to myeloid cells, are relatively unresponsive to P. aeruginosa. We demonstrate that this is mechanistically dependent upon cathepsin B release, and NLRP3-dependent activation of caspase 1. These result in LL-37-mediated release of IL-1β and IL-18 in a manner that is synergistic with P. aeruginosa infection, and can induce caspase 1-dependent death of infected epithelial cells, and promote neutrophil chemotaxis. We propose that cathelicidin can therefore act as a second signal, required by P. aeruginosa infected epithelial cells to promote an inflammasome-mediated altruistic cell death of infection-compromised epithelial cells and act as a "fire alarm" to enhance rapid escalation of protective inflammatory responses to an uncontrolled infection. Understanding this novel modulatory role for cathelicidins, has the potential to inform development of novel therapeutic strategies to antibiotic-resistant pathogens, harnessing innate immunity as a complementation or alternative to current interventions.
Introducing a Spectrum of Long-Range Genomic Deletions in Human Embryonic Stem Cells Using Type I CRISPR-Cas.
Apr 16, 2019   Molecular Cell
Dolan AE, Hou Z, Xiao Y, Gramelspacher MJ, Heo J, Howden SE, Freddolino PL, Ke A, Zhang Y
Introducing a Spectrum of Long-Range Genomic Deletions in Human Embryonic Stem Cells Using Type I CRISPR-Cas.
Apr 16, 2019
Molecular Cell
CRISPR-Cas systems enable microbial adaptive immunity and provide eukaryotic genome editing tools. These tools employ a single effector enzyme of type II or V CRISPR to generate RNA-guided, precise genome breaks. Here we demonstrate the feasibility of using type I CRISPR-Cas to effectively introduce a spectrum of long-range chromosomal deletions with a single RNA guide in human embryonic stem cells and HAP1 cells. Type I CRISPR systems rely on the multi-subunit ribonucleoprotein (RNP) complex Cascade to identify DNA targets and on the helicase-nuclease enzyme Cas3 to degrade DNA processively. With RNP delivery of T. fusca Cascade and Cas3, we obtained 13%-60% editing efficiency. Long-range PCR-based and high-throughput-sequencing-based lesion analyses reveal that a variety of deletions, ranging from a few hundred base pairs to 100 kilobases, are created upstream of the target site. These results highlight the potential utility of type I CRISPR-Cas for long-range genome manipulations and deletion screens in eukaryotes.
Modulating Adaptive Immunity in Vascular Disease: CD4 to the Fore.
Apr 12, 2019   Journal Of The American College Of Cardiology
Libby P, Lichtman AI
Impacts of circadian rhythm and melatonin on the specific activities of immune and antioxidant enzymes of the Chinese mitten crab (Eriocheir sinensis).
Apr 16, 2019   Fish & Shellfish Immunology
She Q, Han Z, Liang S, Xu W, Li X, Zhao Y, Wei H, Dong J, Li Y
Impacts of circadian rhythm and melatonin on the specific activities of immune and antioxidant enzymes of the Chinese mitten crab (Eriocheir sinensis).
Apr 16, 2019
Fish & Shellfish Immunology
Many physiological functions of crustaceans show a rhythmic change to adapt to daily environmental cycles. However, daily variation in the immune and antioxidant status and its possible correlation with circulatory melatonin levels during the daily cycle have not been reported in the Chinese mitten crab, Eriocheir sinensis. In this study, the specific activities of immune and antioxidant enzymes of E. sinensis during the 24 h cycle and its relationship with injected doses of melatonin were evaluated. The results showed that the immune parameters in the hemolymph, such as total hemolymph count, alkaline phosphatase, lysozyme, acid phosphatase, and phenol oxidase, exhibited bimodal patterns during the 24 h cycle, these parameters were synchronized with the activity of antioxidant enzymes such as malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase, and catalase. However, there was only one peak in the muscle (during 1200-1600 h) and gills (during 0400-0800 h). The survival rate reached approximately 80% in 5 days when melatonin concentrations were lower than 0.05 g/L, significantly decreasing as melatonin concentrations increased. Four hours after melatonin injection, MDA levels in the muscle and hemolymph were significantly lower than those in the control group. Eight hours after melatonin injection, SOD levels in the hemolymph were significantly higher than those in the control group. These findings highlight the importance of considering circadian regulation of innate immunity when comparing immune responses at fixed times.
