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Endogenous retroviral signatures predict immunotherapy response in clear cell renal cell carcinoma.
Smith CC, Beckermann KE, Bortone DS, De Cubas AA, Bixby LM, Lee SJ, Panda A, Ganesan S, Bhanot G, Wallen EM, Milowsky MI, Kim WY, Rathmell WK, Swanstrom R, Parker JS, Serody JS, Selitsky SR, Vincent BG
(2018) J Clin Invest 128: 4804-4820
MeSH Terms: Carcinoma, Renal Cell, Endogenous Retroviruses, Humans, Immunotherapy, Kidney Neoplasms, Prognosis, Tumor Microenvironment
Show Abstract · Added October 30, 2019
Human endogenous retroviruses (hERVs) are remnants of exogenous retroviruses that have integrated into the genome throughout evolution. We developed a computational workflow, hervQuant, which identified more than 3,000 transcriptionally active hERVs within The Cancer Genome Atlas (TCGA) pan-cancer RNA-Seq database. hERV expression was associated with clinical prognosis in several tumor types, most significantly clear cell renal cell carcinoma (ccRCC). We explored two mechanisms by which hERV expression may influence the tumor immune microenvironment in ccRCC: (i) RIG-I-like signaling and (ii) retroviral antigen activation of adaptive immunity. We demonstrated the ability of hERV signatures associated with these immune mechanisms to predict patient survival in ccRCC, independent of clinical staging and molecular subtyping. We identified potential tumor-specific hERV epitopes with evidence of translational activity through the use of a ccRCC ribosome profiling (Ribo-Seq) dataset, validated their ability to bind HLA in vitro, and identified the presence of MHC tetramer-positive T cells against predicted epitopes. hERV sequences identified through this screening approach were significantly more highly expressed in ccRCC tumors responsive to treatment with programmed death receptor 1 (PD-1) inhibition. hervQuant provides insights into the role of hERVs within the tumor immune microenvironment, as well as evidence that hERV expression could serve as a biomarker for patient prognosis and response to immunotherapy.
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Endogenous retrovirus expression is associated with response to immune checkpoint blockade in clear cell renal cell carcinoma.
Panda A, de Cubas AA, Stein M, Riedlinger G, Kra J, Mayer T, Smith CC, Vincent BG, Serody JS, Beckermann KE, Ganesan S, Bhanot G, Rathmell WK
(2018) JCI Insight 3:
MeSH Terms: Aged, Aged, 80 and over, Antineoplastic Agents, Immunological, B7-H1 Antigen, Carcinoma, Renal Cell, Datasets as Topic, Drug Resistance, Neoplasm, Endogenous Retroviruses, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Kidney Neoplasms, Male, Middle Aged, Programmed Cell Death 1 Receptor, Progression-Free Survival, Retrospective Studies, Sequence Analysis, RNA
Show Abstract · Added October 30, 2019
Although a subset of clear cell renal cell carcinoma (ccRCC) patients respond to immune checkpoint blockade (ICB), predictors of response remain uncertain. We investigated whether abnormal expression of endogenous retroviruses (ERVs) in tumors is associated with local immune checkpoint activation (ICA) and response to ICB. Twenty potentially immunogenic ERVs (πERVs) were identified in ccRCC in The Cancer Genome Atlas data set, and tumors were stratified into 3 groups based on their expression levels. πERV-high ccRCC tumors showed increased immune infiltration, checkpoint pathway upregulation, and higher CD8+ T cell fraction in infiltrating leukocytes compared with πERV-low ccRCC tumors. Similar results were observed in ER+/HER2- breast, colon, and head and neck squamous cell cancers. ERV expression correlated with expression of genes associated with histone methylation and chromatin regulation, and πERV-high ccRCC was enriched in BAP1 mutant tumors. ERV3-2 expression correlated with ICA in 11 solid cancers, including the 4 named above. In a small retrospective cohort of 24 metastatic ccRCC patients treated with single-agent PD-1/PD-L1 blockade, ERV3-2 expression in tumors was significantly higher in responders compared with nonresponders. Thus, abnormal expression of πERVs is associated with ICA in several solid cancers, including ccRCC, and ERV3-2 expression is associated with response to ICB in ccRCC.
