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Immunology
Frontline Science: Nasal epithelial GM-CSF contributes to TLR5-mediated modulation of airway dendritic cells and subsequent IgA response
May 19, 2017   Journal Of Leukocyte Biology
Cao Y, Zhang E, Yang J, Yang Y, Yu J, Xiao Y, Li W, Zhou D, Li Y, Zhao B, Yan H, Lu M, Zhong M, Yan H
Frontline Science: Nasal epithelial GM-CSF contributes to TLR5-mediated modulation of airway dendritic cells and subsequent IgA response
May 19, 2017
Journal Of Leukocyte Biology
Flagellin, as a TLR5 agonist, is an established mucosal adjuvant for enhancing mucosal IgA responses by i.n. immunization. Nasal epithelial cells (NECs) are the first sentinel cells to be exposed to antigen and adjuvant in i.n. immunization, and it is suggested that they play an important role in the mucosal adjuvant activity of flagellin. However, the molecular mechanism leading to modulation and the response by flagellin-activated NECs remain unknown. We aimed to identify the soluble mediator(s) from flagellin-activated NECs that modulate the functions of airway dendritic cells (DCs) and enhance subsequent IgA response. In vitro studies showed that compared with the TLR4 agonist LPS, flagellin directly triggered slight up-regulation of CD80 on airway DCs but was insufficient to affect CD86 expression and DC-mediated IgA response. With the use of an in vitro system for culturing mouse primary NECs (mNECs), we demonstrated that flagellin-activated mNECs could functionally modulate airway DCs, which manifested as significant up-regulation of CD80/CD86 and enhancement of IgA production. The functional modulation of airway DCs was dependent on TLR5 activation of mNECs rather than direct TLR5 activation of airway DCs. With the use of cytokine array and antibody-blocking assays, we further identified that GM-CSF, a cytokine secreted from TLR5-activated mNECs, contributes to the activation of mNECs to airway DCs and subsequent IgA enhancement. In vivo blocking experiments confirmed that GM-CSF is an important factor in recombinant flagellin derived from Salmonella typhi (FliC)-induced airway DC activation and antigen-specific IgA enhancement. Our data directly demonstrate that nasal epithelial GM-CSF contributes to TLR5-mediated modulation of airway DCs and a subsequent IgA response. © Society for Leukocyte Biology.
Antimicrobial peptides extend lifespan in Drosophila
May 18, 2017   PloS One
Loch G, Zinke I, Mori T, Carrera P, Schroer J, Takeyama H, Hoch M
Antimicrobial peptides extend lifespan in Drosophila
May 18, 2017
PloS One
Antimicrobial peptides (AMPs) are important defense molecules of the innate immune system. High levels of AMPs are induced in response to infections to fight pathogens, whereas moderate levels induced by metabolic stress are thought to shape commensal microbial communities at barrier tissues. We expressed single AMPs in adult flies either ubiquitously or in the gut by using the inducible GeneSwitch system to tightly regulate AMP expression. We found that activation of single AMPs, including Drosocin, resulted in a significant extension of Drosophila lifespan. These animals showed reduced activity of immune pathways over lifetime, less intestinal regenerative processes, reduced stress response and a delayed loss of gut barrier integrity. Furthermore, intestinal Drosocin induction protected the animals against infections with the natural Drosophila pathogen Pseudomonas entomophila, whereas a germ-reduced environment prevented the lifespan extending effect of Drosocin. Our study provides new insights into the crosstalk of innate immunity, intestinal homeostasis and ageing.
USP13 negatively regulates antiviral responses by deubiquitinating STING
May 23, 2017   Nature Communications
Sun H, Zhang Q, Jing YY, Zhang M, Wang HY,   . . . . . .   , Zhu QY, Yao J, Shu HB, Lin D, Zhong B
USP13 negatively regulates antiviral responses by deubiquitinating STING
May 23, 2017
Nature Communications
STING (also known as MITA) is critical for host defence against viruses and the activity of STING is regulated by ubiquitination. However, the deubiquitination of STING is not fully understood. Here, we show that ubiquitin-specific protease 13 (USP13) is a STING-interacting protein that catalyses deubiquitination of STING. Knockdown or knockout of USP13 potentiates activation of IRF3 and NF-κB and expression of downstream genes after HSV-1 infection or transfection of DNA ligands. USP13 deficiency results in impaired replication of HSV-1. Consistently, USP13 deficient mice are more resistant than wild-type littermates to lethal HSV-1 infection. Mechanistically, USP13 deconjugates polyubiquitin chains from STING and prevents the recruitment of TBK1 to the signalling complex, thereby negatively regulating cellular antiviral responses. Our study thus uncovers a function of USP13 in innate antiviral immunity and provides insight into the regulation of innate immunity.