Exposure to artificial light at night increases innate immune activity during development in a precocial bird.
Apr 16, 2019   Comparative Biochemistry And Physiology. Part A, Molecular & Integrative Physiology
Saini C, Hutton P, Gao S, Simpson RK, Giraudeau M, Sepp T, Webb E, McGraw KJ
Exposure to artificial light at night increases innate immune activity during development in a precocial bird.
Apr 16, 2019
Comparative Biochemistry And Physiology. Part A, Molecular & Integrative Physiology
Humans have greatly altered Earth's night-time photic environment via the production of artificial light at night (ALAN; e.g. street lights, car traffic, billboards, lit buildings). ALAN is a problem of growing importance because it may significantly disrupt the seasonal and daily physiological rhythms and behaviors of animals. There has been considerable interest in the impacts of ALAN on health of humans and other animals, but most of this work has centered on adults and we know comparatively little about effects on young animals. We exposed 3-week-old king quail (Excalfactoria chinensis) to a constant overnight blue-light regime for 6 weeks and assessed weekly bactericidal activity of plasma against Escherichia coli - a commonly employed metric of innate immunity in animals. We found that chronic ALAN exposure significantly increased bactericidal activity and that this elevation in immune performance manifested at different developmental time points in males and females. Whether this short-term increase in immune activity can be extended to wild animals, and whether ALAN-mediated increases in immune activity have positive or negative fitness effects, are unknown and will provide interesting avenues for future studies.
Increased mucosal neutrophil survival is associated with altered microbiota in HIV infection.
Apr 11, 2019   PLoS Pathogens
Hensley-McBain T, Wu MC, Manuzak JA, Cheu RK, Gustin A,   . . . . . .   , Burgener AD, Hunt PW, Hope TJ, Collier AC, Klatt NR
Increased mucosal neutrophil survival is associated with altered microbiota in HIV infection.
Apr 11, 2019
PLoS Pathogens
Gastrointestinal (GI) mucosal dysfunction predicts and likely contributes to non-infectious comorbidities and mortality in HIV infection and persists despite antiretroviral therapy. However, the mechanisms underlying this dysfunction remain incompletely understood. Neutrophils are important for containment of pathogens but can also contribute to tissue damage due to their release of reactive oxygen species and other potentially harmful effector molecules. Here we used a flow cytometry approach to investigate increased neutrophil lifespan as a mechanism for GI neutrophil accumulation in chronic, treated HIV infection and a potential role for gastrointestinal dysbiosis. We report that increased neutrophil survival contributes to neutrophil accumulation in colorectal biopsy tissue, thus implicating neutrophil lifespan as a new therapeutic target for mucosal inflammation in HIV infection. Additionally, we characterized the intestinal microbiome of colorectal biopsies using 16S rRNA sequencing. We found that a reduced Lactobacillus: Prevotella ratio associated with neutrophil survival, suggesting that intestinal bacteria may contribute to GI neutrophil accumulation in treated HIV infection. Finally, we provide evidence that Lactobacillus species uniquely decrease neutrophil survival and neutrophil frequency in vitro, which could have important therapeutic implications for reducing neutrophil-driven inflammation in HIV and other chronic inflammatory conditions.
Corrigendum: Neospora Caninum Activates p38 MAPK as an Evasion Mechanism against Innate Immunity.
Apr 14, 2019   Frontiers In Microbiology
Mota CM, Oliveira ACM, Davoli-Ferreira M, Silva MV, Santiago FM, Nadipuram SM, Vashisht AA, Wohlschlegel JA, Bradley PJ, Silva JS, Mineo JR, Mineo TWP
Effects of exogenous melatonin on clinical and pathological features of a human thyroglobulin-induced experimental autoimmune thyroiditis mouse model.