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19 MeSH Terms
Etiology and Impact of Coinfections in Children Hospitalized With Community-Acquired Pneumonia.
Nolan VG, Arnold SR, Bramley AM, Ampofo K, Williams DJ, Grijalva CG, Self WH, Anderson EJ, Wunderink RG, Edwards KM, Pavia AT, Jain S, McCullers JA
(2018) J Infect Dis 218: 179-188
MeSH Terms: Adolescent, Bacteria, Child, Child, Preschool, Cohort Studies, Coinfection, Community-Acquired Infections, Female, Hospitalization, Humans, Infant, Infant, Newborn, Male, Pneumonia, Treatment Outcome, Viruses
Show Abstract · Added July 27, 2018
Background - Recognition that coinfections are common in children with community-acquired pneumonia (CAP) is increasing, but gaps remain in our understanding of their frequency and importance.
Methods - We analyzed data from 2219 children hospitalized with CAP and compared demographic and clinical characteristics and outcomes between groups with viruses alone, bacteria alone, or coinfections. We also assessed the frequency of selected pairings of codetected pathogens and their clinical characteristics.
Results - A total of 576 children (26%) had a coinfection. Children with only virus detected were younger, more likely to be black, and more likely to have comorbidities such as asthma, compared with children infected with typical bacteria alone. Children with virus-bacterium coinfections had a higher frequency of leukocytosis, consolidation on chest radiography, parapneumonic effusions, intensive care unit admission, and need for mechanical ventilation and an increased length of stay, compared with children infected with viruses alone. Virus-virus coinfections were generally comparable to single-virus infections, with the exception of the need for oxygen supplementation, which was higher during the first 24 hours of hospitalization in some virus-virus pairings.
Conclusions - Coinfections occurred in 26% of children hospitalized for CAP. Children with typical bacterial infections, alone or complicated by a viral infection, have worse outcomes than children infected with a virus alone.
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Procalcitonin as a Marker of Etiology in Adults Hospitalized With Community-Acquired Pneumonia.
Self WH, Balk RA, Grijalva CG, Williams DJ, Zhu Y, Anderson EJ, Waterer GW, Courtney DM, Bramley AM, Trabue C, Fakhran S, Blaschke AJ, Jain S, Edwards KM, Wunderink RG
(2017) Clin Infect Dis 65: 183-190
MeSH Terms: Aged, Antimicrobial Stewardship, Biomarkers, Calcitonin, Community-Acquired Infections, Enterobacteriaceae, Female, Hospitalization, Humans, Immunoassay, Male, Middle Aged, Pneumonia, Bacterial, Pneumonia, Viral, Polymerase Chain Reaction, Prospective Studies, ROC Curve, Sensitivity and Specificity, Viruses
Show Abstract · Added July 27, 2018
Background - Recent trials suggest procalcitonin-based guidelines can reduce antibiotic use for respiratory infections. However, the accuracy of procalcitonin to discriminate between viral and bacterial pneumonia requires further dissection.
Methods - We evaluated the association between serum procalcitonin concentration at hospital admission with pathogens detected in a multicenter prospective surveillance study of adults hospitalized with community-acquired pneumonia. Systematic pathogen testing included cultures, serology, urine antigen tests, and molecular detection. Accuracy of procalcitonin to discriminate between viral and bacterial pathogens was calculated.