Signal recognition particle prevents N-terminal processing of bacterial membrane proteins
May 18, 2017   Nature Communications
Ranjan A, Mercier E, Bhatt A, Wintermeyer W
Signal recognition particle prevents N-terminal processing of bacterial membrane proteins
May 18, 2017
Nature Communications
Bacterial proteins are synthesized with an N-formylated amino-terminal methionine, and N-formylated peptides elicit innate-immunity responses against bacterial infections. However, the source of these formylated peptides is not clear, as most bacterial proteins are co-translationally deformylated by peptide deformylase. Here we develop a deformylation assay with translating ribosomes as substrates, to show that the binding of the signal recognition particle (SRP) to signal sequences in nascent proteins on the ribosome prevents deformylation, whereas deformylation of nascent proteins without signal sequence is not affected. Deformylation and its inhibition by SRP are not influenced by trigger factor, a chaperone that interacts with nascent chains on the ribosome. We propose that bacterial inner-membrane proteins, in particular those with N-out topology, can retain their N-terminal formyl group during cotranslational membrane insertion and supply formylated peptides during bacterial infections.
cGAS is essential for cellular senescence
May 23, 2017   Proceedings Of The National Academy Of Sciences Of The United States Of America
Yang H, Wang H, Ren J, Chen Q, Chen ZJ
cGAS is essential for cellular senescence
May 23, 2017
Proceedings Of The National Academy Of Sciences Of The United States Of America
Cellular senescence is a natural barrier to tumorigenesis and it contributes to the antitumor effects of several therapies, including radiation and chemotherapeutic drugs. Senescence also plays an important role in aging, fibrosis, and tissue repair. The DNA damage response is a key event leading to senescence, which is characterized by the senescence-associated secretory phenotype (SASP) that includes expression of inflammatory cytokines. Here we show that cGMP-AMP (cGAMP) synthase (cGAS), a cytosolic DNA sensor that activates innate immunity, is essential for senescence. Deletion of cGAS accelerated the spontaneous immortalization of mouse embryonic fibroblasts. cGAS deletion also abrogated SASP induced by spontaneous immortalization or DNA damaging agents, including radiation and etoposide. cGAS is localized in the cytoplasm of nondividing cells but enters the nucleus and associates with chromatin DNA during mitosis in proliferating cells. DNA damage leads to accumulation of damaged DNA in cytoplasmic foci that contain cGAS. In human lung adenocarcinoma patients, low expression of cGAS is correlated with poor survival. These results indicate that cGAS mediates cellular senescence and retards immortalization. This is distinct from, and complementary to, the role of cGAS in activating antitumor immunity.
Arabidopsis glycosylphosphatidylinositol-anchored protein LLG1 associates with and modulates FLS2 to regulate innate immunity
May 16, 2017   Proceedings Of The National Academy Of Sciences Of The United States Of America
Shen Q, Bourdais G, Pan H, Robatzek S, Tang D
Arabidopsis glycosylphosphatidylinositol-anchored protein LLG1 associates with and modulates FLS2 to regulate innate immunity
May 16, 2017
Proceedings Of The National Academy Of Sciences Of The United States Of America
Plants detect and respond to pathogen invasion with membrane-localized pattern recognition receptors (PRRs), which recognize pathogen-associated molecular patterns (PAMPs) and activate downstream immune responses. Here we report that Arabidopsis thaliana LORELEI-LIKE GPI-ANCHORED PROTEIN 1 (LLG1), a coreceptor of the receptor-like kinase FERONIA, regulates PRR signaling. In a forward genetic screen for suppressors of enhanced disease resistance 1 (edr1), we identified the point mutation llg1-3, which suppresses edr1 disease resistance but does not affect plant growth and development. The llg1 mutants show enhanced susceptibility to various virulent pathogens, indicating that LLG1 has an important role in plant immunity. LLG1 constitutively associates with the PAMP receptor FLAGELLIN SENSING 2 (FLS2) and the elongation factor-Tu receptor, and forms a complex with BRASSINOSTEROID INSENSITIVE 1-ASSOCIATED RECEPTOR KINASE 1 in a ligand-dependent manner, indicating that LLG1 functions as a key component of PAMP-recognition immune complexes. Moreover, LLG1 contributes to accumulation and ligand-induced degradation of FLS2, and is required for downstream innate immunity responses, including ligand-induced phosphorylation of BOTRYTIS-INDUCED KINASE 1 and production of reactive oxygen species. Taken together, our findings reveal that LLG1 associates with PAMP receptors and modulates their function to regulate disease responses. As LLG1 functions as a coreceptor of FERONIA and plays central roles in plant growth and development, our findings indicate that LLG1 participates in separate pathways, and may suggest a potential connection between development and innate immunity in plants.
Lung CD4 Tissue-Resident Memory T Cells Mediate Adaptive Immunity Induced by Previous Infection of Mice with Bordetella pertussis
May 23, 2017   Journal Of Immunology (Baltimore, Md. : 1950)
Wilk MM, Misiak A, McManus RM, Allen AC, Lynch MA, Mills KHG
Lung CD4 Tissue-Resident Memory T Cells Mediate Adaptive Immunity Induced by Previous Infection of Mice with Bordetella pertussis
May 23, 2017
Journal Of Immunology (Baltimore, Md. : 1950)
Th1 and Th17 cells have an established role in protective immunity to Bordetella pertussis, but this evidence is based largely on peripheral T cells. There is emerging evidence that local tissue-resident memory T (TRM) cells that accumulate in tissue following mucosal infection may be crucial for long-term immunity. In this study, we examined the role of respiratory CD4 TRM cells in immunity to B. pertussis Natural immunity to B. pertussis induced by infection is considered long lasting and effective at preventing reinfection. Consistent with this, we found that convalescent mice rapidly cleared the bacteria after reinfection. Furthermore, CD4 T cells with a TRM cell phenotype (CD44+CD62L-CD69+ or CD44+CD62L-CD69+CD103+) accumulated in the lungs of mice during infection with B. pertussis and significantly expanded through local proliferation following reinfection. These CD4 TRM cells were B. pertussis specific and secreted IL-17 or IL-17 and IFN-γ. Treatment of mice with FTY720, which prevented migration of T and B cells from lymph nodes to the circulation, significantly exacerbated B. pertussis infection. This was associated with significantly reduced infiltration of central memory T cells and B cells into the lungs. However, the local expansion of TRM cells and the associated rapid clearance of the secondary infection were not affected by treatment with FTY720 before rechallenge. Moreover, adoptive transfer of lung CD4 TRM cells conferred protection in naive mice. Our findings reveal that Ag-specific CD4 TRM cells play a critical role in adaptive immunity against reinfection and memory induced by natural infection with B. pertussis. Copyright © 2017 by The American Association of Immunologists, Inc.
