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Abstract
Cytomegalovirus (CMV) causes mostly asymptomatic but lifelong infection. Primary infection or reactivation in immunocompromised individuals can be life-threatening. CMV viremia often occurs in solid organ transplant (SOT) recipients and associates with decreased graft survival and higher mortality. Furthering understanding of impaired immunity allowing CMV reactivation is critical to guiding anti-viral therapy and examining CMV’s impact on outcomes of SOT. This study characterized longitudinal immune responses to CMV in 31 kidney transplant recipients with CMV viremia and matched, non-viremic recipients. Subjects were sampled three- and twelve-months post-transplant, with additional samples one-week and one-month post-viremia. Peripheral blood mononuclear cells (PBMC) were stained for NK and T cell markers. PBMC transcriptomes were characterized by RNA-Seq. Plasma proteins were quantified by Luminex. CD8 T cell transcriptomes were characterized by single-cell RNA-Seq. Pre-viremia, patients had high levels of IL-15 with concurrent expansion of immature CD56bright NK cells. Post-viremia, mature CD56dim NK cells and CD28- CD8 T cells upregulating inhibitory and NK-associated receptors were expanded. Phenotype of NK cells and CD28- CD8 T cells were associated with control of viremia. These findings suggest signatures of innate activation may be prognostic for CMV reactivation post-transplant, while CD8 T cell functionality is critical for effective control of CMV.
Authors
Harry Pickering, Subha Sen, Janice Arakawa-Hoyt, Kenichi Ishiyama, Yumeng Sun, Rajesh Parmar, Richard Ahn, Gema Sunga, Megan Llamas, Alexander Hoffmann, Mario Deng, Suphamai Bunnapradist, Joanna M. Schaenman, David W. Gjertson, Maura Rossetti, Lewis L. Lanier, Elaine F. Reed
Abstract
Controlled human malaria infection (CHMI) provides a highly informative means to investigate host-pathogen interactions and enable in vivo proof-of-concept efficacy testing of new drugs and vaccines. However, unlike Plasmodium falciparum, well-characterized P. vivax parasites that are safe and suitable for use in modern CHMI models are limited. Here, two healthy malaria-naïve UK adults with universal donor blood group were safely infected with a clone of P. vivax from Thailand by mosquito-bite CHMI. Parasitemia developed in both volunteers and, prior to treatment, each volunteer donated blood to produce a cryopreserved stabilate of infected red blood cells. Following stringent safety screening, the parasite stabilate from one of these donors (“PvW1”) was thawed and used to inoculate six healthy malaria-naïve UK adults by blood-stage CHMI, at three different dilutions. Parasitemia developed in all volunteers, who were then successfully drug treated. PvW1 parasite DNA was isolated and sequenced to produce a high quality genome assembly by using a hybrid assembly method. We analysed leading vaccine candidate antigens and multigene families, including the Vivax interspersed repeat (VIR) genes of which we identified 1145 in the PvW1 genome. Our genomic analysis will guide future assessment of candidate vaccines and drugs, as well as experimental medicine studies.