Apr 16, 2019   Scientific Reports
Lin JD, Fang WF, Tang KT, Cheng CW
Effects of exogenous melatonin on clinical and pathological features of a human thyroglobulin-induced experimental autoimmune thyroiditis mouse model.
Apr 16, 2019
Scientific Reports
Melatonin (MLT) plays a significant role in both innate and adaptive immunity, and dysregulation of the MLT signature can modify autoimmune disease phenotypes. In this study, the influence of exogenous MLT administration on regulating autoimmune thyroiditis animal models was evaluated. An experimental autoimmune thyroiditis model was established in MLT-synthesizing (CBA) and MLT-deficient (C57BL/6) mice by immunization with human thyroidglobulin (TG), which features thyrotoxicosis, thyrocyte damage, and CD3+ T cell infiltration. In TG-immunized CBA mice, exogenous MLT administration in drinking water (6 μg/ml) enhanced thyroiditis and increased TG-specific splenocyte proliferation but not the anti-thyroglobulin antibody (ATA) titer, while MLT alone caused no significant alteration in thyroid function or histopathology. Meanwhile, MLT administration did not modify thyroid function, the ATA titer, or the thyroid histopathology, but results showed an increase in the splenocyte proliferative capacity in TG-immunized C57BL/6 mice. Collectively, our data showed that early exogenous MLT modified the progression of autoimmune thyroiditis through T cell-driven immunity, and excess MLT worsened the clinical and pathological features.
Understanding the immunology of the Zostavax shingles vaccine.
Apr 16, 2019   Current Opinion In Immunology
Sullivan NL, Eberhardt CS, Wieland A, Vora KA, Pulendran B, Ahmed R
Understanding the immunology of the Zostavax shingles vaccine.
Apr 16, 2019
Current Opinion In Immunology
Zostavax is a live-attenuated varicella zoster virus (VZV) vaccine recommended for use in adults >50 years of age to prevent shingles. The main risk factor for the development of shingles is age, which correlates with decreasing cell-mediated immunity. These data suggest a predominant role of T cell immunity in controlling VZV latency. However, other components of the immune system may also contribute. In this review, we will discuss how the immune system responds to Zostavax, focusing on recent studies examining innate immunity, transcriptomics, metabolomics, cellular, and humoral immunity.
Signal pathways involved in microbe-nematode interactions provide new insights into the biocontrol of plant-parasitic nematodes.
Apr 12, 2019   Philosophical Transactions Of The Royal Society Of London. Series B, Biological Sciences
Liang LM, Zou CG, Xu J, Zhang KQ
Signal pathways involved in microbe-nematode interactions provide new insights into the biocontrol of plant-parasitic nematodes.
Apr 12, 2019
Philosophical Transactions Of The Royal Society Of London. Series B, Biological Sciences
Plant-parasitic nematodes (PPNs) cause severe damage to agricultural crops worldwide. As most chemical nematicides have negative environmental side effects, there is a pressing need for developing efficient biocontrol methods. Nematophagous microbes, the natural enemies of nematodes, are potential biocontrol agents against PPNs. These natural enemies include both bacteria and fungi and they use diverse methods to infect and kill nematodes. For instance, nematode-trapping fungi can sense host signals and produce special trapping devices to capture nematodes, whereas endo-parasitic fungi can kill nematodes by spore adhesion and invasive growth to break the nematode cuticle. By contrast, nematophagous bacteria can secrete virulence factors to kill nematodes. In addition, some bacteria can mobilize nematode-trapping fungi to kill nematodes. In response, nematodes can also sense and defend against the microbial pathogens using strategies such as producing anti-microbial peptides regulated by the innate immunity system. Recent progresses in our understanding of the signal pathways involved in microbe-nematode interactions are providing new insights in developing efficient biological control strategies against PPNs. This article is part of the theme issue 'Biotic signalling sheds light on smart pest management'.
A whitefly effector Bsp9 targets host immunity regulator WRKY33 to promote performance.
Apr 12, 2019   Philosophical Transactions Of The Royal Society Of London. Series B, Biological Sciences
Wang N, Zhao P, Ma Y, Yao X, Sun Y, Huang X, Jin J, Zhang Y, Zhu C, Fang R, Ye J
A whitefly effector Bsp9 targets host immunity regulator WRKY33 to promote performance.