Mitochondrial ROS Production Protects the Intestine from Inflammation through Functional M2 Macrophage Polarization
May 12, 2017   Cell Reports
Formentini L, Santacatterina F, Núñez de Arenas C, Stamatakis K, López-Martínez D, Logan A, Fresno M, Smits R, Murphy MP, Cuezva JM
Mitochondrial ROS Production Protects the Intestine from Inflammation through Functional M2 Macrophage Polarization
May 12, 2017
Cell Reports
Mitochondria are signaling hubs in cellular physiology that play a role in inflammatory diseases. We found that partial inhibition of the mitochondrial ATP synthase in the intestine of transgenic mice triggers an anti-inflammatory response through NFκB activation mediated by mitochondrial mtROS. This shielding phenotype is revealed when mice are challenged by DSS-induced colitis, which, in control animals, triggers inflammation, recruitment of M1 pro-inflammatory macrophages, and the activation of the pro-oncogenic STAT3 and Akt/mTOR pathways. In contrast, transgenic mice can polarize macrophages to the M2 anti-inflammatory phenotype. Using the mitochondria-targeted antioxidant MitoQ to quench mtROS in vivo, we observe decreased NFκB activation, preventing its cellular protective effects. These findings stress the relevance of mitochondrial signaling to the innate immune system and emphasize the potential role of the ATP synthase as a therapeutic target in inflammatory and other related diseases. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.
Epithelial Histone Deacetylase 3 Instructs Intestinal Immunity by Coordinating Local Lymphocyte Activation
May 12, 2017   Cell Reports
Navabi N, Whitt J, Wu SE, Woo V, Moncivaiz J, Jordan MB, Vallance BA, Way SS, Alenghat T
Epithelial Histone Deacetylase 3 Instructs Intestinal Immunity by Coordinating Local Lymphocyte Activation
May 12, 2017
Cell Reports
Mucosal tissues are constantly in direct contact with diverse beneficial and pathogenic microbes, highlighting the need for orchestrating complex microbial signals to sustain effective host defense. Here, we show an essential role for intestinal epithelial cell expression of histone deacetylase 3 (HDAC3) in responding to pathogenic microbes and activating protective innate immunity. Mice lacking HDAC3 in intestinal epithelial cells were more susceptible to Citrobacter rodentium when under tonic stimulation by the commensal microbiota. This impaired host defense reflected significantly decreased IFNγ production by intraepithelial CD8+ T cells early during infection. Further, HDAC3 was necessary for infection-induced epithelial expression of the IFNγ-inducing factor IL-18, and administration of IL-18 restored IFNγ activity to resident CD8+ T cells and reduced infection. Thus, HDAC3 mediates communication between intestinal epithelial cells and resident lymphocytes, revealing that epithelial priming by an epigenetic modifier may direct mucosal regulation of host defense against pathogenic microbes. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.
Innate Recognition of Intracellular Bacterial Growth Is Driven by the TIFA-Dependent Cytosolic Surveillance Pathway
May 17, 2017   Cell Reports
Gaudet RG, Guo CX, Molinaro R, Kottwitz H, Rohde JR, Dangeard AS, Arrieumerlou C, Girardin SE, Gray-Owen SD
Innate Recognition of Intracellular Bacterial Growth Is Driven by the TIFA-Dependent Cytosolic Surveillance Pathway
May 17, 2017
Cell Reports
Intestinal epithelial cells (IECs) act as sentinels for incoming pathogens. Cytosol-invasive bacteria, such as Shigella flexneri, trigger a robust pro-inflammatory nuclear factor κB (NF-κB) response from IECs that is believed to depend entirely on the peptidoglycan sensor NOD1. We found that, during Shigella infection, the TRAF-interacting forkhead-associated protein A (TIFA)-dependent cytosolic surveillance pathway, which senses the bacterial metabolite heptose-1,7-bisphosphate (HBP), functions after NOD1 to detect bacteria replicating free in the host cytosol. Whereas NOD1 mediated a transient burst of NF-κB activation during bacterial entry, TIFA sensed HBP released during bacterial replication, assembling into large signaling complexes to drive a dynamic inflammatory response that reflected the rate of intracellular bacterial proliferation. Strikingly, IECs lacking TIFA were unable to discriminate between proliferating and stagnant intracellular bacteria, despite the NOD1/2 pathways being intact. Our results define TIFA as a rheostat for intracellular bacterial replication, escalating the immune response to invasive Gram-negative bacteria that exploit the host cytosol for growth. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.