Authors
Angela M. Minassian, Yrene Themistocleous, Sarah E. Silk, Jordan R. Barrett, Alison Kemp, Doris Quinkert, Carolyn M. Nielsen, Nick J. Edwards, Thomas A. Rawlinson, Fernando Ramos Lopez, Wanlapa Roobsoong, Katherine J.D. Ellis, Jee-Sun Cho, Eerik Aunin, Thomas D. Otto, Adam J. Reid, Florian A. Bach, Geneviève M.C. Labbé, Ian D. Poulton, Arianna Marini, Marija Zaric, Margaux Mulatier, Raquel Lopez Ramon, Megan Baker, Celia H. Mitton, Jason C. Sousa, Nattawan Rachaphaew, Chalermpon Kumpitak, Nongnuj Maneechai, Chayanut Suansomjit, Tianrat Piteekan, Mimi M. Hou, Baktash Khozoee, Kirsty McHugh, David J. Roberts, Alison M. Lawrie, Andrew M. Blagborough, Fay L. Nugent, Iona J. Taylor, Kimberly J. Johnson, Philip J. Spence, Jetsumon Sattabongkot, Sumi Biswas, Julian C. Rayner, Simon J. Draper
Abstract
Experimental Autoimmune Encephalomyelitis (EAE) is a well-characterized animal model of Multiple Sclerosis. During the early phase of EAE, the infiltrating monocyte and monocyte-derived macrophages and activated resident microglia contribute to T cell recruitment, especially CD4+ T cells, into the CNS resulting in neuronal demyelination, however, in later stages they promote remyelination and recovery by removal of myelin debris by phagocytosis. SIRPα and CD47 are abundantly expressed in the CNS and deletion of either molecule is protective in myelin oligodendrocyte glycoprotein (MOG)-induced EAE due to failed effector T cell expansion and trafficking. Here we report that treatment with the function blocking CD47 antibody (Ab), Miap410 significantly reduced the infiltration of pathogenic immune cells, but impaired recovery from paresis. The underlying mechanism was by blocking the emergence of CD11chigh MHCIIhigh microglia at peak disease that expressed receptors for phagocytosis, scavenging, and lipid catabolism, which mediated clearance of myelin debris, and the transition of monocytes to macrophages in the CNS. In the recovery phase of EAE, Miap410 Ab treated mice had worsening paresis with sustained inflammation and limited remyelination as compared to control Ab treated mice. In summary, Ab blockade of CD47 impaired resolution of CNS inflammation, thus worsening EAE.
Authors
Huan Wang, Gail Newton, Liguo Wu, Lih-Ling Lin, Amy S. Miracco, Sridaran Natesan, Francis W. Luscinskas
Abstract
Hypothesis Obesity is one of the main drivers of type 2 diabetes (T2D), but not uniformly associated with the disease. The location of fat accumulation is critical for metabolic health. Specific patterns of body fat distribution such as visceral fat, are closely related to insulin resistance. There might be further, hitherto unknown features of body fat distribution which could additionally contribute to the disease. Methods We used machine learning with dense convolutional neural networks (DCNN) to detect diabetes related variables from 2,371 T1-weighted whole-body magnetic resonance imaging (MRI) datasets. MRI was performed in participants undergoing metabolic screening with oral glucose tolerance tests. Models were trained for sex, age, BMI, insulin sensitivity, HbA1c and prediabetes or incident diabetes. The results were compared to conventional models. Results The Area Under the Receiver Operator Characteristic curve was 87% for the T2D discrimination and 68% for prediabetes, both superior to conventional models. Mean absolute regression errors were comparable to conventional models. Heatmaps showed that lower visceral abdominal regions were critical in diabetes classification. Subphenotyping revealed a group with high future diabetes and microalbuminuria risk. Interpretation Our results show that diabetes is detectable from whole-body MRI without additional data. Our technique of heatmap visualization unravels plausible anatomical regions and highlights the leading role of fat accumulation in the lower abdomen in diabetes pathogenesis.
Authors
Benedikt Dietz, Jürgen Machann, Vaibhav Agrawal, Martin Heni, Patrick Schwab, Julia Dienes, Steffen Reichert, Andreas L. Birkenfeld, Hans-Ulrich Häring, Fritz Schick, Norbert Stefan, Andreas Fritsche, Hubert Preissl, Bernhard Schölkopf, Stefan Bauer, Robert Wagner
Abstract
Asthma is a common disease with profoundly variable natural history and patient morbidity. Heterogeneity has long been appreciated and much work has focused on identifying subgroups of patients with similar pathobiological underpinnings. Previous studies of the Severe Asthma Research Program (SARP) cohort linked gene expression changes to specific clinical and physiologic characteristics. While invaluable for hypothesis generation, these data include extensive candidate gene lists that complicate target identification and validation. In this analysis, we performed unsupervised clustering of the SARP cohort using bronchial epithelial cell gene expression data, identifying a transcriptional signature for participants suffering exacerbation prone asthma with impaired lung function. Clinically, participants in this asthma cluster exhibited a mixed inflammatory process and bore transcriptional hallmarks of nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1) activation despite high corticosteroid exposure. Using supervised machine learning, we found a set of 31 genes that classified patients with high accuracy and could reconstitute clinical and transcriptional hallmarks of our patient clustering in an external cohort. Of these genes, IL18R1 (IL-18 Receptor 1) negatively associated with lung function and was highly expressed in the most severe patient cluster. We validated IL18R1 protein expression in lung tissue and identified downstream NF-κB and AP-1 activity, supporting IL-18 signaling in severe asthma pathogenesis and highlighting this approach for gene/pathway discovery.