Apr 12, 2019
Philosophical Transactions Of The Royal Society Of London. Series B, Biological Sciences
Whiteflies, Bemisia tabaci (Hemiptera), are pests causing economic damage to many crops, capable of transmitting hundreds of plant vector-borne viruses. They are believed to secrete salivary protein effectors that can improve vector colonization and reproductive fitness in host plants. However, little is known about effector biology and the precise mechanism of action of whitefly effectors. Here, we report a functional screening of B. tabaci salivary effector proteins (Bsp) capable of modulating plant innate immunity triggered by plant endogenous pattern peptide Pep1. Four immunity suppressors and two elicitors were identified. Bsp9, the most effective immunity suppressor, was further identified to directly interact with an immunity regulator WRKY33. We provide evidence that Bsp9 may suppress plant immune signalling by interfering with the interaction between WRKY33 and a central regulator in the MAPK cascade. The interference by Bsp9 therefore reduces plant resistance to whitefly by inhibiting activation of WRKY33-regulated immunity-related genes. Further detailed analysis based on transgenic plants found that whitefly effector Bsp9 could promote whitefly preference and performance, increasing virus transmission. This study enriches our knowledge on insect effector biology. This article is part of the theme issue 'Biotic signalling sheds light on smart pest management'.
An epithelial organoid model with Langerhans cells for assessing virus-host interactions.
Apr 08, 2019   Philosophical Transactions Of The Royal Society Of London. Series B, Biological Sciences
Jackson R, Eade S, Zehbe I
An epithelial organoid model with Langerhans cells for assessing virus-host interactions.
Apr 08, 2019
Philosophical Transactions Of The Royal Society Of London. Series B, Biological Sciences
Persistent infection with oncogenic human papillomavirus (HPV) may lead to cancer in mucosal and skin tissue. Consequently, HPV must have developed strategies to escape host immune surveillance. Nevertheless, most HPV infections are cleared by the infected host. Our laboratory investigates Langerhans cells (LCs), acting at the interface between innate and adaptive immunity. We hypothesize that this first line of defence is vital for potential HPV elimination. As an alternative to animal models, we use smaller-scale epithelial organoids grown from human primary keratinocytes derived from various anatomical sites. This approach is amenable to large sample sizes-an essential aspect for scientific rigour and statistical power. To evaluate LCs phenotypically and molecularly during the viral life cycle and onset of carcinogenesis, we have included an engineered myeloid cell line with the ability to acquire an LC phenotype. This model is accurately tailored for the crucial time-window of early virus elimination in a complex organism and will shed more light on our long-standing research question of how naturally occurring HPV variants influence disease development. It may also be applied to other microorganism-host interaction research or enquiries of epithelium immunobiology. Finally, our continuously updated pathogen-host analysis tool enables state-of-the-art bioinformatics analyses of next-generation sequencing data. This article is part of the theme issue 'Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses'.
Lifespan Extension in C. elegans Caused by Bacterial Colonization of the Intestine and Subsequent Activation of an Innate Immune Response.
Apr 09, 2019   Developmental Cell
Kumar S, Egan BM, Kocsisova Z, Schneider DL, Murphy JT, Diwan A, Kornfeld K
Lifespan Extension in C. elegans Caused by Bacterial Colonization of the Intestine and Subsequent Activation of an Innate Immune Response.
Apr 09, 2019
Developmental Cell
Mechanisms that control aging are important yet poorly defined. To discover longevity control genes, we performed a forward genetic screen for delayed reproductive aging in C. elegans. Here, we show that am117 is a nonsense mutation in the phm-2 gene, which encodes a protein homologous to human scaffold attachment factor B. phm-2(lf) mutant worms have an abnormal pharynx grinder, which allows live bacteria to accumulate in the intestine. This defect shortens lifespan on highly pathogenic bacteria but extends lifespan and health span on the standard E. coli diet by activating innate immunity pathways that lead to bacterial avoidance behavior and dietary restriction. eat-2(lf) mutants displayed a similar phenotype, indicating accumulation of live bacteria also triggers extended longevity in this mutant. The analysis of phm-2 elucidates connections between pathogen response and aging by defining a mechanism of longevity extension in C. elegans-bacterial colonization, innate immune activation, and bacterial avoidance behavior.
