Featured
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Article
| Open AccessPneumolysin boosts the neuroinflammatory response to Streptococcus pneumoniae through enhanced endocytosis
Pneumococcal infection of the cerebrospinal fluid results in bacterial lysis, the release of toxic factors and induction of neuroinflammation. Here, the authors show that the virulence factor pneumolysin enhances the neuroinflammatory response to Streptococcus pneumoniae by the enhancement of endocytosis.
- Sabrina Hupp
- , Christina Förtsch
- & Asparouh I. Iliev
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Article
| Open AccessEGFR-mediated activation of adipose tissue macrophages promotes obesity and insulin resistance
In obesity, adipose tissue is chronically inflamed, leading to insulin resistance, and adipose tissue macrophages (ATMs) are a major source of cytokines that aggravate adipocyte dysfunction. Here, the authors show that selective deletion of the epidermal growth factor receptor in ATMs decreased obesity and development of insulin resistance.
- Shirong Cao
- , Yu Pan
- & Ming-Zhi Zhang
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Article
| Open AccessA CRISPR-based ultrasensitive assay detects attomolar concentrations of SARS-CoV-2 antibodies in clinical samples
CRISPR diagnostics are routinely used for the detecting nucleic acids, but rarely for clinically important proteins. Here, by translating a CRISPR-based DNA test into an ultrasensitive assay for antibodies, the authors achieve antibody detection from serum samples at attomolar concentrations.
- Yanan Tang
- , Turun Song
- & Feng Li
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Article
| Open AccessMaturation and substrate processing topography of the Plasmodium falciparum invasion/egress protease plasmepsin X
Egress of Plasmodium from host erythrocytes is mediated by effector proteins. Aspartic protease plasmepsin X (PM X) regulates the activity for many of these effectors, is essential for replication and is a promising drug target. Here, Mukherjee et al. map the self-cleavage sites of PM X, show that the N-terminal part of its prodomain is required for intracellular trafficking and correlate the maturation and subcellular activity of PM X in microneme, exoneme and rhoptry organelle function.
- Sumit Mukherjee
- , Suong Nguyen
- & Daniel E. Goldberg
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Article
| Open AccessIn mouse chronic pancreatitis CD25+FOXP3+ regulatory T cells control pancreatic fibrosis by suppression of the type 2 immune response
The function of T regulatory cells in the tissue fibrosis in chronic pancreatitis is not fully understood. Here the authors use a mouse model of chronic pancreatitis to show that Treg cells reduce IL-4 mediated chronic inflammation in the pancreas associated with M2-like macrophages in vivo.
- Juliane Glaubitz
- , Anika Wilden
- & Matthias Sendler
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Article
| Open AccessWASp modulates RPA function on single-stranded DNA in response to replication stress and DNA damage
Cancer develops in Wiskott-Aldrich syndrome (WAS). Here the authors identify a role for WAS-protein (WASp) in the DNA stress-resolution pathway by promoting the function of Replication Protein A at replication forks after DNA damage.
- Seong-Su Han
- , Kuo-Kuang Wen
- & Yatin M. Vyas
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Article
| Open AccessSARS-CoV-2 Omicron variant causes mild pathology in the upper and lower respiratory tract of hamsters
Since the emergence of SARS-CoV-2 several variants of concerns have been identified, with altered disease progression and transmission dynamics. Here, Armando et al. compare virus spread and pathology in the upper and lower respiratory tracts of Syrian golden hamster after 4 days post infection for VOCs Gamma, Delta and Omicron and find milder pathology for Omicron.
- Federico Armando
- , Georg Beythien
- & Wolfgang Baumgärtner
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Poster
| Open AccessImmune monitoring and treatment in immune-mediated inflammatory diseases
Immune monitoring assists in the diagnosis and clinical management of immune-mediated inflammatory diseases.
- Femke van Wijk
- , Marjolein de Bruin
- & Stefan Nierkens
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Article
| Open AccessRegulatory B cell repertoire defects predispose lung cancer patients to immune-related toxicity following checkpoint blockade
Immune checkpoint blockade is a promising approach to treat lung cancer, however, immune related adverse events hold back success in some patients. Here authors show that regulatory B cells fail to limit self-reactive T cells in these patients, and B cell phenotyping prior treatment may identify those at risk for these unfavourable outcomes.
- Akshay J. Patel
- , Zena N. Willsmore
- & Gary W. Middleton
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Article
| Open AccessEstrogen receptor positive breast cancers have patient specific hormone sensitivities and rely on progesterone receptor
The role of progesterone receptor (PR) and its interplay with estrogen receptor (ER) in breast cancer is controversial. Here, the authors demonstrate that PR can have an ER-independent role in breast cancer growth and metastasis and that its effects are dependent on MYC and androgen receptor signatures.