Absence of Specific Chlamydia trachomatis Inclusion Membrane Proteins Triggers Premature Inclusion Membrane Lysis and Host Cell Death
May 17, 2017   Cell Reports
Weber MM, Lam JL, Dooley CA, Noriea NF, Hansen BT, Hoyt FH, Carmody AB, Sturdevant GL, Hackstadt T
Absence of Specific Chlamydia trachomatis Inclusion Membrane Proteins Triggers Premature Inclusion Membrane Lysis and Host Cell Death
May 17, 2017
Cell Reports
Chlamydia trachomatis is a human pathogen associated with significant morbidity worldwide. As obligate intracellular parasites, chlamydiae must survive within eukaryotic cells for sufficient time to complete their developmental cycle. To promote host cell survival, chlamydiae express poorly understood anti-apoptotic factors. Using recently developed genetic tools, we show that three inclusion membrane proteins (Incs) out of eleven examined are required for inclusion membrane stability and avoidance of host cell death pathways. In the absence of specific Incs, premature inclusion lysis results in recognition by autophagolysosomes, activation of intrinsic apoptosis, and premature termination of the chlamydial developmental cycle. Inhibition of autophagy or knockdown of STING prevented host cell death and activation of intrinsic apoptosis. Significantly, these findings emphasize the importance of Incs in the establishment of a replicative compartment that sequesters the pathogen from host surveillance systems. Published by Elsevier Inc.
Recognition of nectin-2 by the natural killer cell receptor TIGIT
May 18, 2017   The Journal Of Biological Chemistry
Deuss FA, Gully BS, Rossjohn J, Berry R
Recognition of nectin-2 by the natural killer cell receptor TIGIT
May 18, 2017
The Journal Of Biological Chemistry
T cell immunoglobulin and ITIM domain (TIGIT) is an inhibitory receptor expressed on the surface of natural killer (NK) cells. TIGIT recognizes nectin and nectin-like adhesion molecules and thus plays a critical role in the innate immune response to malignant transformation. While the TIGIT nectin-like protein-5 (necl-5) interaction is well understood, how TIGIT engages nectin-2, a receptor that is broadly over-expressed in breast and ovarian cancer, remains unknown. Here, we show that TIGIT bound to the immunoglobulin domain of nectin-2 that is most distal from the membrane with an affinity of 6 μM, which was moderately lower than the affinity observed for the TIGIT-necl-5 interaction (3.2 μM). The TIGIT-nectin-2 binding disrupted pre-assembled nectin-2 oligomers, suggesting that receptor-ligand and ligand-ligand associations are mutually exclusive events. Indeed, the crystal structure of TIGIT bound to the first immunoglobulin domain of nectin-2 indicated that the receptor and ligand dock using the same molecular surface and a conserved ″lock and key″ binding motifs previously observed to mediate nectin-nectin homotypic interactions as well as TIGIT-necl-5 recognition. Using a mutagenesis approach, we dissected the energetic basis for the TIGIT-nectin-2 interaction and revealed that an ″aromatic key″ of nectin-2 is critical for this interaction, while variations in the lock were tolerated. Moreover, we found that the C-C' loop of the ligand dictates the TIGIT binding hierarchy. Altogether, these findings broaden our understanding of nectin-nectin receptor interactions and have implications for better understanding the molecular basis for autoimmune disease and cancer. Copyright © 2017, The American Society for Biochemistry and Molecular Biology.
Carbon dioxide-dependent regulation of NF-κB family members RelB and p100 gives molecular insight into CO2-dependent immune regulation
May 16, 2017   The Journal Of Biological Chemistry
Keogh CE, Scholz CC, Rodriguez J, Selfridge AC, von Kriegshiem A, Cummins EP
Carbon dioxide-dependent regulation of NF-κB family members RelB and p100 gives molecular insight into CO2-dependent immune regulation
May 16, 2017
The Journal Of Biological Chemistry
CO2 is a physiological gas normally produced in the body during aerobic respiration. Hypercapnia (elevated blood pCO2 > ≈ 50mmHg) is a feature of several lung pathologies e.g. chronic obstructive pulmonary disease (COPD). Hypercapnia is associated with increased susceptibility to bacterial infections and suppression of inflammatory signaling. The NF-κB pathway has been implicated in these effects, however, the molecular mechanisms underpinning cellular sensitivity of the NF-κB pathway to CO2 is not fully elucidated. Here we identify several novel CO2-dependent changes in the NF-κB pathway. NF-κB family members p100 and RelB translocate to the nucleus in response to CO2. A cohort of RelB protein-protein interactions (e.g. with Raf-1 and IκBα) are altered by CO2 exposure, while others are maintained (e.g. with p100). RelB is processed by CO2 in a manner dependent on a key C-terminal domain located in its transactivation domain. Loss of the RelB transactivation domain alters NF-κB -dependent transcriptional activity and loss of p100 alters sensitivity of RelB to CO2. Thus, we provide molecular insight into the CO2-sensitivity of the NF-κB pathway and implicate altered RelB/p100-dependent signaling in the CO2-dependent regulation of inflammatory signaling. Copyright © 2017, The American Society for Biochemistry and Molecular Biology.