Shigella-mediated immunosuppression in the human gut: subversion extends from innate to adaptive immune responses.
Apr 09, 2019   Human Vaccines & Immunotherapeutics
Brunner K, Samassa F, Sansonetti PJ, Phalipon A
Shigella-mediated immunosuppression in the human gut: subversion extends from innate to adaptive immune responses.
Apr 09, 2019
Human Vaccines & Immunotherapeutics
The enteropathogen, Shigella, is highly virulent and remarkably adjusted to the intestinal environment of its almost exclusive human host. Key for Shigella pathogenicity is the injection of virulence effectors into the host cell via its type three secretion system (T3SS), initiating disease onset and progression by the vast diversity of the secreted T3SS effectors and their respective cellular targets. The multifaceted modulation of host signaling pathways exerted by Shigella T3SS effectors, which include the subversion of host innate immune defenses and the promotion of intracellular bacterial survival and dissemination, have been extensively reviewed in the recent past. This review focuses on the human species specificity of Shigella by discussing some possible evasion mechanisms towards the human, but not non-human or rodent gut innate defense barrier, leading to the lack of a relevant animal infection model. In addition, subversion mechanisms of the adaptive immune response are highlighted summarizing research advances of the recent years. In particular, the new paradigm of Shigella pathogenicity constituted of invasion-independent T3SS effector-mediated targeting of activated, human lymphocytes is discussed. Along with consequences on vaccine development, these findings offer new directions for future research endeavors towards a better understanding of immunity to Shigella infection.
Myeloid C-type lectin receptors in skin/mucoepithelial diseases and tumors.
Apr 09, 2019   Journal Of Leukocyte Biology
Tang C, Makusheva Y, Sun H, Han W, Iwakura Y
Myeloid C-type lectin receptors in skin/mucoepithelial diseases and tumors.
Apr 09, 2019
Journal Of Leukocyte Biology
Myeloid C-type lectin receptors (CLRs), which consist of an extracellular carbohydrate recognition domain and intracellular signal transducing motif such as the immunoreceptor tyrosine-based activation motif (ITAM) or immunoreceptor tyrosine-based inhibitory motif (ITIM), are innate immune receptors primarily expressed on myeloid lineage cells such as dendritic cells (DCs) and Mϕs. CLRs play important roles in host defense against infection by fungi and bacteria by recognizing specific carbohydrate components of these pathogens. However, these immune receptors also make important contributions to immune homeostasis of mucosa and skin in mammals by recognizing components of microbiota, as well as by recognizing self-components such as alarmins from dead cells and noncanonical non-carbohydrate ligands. CLR deficiency not only induces hypersensitivity to infection, but also causes dysregulation of muco-cutaneous immune homeostasis, resulting in the development of allergy, inflammation, autoimmunity, and tumors. In this review, we introduce recent discoveries regarding the roles of myeloid CLRs in the immune system exposed to the environment, and discuss the roles of these lectin receptors in the development of colitis, asthma, psoriasis, atopic dermatitis, and cancer. Although some CLRs are suggested to be involved in the development of these diseases, the function of CLRs and their ligands still largely remain to be elucidated.
Functional crosstalk across IMD and Toll pathways: insight into the evolution of incomplete immune cascades.
Apr 11, 2019   Proceedings. Biological Sciences
Nishide Y, Kageyama D, Yokoi K, Jouraku A, Tanaka H, Futahashi R, Fukatsu T
Functional crosstalk across IMD and Toll pathways: insight into the evolution of incomplete immune cascades.