Authors
Matthew J. Camiolo, Xiuxia Zhou, Qi Wei, Humberto E. Trejo Bittar, Naftali Kaminski, Anuradha Ray, Sally Wenzel
Abstract
Chikungunya is a mosquito-borne disease that causes periodic but explosive epidemics of acute disease throughout the tropical world. Vaccine development against chikungunya virus (CHIKV) has been hampered by the inability to conduct efficacy trials due to the unpredictability of CHIKV outbreaks. Therefore, immune correlates are being explored to gain inference into vaccine-induced protection. Current study is an in-depth serological characterization of Fab and Fc-mediated antibody responses in selected Phase 2 clinical trial participants following immunization with the recombinant measles-vectored CHIKV vaccine, MV-CHIK. Antibody comparisons were conducted between participants who received prime versus prime-boost vaccine regimens. MV-CHIK vaccination elicited potent Fab-mediated antibodies (such as CHIKV-specific IgG, neutralization and avidity), including dominant IgG3 responses which translated into strong antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). At 1-month, prime-boost immunization lead to significantly greater responses in every measured Fab and Fc antibody parameter. Interestingly, prime-boost-elicited antibodies decreased rapidly over time, until at 6-months both vaccine regimens displayed similar antibody profiles. Nonetheless, antibody avidity and ADCP remained significantly greater following boost immunization. Our observations suggest that a prime-boost administration of MV-CHIK will be more appropriate for CHIKV-endemic regions, while a prime only regimen may be sufficient for travel purposes or outbreak situations.
Authors
Roland Tschismarov, Raphaël M. Zellweger, Min Jie Koh, Yan Shan Leong, Jenny G. Low, Eng Eong Ooi, Christian W. Mandl, Katrin Ramsauer, Ruklanthi de Alwis
Abstract
mascRNA is a highly conserved tRNA-like noncoding RNA whose function remains largely unknown. We show here that this small RNA molecule played a role in the stringent control of Toll-like receptor (TLR)-mediated innate immune responses. mascRNA inhibited activation of NF-κB and mitogen-activated protein kinase (MAPK) signaling and the production of inflammatory cytokines in macrophages stimulated with lipopolysaccharide (LPS), a TLR4 ligand. Furthermore, exogenous mascRNA alleviated LPS-induced lung inflammation. On the contrary, mascRNA potentiated the phosphorylation of IRF3 and STAT1 and the transcription of interferon-related genes in response to the TLR3 ligand poly(I:C) both in vitro and in vivo. Mechanistically, mascRNA was found to enhance K48-linked ubiquitination and proteasomal degradation of TRAF6, thereby negatively regulating TLR-mediated MyD88-dependent proinflammatory signaling while positively regulating TRIF-dependent interferon signaling. Additionally, hnRNP H and hnRNP F were found to interact with mascRNA, promote its degradation, and contribute to the fine-tuning of TLR-triggered immune responses. Taken together, our data identify a dual role of mascRNA in both negative and positive regulation of innate immune responses.