NleB/SseK effectors from Citrobacter rodentium, Escherichia coli, and Salmonella enterica display distinct differences in host substrate specificity
May 19, 2017   The Journal Of Biological Chemistry
El Qaidi S, Chen K, Halim A, Siukstaite L, Rueter C, Hurtado-Guerrero R, Clausen H, Hardwidge PR
NleB/SseK effectors from Citrobacter rodentium, Escherichia coli, and Salmonella enterica display distinct differences in host substrate specificity
May 19, 2017
The Journal Of Biological Chemistry
Many Gram-negative bacterial pathogens use a syringe-like apparatus called a type III secretion system to inject virulence factors into host cells. Some of these effectors are enzymes that modify host proteins to subvert their normal functions. NleB is a glycosyltransferase that modifies host proteins with N-acetyl-D-glucosamine to inhibit antibacterial and inflammatory host responses. NleB is conserved among the attaching/effacing pathogens enterohemorrhagic E. coli (EHEC), enteropathogenic E. coli (EPEC), and Citrobacter rodentium. Moreover, Salmonella enterica strains encode up to three NleB orthologs named SseK1, SseK2, and SseK3. However, there are conflicting reports regarding the activities and host protein targets among the NleB/SseK orthologs. Therefore, here we performed in vitro glycosylation assays and cell culture experiments to compare the activities and substrate specificities of these effectors. SseK1, SseK3, EHEC NleB1, EPEC NleB1, and C. rodentium NleB blocked TNF-mediated NF-κB pathway activation, whereas SseK2 and NleB2 did not. C. rodentium NleB, EHEC NleB1, and SseK1 glycosylated host glyceraldehyde 3-phosphate dehydrogenase (GAPDH). C. rodentium NleB, EHEC NleB1, EPEC NleB1, and SseK2 glycosylated the Fas-associated death domain protein (FADD). SseK3 and NleB2 were not active against either substrate. We also found that EHEC NleB1 glycosylated two GAPDH arginine residues, R197 and R200 and that these two residues were essential for GAPDH-mediated activation of tumor necrosis factor (TNF) Receptor-Associated Factor 2 (TRAF2) ubiquitination. These results provide evidence that members of this highly conserved family of bacterial virulence effectors target different host protein substrates and exhibit distinct cellular modes of action to suppress host responses. Copyright © 2017, The American Society for Biochemistry and Molecular Biology.
Histone acetyltransferase KAT8 is essential for mouse oocyte development by regulating ROS levels
May 16, 2017   Development (Cambridge, England)
Yin S, Jiang X, Jiang H, Gao Q, Wang F,   . . . . . .   , Xu P, Pandita TK, Fan HY, Zhang Y, Shi Q
Histone acetyltransferase KAT8 is essential for mouse oocyte development by regulating ROS levels
May 16, 2017
Development (Cambridge, England)
Proper oocyte development is critical for female fertility and requires timely and accurate control of gene expression. K (Lysine) Acetyltransferase 8 (KAT8), an important component of the X chromosome dosage compensation system in Drosophila, regulates gene activity by acetylating histone H4 preferentially at lysine 16. To explore the function of Kat8 during mouse oocyte development, we crossed Kat8flox/flox mice with Gdf9-Cre mice to specifically delete Kat8 in oocytes. Oocyte Kat8 deletion resulted in female infertility with follicle development failure in the secondary and preantral follicle stages. RNA-seq analysis revealed that Kat8 deficiency in oocytes resulted in significant down-regulation of antioxidant genes with a subsequent increase in reactive oxygen species. Intraperitoneal injection of the antioxidant N-acetylcysteine rescued defective follicle and oocyte development resulting from Kat8 deficiency. Chromatin immunoprecipitation assay indicated that KAT8 regulates antioxidant gene expression by direct binding to promoter regions. Taken together, our findings demonstrate that KAT8 is essential for female fertility by regulating antioxidant gene expression and identify KAT8 as the first acetyltransferase with an essential function in oogenesis. © 2017. Published by The Company of Biologists Ltd.
HIV-Enhancing and HIV-Inhibiting Properties of Cationic Peptides and Proteins
May 15, 2017   Viruses
Cole AM, Cole AL
HIV-Enhancing and HIV-Inhibiting Properties of Cationic Peptides and Proteins
May 15, 2017
Viruses
Cationic antimicrobial peptides and proteins have historically been ascribed roles in innate immunity that infer killing of microbial and viral pathogens and protection of the host. In the context of sexually transmitted HIV-1, we take an unconventional approach that questions this paradigm. It is becoming increasingly apparent that many of the cationic polypeptides present in the human genital or anorectal mucosa, or human semen, are capable of enhancing HIV-1 infection, often in addition to other reported roles as viral inhibitors. We explore how the in vivo environment may select for or against the HIV-enhancing aspects of these cationic polypeptides by focusing on biological relevance. We stress that the distinction between enhancing and inhibiting HIV-1 infection is not mutually exclusive to specific classes of cationic polypeptides. Understanding how virally enhancing peptides and proteins act to promote sexual transmission of HIV-1 would be important for the design of topical microbicides, mucosal vaccines, and other preventative measures.