Apr 11, 2019
Proceedings. Biological Sciences
In insects, antimicrobial humoral immunity is governed by two distinct gene cascades, IMD pathway mainly targeting Gram-negative bacteria and Toll pathway preferentially targeting Gram-positive bacteria, which are widely conserved among diverse metazoans. However, recent genomic studies uncovered that IMD pathway is exceptionally absent in some hemipteran lineages like aphids and assassin bugs. How the apparently incomplete immune pathways have evolved with functionality is of interest. Here we report the discovery that, in the hemipteran stinkbug Plautia stali, both IMD and Toll pathways are present but their functional differentiation is blurred. Injection of Gram-negative bacteria and Gram-positive bacteria upregulated effector genes of both pathways. Notably, RNAi experiments unveiled significant functional permeation and crosstalk between IMD and Toll pathways: RNAi of IMD pathway genes suppressed upregulation of effector molecules of both pathways, where the suppression was more remarkable for IMD effectors; and RNAi of Toll pathway genes reduced upregulation of effector molecules of both pathways, where the suppression was more conspicuous for Toll effectors. These results suggest the possibility that, in hemipterans and other arthropods, IMD and Toll pathways are intertwined to target wider and overlapping arrays of microbes, which might have predisposed and facilitated the evolution of incomplete immune pathways.
The WY domain in the Phytophthora effector PSR1 is required for infection and RNA silencing suppression activity.
Apr 09, 2019   The New Phytologist
Zhang P, Jia Y, Shi J, Chen C, Ye W, Wang Y, Ma W, Qiao Y
The WY domain in the Phytophthora effector PSR1 is required for infection and RNA silencing suppression activity.
Apr 09, 2019
The New Phytologist
Phytophthora pathogens manipulate host innate immunity by secreting numerous RxLR effectors, thereby facilitating pathogen colonization. Predicted single and tandem repeats of WY domains are the most prominent C-terminal motifs conserved across the Phytophthora RxLR superfamily. However, the functions of individual WY domains in effectors remain poorly understood. The Phytophthora sojae effector PSR1 promotes infection by suppressing small RNA biogenesis in plant hosts. We identified one single WY domain following the RxLR motif in PSR1. This domain was required for RNA silencing suppression activity and infection in Nicotiana benthamiana, Arabidopsis, and soybean. Mutations of the conserved residues in the WY domain did not affect the subcellular localization of PSR1 but abolished its effect on plant development and resistance to viral and Phytophthora pathogens. This is at least in part due to decreased protein stability of the PSR1 mutants in planta. The identification of the WY domain in PSR1 allows the prediction of a family of PSR1-like effectors also possess RNA silencing suppression activity. Mutation of the conserved residues in two members of this family, PpPSR1L from P. parasitica and PcPSR1L from P. capsici, perturbed their biological functions, indicating that the WY domain is critical in Phytophthora PSR1 and PSR1-like effectors. This article is protected by copyright. All rights reserved.
Innate immunity to intracellular LPS.
Apr 09, 2019   Nature Immunology Add nature.com free-link Cancel
Rathinam VAK, Zhao Y, Shao F
Innate immunity to intracellular LPS.
Apr 09, 2019
Nature Immunology
Monitoring of the cytosolic compartment by the innate immune system for pathogen-encoded products or pathogen activities often enables the activation of a subset of caspases. In most cases, the cytosolic surveillance pathways are coupled to activation of caspase-1 via canonical inflammasome complexes. A related set of caspases, caspase-11 in rodents and caspase-4 and caspase-5 in humans, monitors the cytosol for bacterial lipopolysaccharide (LPS). Direct activation of caspase-11, caspase-4 and caspase-5 by intracellular LPS elicits the lytic cell death called 'pyroptosis', which occurs in multiple cell types. The pyroptosis is executed by the pore-forming protein GSDMD, which is activated by cleavage mediated by caspase-11, caspase-4 or caspase-5. In monocytes, formation of GSDMD pores can induce activation of the NLRP3 inflammasome for maturation of the cytokines IL-1β and IL-18. Caspase-11-mediated pyroptosis in response to cytosolic LPS is critical for antibacterial defense and septic shock. Here we review the emerging literature on the sensing of cytosolic LPS and its regulation and pathophysiological functions.