Results - Among 1735 patients, pathogens were identified in 645 (37%), including 169 (10%) with typical bacteria, 67 (4%) with atypical bacteria, and 409 (24%) with viruses only. Median procalcitonin concentration was lower with viral pathogens (0.09 ng/mL; interquartile range [IQR], <0.05-0.54 ng/mL) than atypical bacteria (0.20 ng/mL; IQR, <0.05-0.87 ng/mL; P = .05), and typical bacteria (2.5 ng/mL; IQR, 0.29-12.2 ng/mL; P < .01). Procalcitonin discriminated bacterial pathogens, including typical and atypical bacteria, from viral pathogens with an area under the receiver operating characteristic (ROC) curve of 0.73 (95% confidence interval [CI], .69-.77). A procalcitonin threshold of 0.1 ng/mL resulted in 80.9% (95% CI, 75.3%-85.7%) sensitivity and 51.6% (95% CI, 46.6%-56.5%) specificity for identification of any bacterial pathogen. Procalcitonin discriminated between typical bacteria and the combined group of viruses and atypical bacteria with an area under the ROC curve of 0.79 (95% CI, .75-.82).
Conclusions - No procalcitonin threshold perfectly discriminated between viral and bacterial pathogens, but higher procalcitonin strongly correlated with increased probability of bacterial pathogens, particularly typical bacteria.
© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
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Structural basis for antibody cross-neutralization of respiratory syncytial virus and human metapneumovirus.
Wen X, Mousa JJ, Bates JT, Lamb RA, Crowe JE, Jardetzky TS
(2017) Nat Microbiol 2: 16272
MeSH Terms: Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Cross Reactions, Crystallography, X-Ray, Metapneumovirus, Models, Molecular, Protein Binding, Protein Conformation, Respiratory Syncytial Viruses, Viral Fusion Proteins
Show Abstract · Added April 13, 2017
Respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) are two closely related viruses that cause bronchiolitis and pneumonia in infants and the elderly, with a significant health burden. There are no licensed vaccines or small-molecule antiviral treatments specific to these two viruses at present. A humanized murine monoclonal antibody (palivizumab) is approved to treat high-risk infants for RSV infection, but other treatments, as well as vaccines, for both viruses are still in development. Recent epidemiological modelling suggests that cross-immunity between RSV, HMPV and human parainfluenzaviruses may contribute to their periodic outbreaks, suggesting that a deeper understanding of host immunity to these viruses may lead to enhanced strategies for their control. Cross-reactive neutralizing antibodies to the RSV and HMPV fusion (F) proteins have been identified. Here, we examine the structural basis for cross-reactive antibody binding to RSV and HMPV F protein by two related, independently isolated antibodies, MPE8 and 25P13. We solved the structure of the MPE8 antibody bound to RSV F protein and identified the 25P13 antibody from an independent blood donor. Our results indicate that both antibodies use germline residues to interact with a conserved surface on F protein that could guide the emergence of cross-reactivity. The induction of similar cross-reactive neutralizing antibodies using structural vaccinology approaches could enhance intrinsic cross-immunity to these paramyxoviruses and approaches to controlling recurring outbreaks.
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Iterative structure-based improvement of a fusion-glycoprotein vaccine against RSV.
Joyce MG, Zhang B, Ou L, Chen M, Chuang GY, Druz A, Kong WP, Lai YT, Rundlet EJ, Tsybovsky Y, Yang Y, Georgiev IS, Guttman M, Lees CR, Pancera M, Sastry M, Soto C, Stewart-Jones GBE, Thomas PV, Van Galen JG, Baxa U, Lee KK, Mascola JR, Graham BS, Kwong PD
(2016) Nat Struct Mol Biol 23: 811-820
MeSH Terms: Animals, Crystallography, X-Ray, Female, Glycoproteins, HEK293 Cells, Humans, Male, Mice, Inbred C57BL, Models, Molecular, Protein Engineering, Protein Stability, Respiratory Syncytial Virus Infections, Respiratory Syncytial Viruses, Vaccination, Viral Fusion Proteins, Viral Vaccines
Show Abstract · Added May 3, 2017
Structure-based design of vaccines, particularly the iterative optimization used so successfully in the structure-based design of drugs, has been a long-sought goal. We previously developed a first-generation vaccine antigen called DS-Cav1, comprising a prefusion-stabilized form of the fusion (F) glycoprotein, which elicits high-titer protective responses against respiratory syncytial virus (RSV) in mice and macaques. Here we report the improvement of DS-Cav1 through iterative cycles of structure-based design that significantly increased the titer of RSV-protective responses. The resultant second-generation 'DS2'-stabilized immunogens have their F subunits genetically linked, their fusion peptides deleted and their interprotomer movements stabilized by an additional disulfide bond. These DS2 immunogens are promising vaccine candidates with superior attributes, such as their lack of a requirement for furin cleavage and their increased antigenic stability against heat inactivation. The iterative structure-based improvement described here may have utility in the optimization of other vaccine antigens.