Authors
Tao Sun, Chunxue Wei, Daoyong Wang, Xuxu Wang, Jiao Wang, Yuqing Hu, Xiaohua Mao
Abstract
BACKGROUND. Childhood cancer survivors who received abdominal radiotherapy (RT) or total body irradiation (TBI) are at increased risk for cardiometabolic disease, but the underlying mechanisms are unknown. We hypothesize that RT-induced adipose tissue dysfunction contributes to the development of cardiometabolic disease in the expanding population of childhood cancer survivors. METHODS. We performed clinical metabolic profiling of adult childhood cancer survivors previously exposed to TBI, abdominal RT, or chemotherapy alone, alongside a group of healthy controls. Study participants underwent abdominal subcutaneous adipose biopsies to obtain tissue for bulk RNA-sequencing. Transcriptional signatures were analyzed using pathway and network analyses and cellular deconvolution. RESULTS. Irradiated adipose tissue is characterized by a gene expression signature indicative of a complex macrophage expansion. This signature includes activation of the TREM2-TYROBP network, a pathway described in diseases of chronic tissue injury. Radiation exposure of adipose is further associated with dysregulated adipokine secretion, specifically a decrease in insulin-sensitizing adiponectin and an increase in insulin resistance-promoting plasminogen activator inhibitor-1. Accordingly, survivors exhibiting these changes have early signs of clinical metabolic derangement such as increased fasting glucose and hemoglobin A1c. CONCLUSION. Childhood cancer survivors exposed to abdominal RT or TBI during treatment exhibit signs of chronic subcutaneous adipose tissue dysfunction, manifested as dysregulated adipokine secretion that may negatively impact their systemic metabolic health. FUNDING. Rockefeller University Hospital; National Institute of General Medical Sciences (T32GM007739); National Center for Advancing Translational Sciences (UL1TR001866); National Cancer Institute (P30CA008748); American Cancer Society (133831-CSDG-19-117-01-CPHPS); American Diabetes Association (1-17-ACE-17); anonymous donor (Memorial Sloan Kettering Cancer Center).
Authors
Xiaojing Huang, Olivia A. Maguire, Jeanne M. Walker, Caroline S. Jiang, Thomas S. Carroll, Ji-Dung Luo, Emily Tonorezos, Danielle Novetsky Friedman, Paul Cohen
Abstract
Fibrotic posterior capsular opacification (PCO), a major complication of cataract surgery, is driven by transforming growth factor β (TGFβ). Previously, αV integrins were found to be critical for the onset of TGFβ-mediated PCO in vivo, however, the functional heterodimer was unknown. Here, β8 integrin conditional knockout (β8ITGcKO) lens cells (LCs) were observed to attenuate their fibrotic responses, while both β5 and β6 integrin null LCs underwent fibrotic changes similar to WT at 5 days PCS. RNAseq revealed that β8ITGcKO LCs attenuated their upregulation of integrins and their ligands, as well as known targets of TGFβ induced signaling at 24 hours PCS. Treatment of β8ITGcKO eyes with active TGFβ1 at the time of surgery rescued the fibrotic response. Treatment of wild type mice with an anti- αVβ8 integrin function blocking antibody at the time of surgery ameliorated both canonical TGFβ signaling and LC fibrotic response PCS, and treatment at 5 days PCS, after surgically induced fibrotic responses are established, largely reversed this fibrotic response. These data suggest that αVβ8 integrin is a major regulator of TGFβ activation by LCs PCS and that therapeutics targeting αVβ8 integrin could be effective for fibrotic PCO prevention and treatment.
Authors
Mahbubul H. Shihan, Samuel G. Novo, Yan Wang, Dean Sheppard, Amha Atakilit, Thomas D. Arnold, Nicole M. Rossi, Adam P. Faranda, Melinda K. Duncan
Abstract
Cytokine-producing CD4+ T cells play a crucial role in the control of Mycobacterium tuberculosis (Mtb) infection; however, there is a delayed appearance of effector T cells in the lungs following aerosol infection. The immunomodulatory cytokine IL-10 antagonizes control of Mtb infection through mechanisms associated with reduced CD4+ T cell responses. Here, we show that IL-10 overexpression only before the onset of the T cell response impairs control of Mtb growth. During chronic infection, IL-10 overexpression reduces the CD4+ T cell response without impacting the outcome of infection. IL-10 overexpression early during infection did not significantly impair the kinetics of CD4+ T cell priming and effector differentiation; however, CD4+ T cells primed and differentiated in a IL-10-enriched environment display reduced expression of CXCR3 and do not migrate into the lung parenchyma thereby limiting their ability to control infection. Importantly, these CD4+ T cells maintain their vasculature phenotype and are unable to control infection even after adoptively transferred into low IL-10 settings. Together our data support a model wherein, during Mtb infection, IL-10 acts intrinsically on T cells impairing their parenchymal migratory capacity and ability to engage with infected phagocytic cells thereby impeding control of infection.
Authors
Catarina M. Ferreira, Ana Margarida Barbosa, Palmira Barreira-Silva, Ricardo Silvestre, Cristina Cunha, Agostinho Carvalho, Fernando Rodrigues, Margarida Correia-Neves, António G. Castro, Egídio Torrado
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