Blockage of myeloid differentiation 2 attenuates diabetic nephropathy via reducing local RAS activation in mouse kidneys.
Apr 08, 2019   British Journal Of Pharmacology
Wang Y, Fang Q, Jin Y, Liu Z, Zou C, Yu W, Li W, Shan X, Chen R, Khan Z, Liang G
Blockage of myeloid differentiation 2 attenuates diabetic nephropathy via reducing local RAS activation in mouse kidneys.
Apr 08, 2019
British Journal Of Pharmacology
BACKGROUND AND PURPOSE: Both innate immunity and renin-angiotensin system (RAS) play important roles in the pathogenesis of diabetic nephropathy (DN). Myeloid differentiation factor 2 (MD2) is a co-receptor of toll-like receptor 4 (TLR4) in innate immunity. While TLR4 has been reported to mediate the development of DN, the role of MD2 in DN has not been characterized, and it also remains unclear whether MD2/TLR4 signaling pathway is associated with RAS activation in diabetes. EXPERIMENTAL APPROACH: MD2 was blocked using siRNA or pharmacological small-molecule inhibitor L6H9 in high-level glucose (HG)-challenged renal proximal tubular cells. In vivo, C57BL/6 and MD2-/- mice was injected with streptozotocin (STZ) to induce type 1 diabetic nephropathy. Key results We found that inhibition of MD2 by genetic knockdown or small-molecule inhibitor suppressed HG-induced expression of ACE and AT1 receptor and Angiotensin II (AngII) production in renal NRK-52E cells, resulting in the decrease in fibrosis markers such as TGF-β and collagen IV. Interestingly, inhibition on MD2/TLR4-MAPKs pathway did not affect HG-induced renin overproduction. In in vivo studies using the STZ-induced diabetic mice, MD2 was overexpressed in diabetic kidney and MD2 gene knockout or small-molecule inhibitor successfully attenuate renal fibrosis and dysfunction by suppressing local RAS activation and inflammation. CONCLUSIONS AND IMPLICATIONS: Hyperglycemia activates MD2/TLR4-MAPKs signaling cascade to induce renal RAS activation, which leads to renal fibrosis and dysfunction. Pharmacological inhibition of MD2 may be considered as a therapeutic approach to mitigate DN and that small-molecule inhibitor L6H9 could be a potential candidate for such therapy.
Early clearance of Mycobacterium tuberculosis is associated with increased innate immune responses.
Apr 08, 2019   The Journal Of Infectious Diseases
Verrall AJ, Schneider M, Alisjahbana B, Apriani L, van Laarhoven A,   . . . . . .   , Netea MG, Sharples K, Hill PC, Ussher JE, van Crevel R
Early clearance of Mycobacterium tuberculosis is associated with increased innate immune responses.
Apr 08, 2019
The Journal Of Infectious Diseases
INTRODUCTION: A proportion of tuberculosis (TB) case contacts do not become infected, even when heavily exposed. We studied the innate immune responses of TB case contacts to understand their role in protection against infection with Mycobacterium tuberculosis, termed 'early clearance'. METHODS: Indonesian household contacts of TB cases were tested for interferon-γ release assay (IGRA) conversion between baseline and 14 weeks post-recruitment. Blood cell populations and ex-vivo innate whole blood cytokine responses were measured at baseline and, in a subgroup, flow cytometry was performed at weeks 2 and 14. Immunological characteristics were measured for early clearers, defined as a persistently negative IGRA at 3 months, and converters, whose IGRA converted from negative to positive. RESULTS: Among 1347 case contacts, 317 were early clearers and 116 converters. Flow cytometry showed a resolving innate cellular response from 2 to 14 weeks in persistently IGRA negative contacts but not converters. There were no differences in cytokine responses to mycobacterial stimuli, but compared to converters, persistently IGRA negative contacts produced more proinflammatory cytokines following heterologous stimulation with Escherichia coli and Streptococcus pneumoniae. CONCLUSIONS: Early clearance of M. tuberculosis is associated with enhanced heterologous innate immune responses similar to those activated during induction of trained immunity.
Resistance is not futile: bacterial 'innate' and CRISPR-Cas 'adaptive' immune systems.