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Structure-Based Design of Head-Only Fusion Glycoprotein Immunogens for Respiratory Syncytial Virus.
Boyington JC, Joyce MG, Sastry M, Stewart-Jones GB, Chen M, Kong WP, Ngwuta JO, Thomas PV, Tsybovsky Y, Yang Y, Zhang B, Chen L, Druz A, Georgiev IS, Ko K, Zhou T, Mascola JR, Graham BS, Kwong PD
(2016) PLoS One 11: e0159709
MeSH Terms: Animals, Antibodies, Viral, Female, HEK293 Cells, Humans, Immunogenicity, Vaccine, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Protein Conformation, Respiratory Syncytial Viruses, Viral Fusion Proteins, Viral Vaccines
Show Abstract · Added May 3, 2017
Respiratory syncytial virus (RSV) is a significant cause of severe respiratory illness worldwide, particularly in infants, young children, and the elderly. Although no licensed vaccine is currently available, an engineered version of the metastable RSV fusion (F) surface glycoprotein-stabilized in the pre-fusion (pre-F) conformation by "DS-Cav1" mutations-elicits high titer RSV-neutralizing responses. Moreover, pre-F-specific antibodies, often against the neutralization-sensitive antigenic site Ø in the membrane-distal head region of trimeric F glycoprotein, comprise a substantial portion of the human response to natural RSV infection. To focus the vaccine-elicited response to antigenic site Ø, we designed a series of RSV F immunogens that comprised the membrane-distal head of the F glycoprotein in its pre-F conformation. These "head-only" immunogens formed monomers, dimers, and trimers. Antigenic analysis revealed that a majority of the 70 engineered head-only immunogens displayed reactivity to site Ø-targeting antibodies, which was similar to that of the parent RSV F DS-Cav1 trimers, often with increased thermostability. We evaluated four of these head-only immunogens in detail, probing their recognition by antibodies, their physical stability, structure, and immunogenicity. When tested in naïve mice, a head-only trimer, half the size of the parent RSV F trimer, induced RSV titers, which were statistically comparable to those induced by DS-Cav1. When used to boost DS-Cav1-primed mice, two head-only RSV F immunogens, a dimer and a trimer, boosted RSV-neutralizing titers to levels that were comparable to those boosted by DS-Cav1, although with higher site Ø-directed responses. Our results provide proof-of-concept for the ability of the smaller head-only RSV F immunogens to focus the vaccine-elicited response to antigenic site Ø. Decent primary immunogenicity, enhanced physical stability, potential ease of manufacture, and potent immunogenicity upon boosting suggest these head-only RSV F immunogens, engineered to retain the pre-fusion conformation, may have advantages as candidate RSV vaccines.
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14 MeSH Terms
A Chimeric Pneumovirus Fusion Protein Carrying Neutralizing Epitopes of Both MPV and RSV.