Danger signals in regulating the immune response to solid organ transplantation
May 22, 2017   The Journal Of Clinical Investigation
Todd JL, Palmer SM
Danger signals in regulating the immune response to solid organ transplantation
May 22, 2017
The Journal Of Clinical Investigation
Endogenous danger signals, or damage-associated molecular patterns (DAMPs), are generated in response to cell stress and activate innate immunity to provide a pivotal mechanism by which an organism can respond to damaged self. Accumulating experimental and clinical data have established the importance of DAMPs, which signal through innate pattern recognition receptors (PRRs) or DAMP-specific receptors, in regulating the alloresponse to solid organ transplantation (SOT). Moreover, DAMPs may incite distinct downstream cellular responses that could specifically contribute to the development of allograft fibrosis and chronic graft dysfunction. A growing understanding of the role of DAMPs in directing the immune response to transplantation has suggested novel avenues for the treatment or prevention of allograft rejection that complement contemporary immunosuppression and could lead to improved outcomes for solid organ recipients.
Hepatitis B Virus e Antigen Activates the Suppressor of Cytokine Signaling 2 to Repress Interferon Action
May 12, 2017   Scientific Reports
Yu Y, Wan P, Cao Y, Zhang W, Chen J,   . . . . . .   , Zhu Y, Liu F, Wu K, Liu Y, Wu J
Hepatitis B Virus e Antigen Activates the Suppressor of Cytokine Signaling 2 to Repress Interferon Action
May 12, 2017
Scientific Reports
Hepatitis B virus (HBV) infection causes acute hepatitis B (AHB), chronic hepatitis B (CHB), liver cirrhosis (LC), and eventually hepatocellular carcinoma (HCC). The presence of hepatitis B e antigen (HBeAg) in the serum generally indicates ongoing viral replication and disease progression. However, the mechanism by which HBeAg regulates HBV infection remains unclear. Interferons (IFNs) are pleiotropic cytokines that participate in host innate immunity. After binding to receptors, IFNs activate the JAK/STAT pathway to stimulate expression of IFN-stimulated genes (ISGs), leading to induction of antiviral responses. Here, we revealed that HBeAg represses IFN/JAK/STAT signaling to facilitate HBV replication. Initially, HBeAg stimulates the expression of suppressor of cytokine signaling 2 (SOCS2). Subsequently, SOCS2 impairs IFN/JAK/STAT signaling through reducing the stability of tyrosine kinase 2 (TYK2), downregulating the expression of type I and III IFN receptors, attenuating the phosphorylation and nucleus translocation of STAT1. Finally, SOCS2 inhibits the expression of ISGs, which leads to the repression of IFN action and facilitation of viral replication. These results demonstrate an important role of HBeAg in the regulation of IFN action, and provide a possible molecular mechanism by which HBV resists the IFN therapy and maintains persistent infection.
Unfolding the pathogenesis of scleroderma through genomics and epigenomics
May 20, 2017   Journal Of Autoimmunity
Tsou PS, Sawalha AH
Unfolding the pathogenesis of scleroderma through genomics and epigenomics
May 20, 2017
Journal Of Autoimmunity
With unknown etiology, scleroderma (SSc) is a multifaceted disease characterized by immune activation, vascular complications, and excessive fibrosis in internal organs. Genetic studies, including candidate gene association studies, genome-wide association studies, and whole-exome sequencing have supported the notion that while genetic susceptibility to SSc appears to be modest, SSc patients are genetically predisposed to this disease. The strongest genetic association for SSc lies within the MHC region, with loci in HLA-DRB1, HLA-DQB1, HLA-DPB1, and HLA-DOA1 being the most replicated. The non-HLA genes associated with SSc are involved in various functions, with the most robust associations including genes for B and T cell activation and innate immunity. Other pathways include genes involved in extracellular matrix deposition, cytokines, and autophagy. Among these genes, IRF5, STAT4, and CD247 were replicated most frequently while SNPs rs35677470 in DNASE1L3, rs5029939 in TNFAIP3, and rs7574685 in STAT4 have the strongest associations with SSc. In addition to genetic predisposition, it became clear that environmental factors and epigenetic influences also contribute to the development of SSc. Epigenetics, which refers to studies that focus on heritable phenotypes resulting from changes in chromatin structure without affecting the DNA sequence, is one of the most rapidly expanding fields in biomedical research. Indeed extensive epigenetic changes have been described in SSc. Alteration in enzymes and mediators involved in DNA methylation and histone modification, as well as dysregulated non-coding RNA levels all contribute to fibrosis, immune dysregulation, and impaired angiogenesis in this disease. Genes that are affected by epigenetic dysregulation include ones involved in autoimmunity, T cell function and regulation, TGFβ pathway, Wnt pathway, extracellular matrix, and transcription factors governing fibrosis and angiogenesis. In this review, we provide a comprehensive overview of the current findings of SSc genetic susceptibility, followed by an extensive description and a systematic review of epigenetic research that has been carried out to date in SSc. We also summarize the therapeutic potential of drugs that affect epigenetic mechanisms, and outline the future prospective of genomics and epigenomics research in SSc. Copyright © 2017 Elsevier Ltd. All rights reserved.