Apr 08, 2019   Microbiology (Reading, England)
Fineran PC
Resistance is not futile: bacterial 'innate' and CRISPR-Cas 'adaptive' immune systems.
Apr 08, 2019
Microbiology (Reading, England)
Bacteria are under a constant pressure from their viruses (phages) and other mobile genetic elements. They protect themselves through a range of defence strategies, which can be broadly classified as 'innate' and 'adaptive'. The bacterial innate immune systems include defences provided by restriction modification and abortive infection, among others. Bacterial adaptive immunity is elicited by a diverse range of CRISPR-Cas systems. Here, I discuss our research on both innate and adaptive phage resistance mechanisms and some of the evasion strategies employed by phages.
CEH-60/PBX and UNC-62/MEIS Coordinate a Metabolic Switch that Supports Reproduction in C. elegans.
Apr 08, 2019   Developmental Cell
Dowen RH
CEH-60/PBX and UNC-62/MEIS Coordinate a Metabolic Switch that Supports Reproduction in C. elegans.
Apr 08, 2019
Developmental Cell
The molecular basis of how animals integrate metabolic, developmental, and environmental information before committing resources to reproduction is an unresolved issue in developmental biology. In C. elegans, adult animals reallocate fat stores from intestinal cells to the germline via low-density lipoprotein (LDL)-like particles to promote embryogenesis. Here, I demonstrate that two conserved homeodomain transcription factors, CEH-60/PBX and UNC-62/MEIS, coordinate a transcriptional network that supports reproduction while suppressing longevity and stress-response pathways. The CEH-60:UNC-62 heterodimer serves an unanticipated dual function in intestinal nuclei by directly activating the expression of lipoprotein genes while directly repressing stress-responsive genes. Consequently, ceh-60 mutants display fat storage defects, a dramatic lifespan extension, and hyper-activation of innate immunity genes. Finally, CEH-60 associates with PQM-1 at the DAF-16-associated element within the promoters of stress-responsive genes to control gene expression. Thus, CEH-60 governs an elaborate transcriptional network that balances stress responses and longevity against reproduction during developmental transitions.
Plasmodium infection inhibits the expansion and activation of MDSCs and Tregs in the tumor microenvironment in a murine Lewis lung cancer model.
Apr 13, 2019   Cell Communication And Signaling : CCS
Adah D, Yang Y, Liu Q, Gadidasu K, Tao Z, Yu S, Dai L, Li X, Zhao S, Qin L, Qin L, Chen X
Plasmodium infection inhibits the expansion and activation of MDSCs and Tregs in the tumor microenvironment in a murine Lewis lung cancer model.
Apr 13, 2019
Cell Communication And Signaling : CCS
BACKGROUND: A major challenge in the development of effective cancer immunotherapy is the ability of tumors and their microenvironment to suppress immune cells through immunosuppressive cells such as myeloid -derived suppressor cells and regulatory T cells. We previously demonstrated that Plasmodium infection promotes innate and adaptive immunity against cancer in a murine Lewis lung cancer model but its effects on immunosuppressive cells in the tumor microenvironment are unknown. METHODS: Whole Tumors and tumor-derived sorted cells from tumor-bearing mice treated with or without plasmodium infected red blood cells were harvested 17 days post tumor implantation and analyzed using QPCR, western blotting, flow cytometry, and functional assays. Differences between groups were analyzed for statistical significance using Student's t-test. RESULTS: Here we found that Plasmodium infection significantly reduced the proportions of MDSCs and Tregs in the lung tumor tissues of the treated mice by downregulating their recruiting molecules and blocking cellular activation pathways. Importantly, CD8+ T cells isolated from the tumors of Plasmodium-treated mice exhibited significantly higher levels of granzyme B and perforin and remarkably lower levels of PD-1. CONCLUSION: We reveal for the first time, the effects of Plasmodium infection on the expansion and activation of MDSCs and Tregs with a consequent elevation of CD8+T cell-mediated cytotoxicity within the tumor microenvironment and hold great promise for the development of effective immunotherapeutic strategies.

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