Wen X, Pickens J, Mousa JJ, Leser GP, Lamb RA, Crowe JE, Jardetzky TS
(2016) PLoS One 11: e0155917
MeSH Terms: Animals, Antibodies, Neutralizing, Antibodies, Viral, Antibody Specificity, Epitopes, Metapneumovirus, Mice, Mice, Inbred BALB C, Recombinant Fusion Proteins, Respiratory Syncytial Viruses, Viral Fusion Proteins
Show Abstract · Added April 13, 2017
Respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) are paramyxoviruses that are responsible for substantial human health burden, particularly in children and the elderly. The fusion (F) glycoproteins are major targets of the neutralizing antibody response and studies have mapped dominant antigenic sites in F. Here we grafted a major neutralizing site of RSV F, recognized by the prophylactic monoclonal antibody palivizumab, onto HMPV F, generating a chimeric protein displaying epitopes of both viruses. We demonstrate that the resulting chimeric protein (RPM-1) is recognized by both anti-RSV and anti-HMPV F neutralizing antibodies indicating that it can be used to map the epitope specificity of antibodies raised against both viruses. Mice immunized with the RPM-1 chimeric antigen generate robust neutralizing antibody responses to MPV but weak or no cross-reactive recognition of RSV F, suggesting that grafting of the single palivizumab epitope stimulates a comparatively limited antibody response. The RPM-1 protein provides a new tool for characterizing the immune responses resulting from RSV and HMPV infections and provides insights into the requirements for developing a chimeric subunit vaccine that could induce robust and balanced immunity to both virus infections.
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Mechanisms of polarity protein expression control.
Ahmed SM, Macara IG
(2016) Curr Opin Cell Biol 42: 38-45
MeSH Terms: Animals, Cell Polarity, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Humans, Proteins, Proteolysis, Viruses
Show Abstract · Added April 10, 2018
Polarity is a universal feature of cells during division and often at other stages of the cell cycle or after post-mitotic differentiation. A conserved machinery, present in all animals, initiates and maintains polarity. Multi-cellular animals organize themselves with respect to the axes of symmetry of the organism through the process of planar cell polarity, but many tissues also express a cell-intrinsic form of polarity, for instance to segregate the apical and basolateral membranes of epithelial cells. Although the genes and proteins involved in apical-basal polarity have been known for many years, the regulation of their expression remains ill-defined. Maintenance of the correct expression levels is essential for normal cell lineage allocation, tissue morphogenesis and cell survival. Here we summarize what is known about the transcriptional and post-transcriptional regulation of polarity protein expression, and discuss areas that remain to be understood.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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Insect immunology and hematopoiesis.
Hillyer JF
(2016) Dev Comp Immunol 58: 102-18
MeSH Terms: Animals, Apoptosis, Autophagy, Hematopoiesis, Hemocytes, Host-Pathogen Interactions, Immunity, Innate, Insect Proteins, Insect Viruses, Insecta, Phagocytosis, Receptors, Pattern Recognition
Show Abstract · Added February 5, 2016
Insects combat infection by mounting powerful immune responses that are mediated by hemocytes, the fat body, the midgut, the salivary glands and other tissues. Foreign organisms that have entered the body of an insect are recognized by the immune system when pathogen-associated molecular patterns bind host-derived pattern recognition receptors. This, in turn, activates immune signaling pathways that amplify the immune response, induce the production of factors with antimicrobial activity, and activate effector pathways. Among the immune signaling pathways are the Toll, Imd, Jak/Stat, JNK, and insulin pathways. Activation of these and other pathways leads to pathogen killing via phagocytosis, melanization, cellular encapsulation, nodulation, lysis, RNAi-mediated virus destruction, autophagy and apoptosis. This review details these and other aspects of immunity in insects, and discusses how the immune and circulatory systems have co-adapted to combat infection, how hemocyte replication and differentiation takes place (hematopoiesis), how an infection prepares an insect for a subsequent infection (immune priming), how environmental factors such as temperature and the age of the insect impact the immune response, and how social immunity protects entire groups. Finally, this review highlights some underexplored areas in the field of insect immunobiology.
Copyright © 2015 Elsevier Ltd. All rights reserved.
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12 MeSH Terms