RPL10L Is Required for Male Meiotic Division by Compensating for RPL10 during Meiotic Sex Chromosome Inactivation in Mice
May 15, 2017   Current Biology : CB
Jiang L, Li T, Zhang X, Zhang B, Yu C,   . . . . . .   , Huleihel M, Lunenfeld E, Wang PJ, Zhang Y, Shi Q
RPL10L Is Required for Male Meiotic Division by Compensating for RPL10 during Meiotic Sex Chromosome Inactivation in Mice
May 15, 2017
Current Biology : CB
The mammalian sex chromosomes have undergone profound changes during their evolution from an ancestral pair of autosomes [1-4]. Specifically, the X chromosome has acquired a paradoxical sex-biased function by redistributing gene contents [5, 6] and has generated a disproportionately high number of retrogenes that are located on autosomes and exhibit male-biased expression patterns [6]. Several selection-based models have been proposed to explain this phenomenon, including a model of sexual antagonism driving X inactivation (SAXI) [6-8] and a compensatory mechanism based on meiotic sex chromosome inactivation (MSCI) [6, 8-11]. However, experimental evidence correlating the function of X-chromosome-derived autosomal retrogenes with evolutionary forces remains limited [12-17]. Here, we show that the deficiency of Rpl10l, a murine autosomal retrogene of Rpl10 with testis-specific expression, disturbs ribosome biogenesis in late-prophase spermatocytes and prohibits the transition from prophase into metaphase of the first meiotic division, resulting in male infertility. Rpl10l expression compensates for the lack of Rpl10, which exhibits a broad expression pattern but is subject to MSCI during spermatogenesis. Importantly, ectopic expression of RPL10L prevents the death of cultured RPL10-deficient somatic cells, and Rpl10l-promoter-driven transgenic expression of Rpl10 in spermatocytes restores spermatogenesis and fertility in Rpl10l-deficient mice. Our results demonstrate that Rpl10l plays an essential role during the meiotic stage of spermatogenesis by compensating for MSCI-mediated transcriptional silencing of Rpl10. These data provide direct evidence for the compensatory hypothesis and add novel insight into the evolution of X-chromosome-derived autosomal retrogenes and their role in male fertility. Copyright © 2017 Elsevier Ltd. All rights reserved.
Comparative genomic analysis of innate immunity reveals novel and conserved components in crustacean food crop species
May 19, 2017   BMC Genomics
Lai AG, Aboobaker AA
Comparative genomic analysis of innate immunity reveals novel and conserved components in crustacean food crop species
May 19, 2017
BMC Genomics
Growing global demands for crustacean food crop species have driven large investments in aquaculture research worldwide. However, large-scale production is susceptible to pathogen-mediated destruction particularly in developing economies. Thus, a thorough understanding of the immune system components of food crop species is imperative for research to combat pathogens. Through a comparative genomics approach utilising extant data from 55 species, we describe the innate immune system of the class Malacostraca, which includes all food crop species. We identify 7407 malacostracan genes from 39 gene families implicated in different aspects of host defence and demonstrate dynamic evolution of innate immunity components within this group. Malacostracans have achieved flexibility in recognising infectious agents through divergent evolution and expansion of pathogen recognition receptors genes. Antiviral RNAi, Toll and JAK-STAT signal transduction pathways have remained conserved within Malacostraca, although the Imd pathway appears to lack several key components. Immune effectors such as the antimicrobial peptides (AMPs) have unique evolutionary profiles, with many malacostracan AMPs not found in other arthropods. Lastly, we describe four putative novel immune gene families, potentially representing important evolutionary novelties of the malacostracan immune system. Our analyses across the broader Malacostraca have allowed us to not only draw analogies with other arthropods but also to identify evolutionary novelties in immune modulation components and form strong hypotheses as to when key pathways have evolved or diverged. This will serve as a key resource for future immunology research in crustacean food crops.
Brain Perivascular Macrophages Initiate the Neurovascular Dysfunction of Alzheimer Aβ Peptides
May 18, 2017   Circulation Research
Park L, Uekawa K, Garcia-Bonilla L, Koizumi K, Murphy M, Pitstick R, Younkin LH, Younkin SG, Zhou P, Carlson GA, Anrather J, Iadecola C
Brain Perivascular Macrophages Initiate the Neurovascular Dysfunction of Alzheimer Aβ Peptides
May 18, 2017
Circulation Research
Rationale: Increasing evidence indicates that alterations of the cerebral microcirculation may play a role in Alzheimer's disease (AD), the leading cause of late-life dementia. The amyloid-β peptide (Aβ), a key pathogenic factor in AD, induces profound alterations in neurovascular regulation through the innate immunity receptor CD36, which, in turn, activates a Nox2-containing NADPH oxidase leading to cerebrovascular oxidative stress. Brain perivascular macrophages (PVM) located in the perivascular space, a major site of brain Aβ collection and clearance, are juxtaposed to the wall of intracerebral resistance vessels and are a powerful source of reactive oxygen species (ROS). Objective: We tested the hypothesis that PVM are the main source of ROS responsible for the cerebrovascular actions of Aβ, and that CD36 and Nox2 in PVM are the molecular substrates of the effect. Methods and Results: Selective depletion of PVM using intracerebroventricular injection of clodronate abrogates the ROS production and cerebrovascular dysfunction induced by Aβ applied directly to the cerebral cortex, administered intravascularly or overproduced in the brain of transgenic mice expressing mutated forms of the amyloid precursor protein (Tg2576 mice). In addition, using bone marrow chimeras we demonstrate that PVM are the cells expressing CD36 and Nox2 responsible for the dysfunction. Thus, deletion of CD36 or Nox2 from PVM abrogates the deleterious vascular effects of Aβ, whereas wild-type PVM reconstitute the vascular dysfunction in CD36-null mice. Conclusions: The data identify PVM as a previously unrecognized effector of the damaging neurovascular actions of Aβ and unveil a new mechanism by which brain-resident innate immune cells and their receptors may contribute to the pathobiology of AD.
MicroRNA-155 attenuates late sepsis-induced cardiac dysfunction through JNK and β-arrestin 2
May 19, 2017   Oncotarget
Zhou Y, Song Y, Shaikh Z, Li H, Zhang H, Caudle Y, Zheng S, Yan H, Hu D, Stuart C, Yin D
MicroRNA-155 attenuates late sepsis-induced cardiac dysfunction through JNK and β-arrestin 2
May 19, 2017
Oncotarget
Cardiac dysfunction is correlated with detrimental prognosis of sepsis and contributes to a high risk of mortality. After an initial hyperinflammatory reaction, most patients enter a protracted state of immunosuppression (late sepsis) that alters both innate and adaptive immunity. The changes of cardiac function in late sepsis are not yet known. MicroRNA-155 (miR-155) is previously found to play important roles in both regulations of immune activation and cardiac function. In this study, C57BL/6 mice were operated to develop into early and late sepsis phases, and miR-155 mimic was injected through the tail vein 48 h after cecal ligation and puncture (CLP). The effect of miR-155 on CLP-induced cardiac dysfunction was explored in late sepsis. We found that increased expression of miR-155 in the myocardium protected against cardiac dysfunction in late sepsis evidenced by attenuating sepsis-reduced cardiac output and enhancing left ventricular systolic function. We also observed that miR-155 markedly reduced the infiltration of macrophages and neutrophils into the myocardium and attenuated the inflammatory response via suppression of JNK signaling pathway. Moreover, overexpression of β-arrestin 2 (Arrb2) exacerbated the mice mortality and immunosuppression in late sepsis. Furthermore, transfection of miR-155 mimic reduced Arrb2 expression, and then restored immunocompetence and improved survival in late septic mice. We conclude that increased miR-155 expression through systemic administration of miR-155 mimic attenuates cardiac dysfunction and improves late sepsis survival by targeting JNK associated inflammatory signaling and Arrb2 mediated immunosuppression.
The novel complex combination of alum, CpG ODN and HH2 as adjuvant in cancer vaccine effectively suppresses tumor growth in vivo
May 18, 2017   Oncotarget
Tian Y, Li M, Yu C, Zhang R, Zhang X, Huang R, Lu L, Yuan F, Fan Y, Zhou B, Men K, Xu H, Yang L
The novel complex combination of alum, CpG ODN and HH2 as adjuvant in cancer vaccine effectively suppresses tumor growth in vivo
May 18, 2017
Oncotarget
Single-component adjuvant is prone to eliciting a specific type of Th1 or Th2 response. So, the development of combinatorial adjuvants inducing a robust mixed Th1/Th2 response is a promising vaccination strategy against cancer. Here, we describe a novel combination of aluminum salts (alum), CpG oligodeoxynucleotide (CpG) and innate defense regulator peptide HH2 for improving anti-tumor immune responses. The CpG-HH2 complex significantly enhanced the production of IFN-γ, TNF-α and IL-1β, promoted the uptake of antigen and strengthened the activation of p38, Erk1/2 and NF-κB in vitro, compared to CpG or HH2 alone. Immunization with NY-ESO-1 antigen plus alum-CpG-HH2 combinatorial adjuvant effectively inhibited tumor growth and reduced tumor burden in prophylactic and therapeutic tumor models and even in passive serum or cellular therapy. In addition, co-administration of NY-ESO-1 with alum-CpG-HH2 combinatorial adjuvant markedly activated NK cell cytotoxicity, induced antibody-dependent cellular cytotoxicity (ADCC), dramatically elicited cytotoxic T lymphocytes (CTLs) response, and increased infiltrating lymphocytes in tumors. Moreover, in vivo depletion of CD8+ T cells completely and depletion of NK cells partially blocked the anti-tumor activity of NY-ESO-1-alum-CpG-HH2 immunization. Overall, our results demonstrate a novel adjuvant combination for cancer vaccine with efficient immunomodulation by stimulating innate immunity and mediating adaptive immunity.
Combination Immunotherapy for Type 1 Diabetes
May 23, 2017   Current Diabetes Reports
Bone RN, Evans-Molina C
Combination Immunotherapy for Type 1 Diabetes
May 23, 2017
Current Diabetes Reports
Type 1 diabetes (T1D) is an autoimmune disease marked by β-cell destruction. Immunotherapies for T1D have been investigated since the 1980s and have focused on restoration of tolerance, T cell or B cell inhibition, regulatory T cell (Treg) induction, suppression of innate immunity and inflammation, immune system reset, and islet transplantation. The purpose of this review is to provide an overview and lessons learned from single immunotherapy trials, describe recent and ongoing combination immunotherapy trials, and provide perspectives on strategies for future combination clinical interventions aimed at preserving insulin secretion in T1D. Combination immunotherapies have had mixed results in improving short-term glycemic control and insulin secretion in recent-onset T1D. A handful of studies have successfully reached their primary end-point of improved insulin secretion in recent-onset T1D. However, long-term improvements glycemic control and the restoration of insulin independence remain elusive. Future interventions should focus on strategies that combine immunomodulation with efforts to alleviate β-cell stress and address the formation of antigens that activate autoimmunity.

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