- Valentina Scabia
- , Ayyakkannu Ayyanan
- & Cathrin Brisken
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Article
| Open AccessGenomic dissection of Klebsiella pneumoniae infections in hospital patients reveals insights into an opportunistic pathogen
Klebsiella pneumoniae is an opportunistic pathogen of increasing public health concern due to the prevalence of antimicrobial resistance. Here, the authors provide insight into the resistance profiles, bacterial genome features and virulence genes, in a year-long prospective study of K. pneumoniae clinical isolates.
- Claire L. Gorrie
- , Mirjana Mirčeta
- & Kathryn E. Holt
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Article
| Open AccessOmega-3 fatty acid epoxides produced by PAF-AH2 in mast cells regulate pulmonary vascular remodeling
Pulmonary hypertension is a fatal disease that causes right heart failure due to pulmonary artery stenosis. Here, the authors find that ω-3 epoxides produced by the phospholipase PAF-AH2 in mast cells regulate pulmonary vascular remodeling.
- Hidenori Moriyama
- , Jin Endo
- & Motoaki Sano
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Article
| Open AccessCinA mediates multidrug tolerance in Mycobacterium tuberculosis
Drug tolerance complicates the treatment of tuberculosis. Here, Kreutzfeldt et al. show that the protein CinA mediates drug tolerance in Mycobacterium tuberculosis by cleaving NAD-drug adducts, suggesting CinA as a potential target to shorten tuberculosis treatment by potentiating the efficacy of currently used antibiotics.
- Kaj M. Kreutzfeldt
- , Robert S. Jansen
- & Sabine Ehrt
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Article
| Open AccessInhibition of lung microbiota-derived proapoptotic peptides ameliorates acute exacerbation of pulmonary fibrosis
Here, the authors show that treatment with a monoclonal neutralizing antibody against the lung microbiota-derived proapoptotic peptide corisin ameliorates acute exacerbation of pulmonary fibrosis and severity of endotoxin-induced acute lung injury in mice.
- Corina N. D’Alessandro-Gabazza
- , Taro Yasuma
- & Esteban C. Gabazza
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Article
| Open AccessA systematic review and meta-analysis of gene therapy with hematopoietic stem and progenitor cells for monogenic disorders
Ex-vivo gene therapy with hematopoietic stem and progenitor cells (HSPCs) is a promising treatment for monogenic diseases. Here the authors report a systematic review and meta-analysis of available evidence assessing clinical outcomes of HSPC gene therapy from clinical trials.
- Francesca Tucci
- , Stefania Galimberti
- & Alessandro Aiuti
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Article
| Open AccessSingle-cell transcriptomics links malignant T cells to the tumor immune landscape in cutaneous T cell lymphoma
Cutaneous T cell lymphomas (CTCL) are still poorly characterised at the molecular and single-cell level. Here, the authors analyse CTCL patient samples using single-cell RNA-seq, TCR and whole-exome sequencing, revealing the molecular profiles of malignant T cells and their association with the microenvironment and clinical outcomes.
- Xiangjun Liu
- , Shanzhao Jin
- & Yang Wang
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Article
| Open AccessPrognostic tools and candidate drugs based on plasma proteomics of patients with severe COVID-19 complications
Prognostic markers for patients with COVID-19 are of critical importance in determining the course of SARS-CoV-2 infection and patient handling. Here the authors determine and apply a prognostic proteomic panel for risk and drug prediction in the management of SARS-CoV-2 infected patients.
- Maryam A. Y. Al-Nesf
- , Houari B. Abdesselem
- & Fares Al-Ejeh
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Article
| Open AccessTLR4 is a regulator of trained immunity in a murine model of Duchenne muscular dystrophy
The immunopathology of Duchenne Muscular Dystrophy includes a disturbed balance of pro and anti-inflammatory macrophages. Here the authors implicate trained innate immunity in a murine model of the disease, and reveal TLR4 as a key regulator of this process.
- Salyan Bhattarai
- , Qian Li
- & Basil J. Petrof
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Article
| Open AccessDeciphering spatial genomic heterogeneity at a single cell resolution in multiple myeloma
Osteolytic lesions (OL) are frequent in multiple myeloma (MM), but are poorly understood. Here, the authors characterise OLs in MM patient samples using single-cell RNA-seq, revealing genes that are specifically regulated in OL compared to random bone marrow aspirates and that reflect the response to induction therapy.
- Maximilian Merz
- , Almuth Maria Anni Merz
- & Jens Hillengass
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Article
| Open AccessLymphocyte infiltration and thyrocyte destruction are driven by stromal and immune cell components in Hashimoto’s thyroiditis
Hashimoto’s Thyroiditis is an autoimmune disease with a complex pathomechanism. Authors here show by single cell RNA sequencing that the thyroidal microenvironment in the disease is characterised by three stromal cell subtypes that are potentially responsible for the recruitment of infiltrating inflammatory immune cells, such as macrophages and dendritic cells.
- Qian-Yue Zhang
- , Xiao-Ping Ye
- & Huai-Dong Song
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Article
| Open AccessC-type lectin receptor CLEC4A2 promotes tissue adaptation of macrophages and protects against atherosclerosis
The contribution of distinct subsets of macrophages to atherosclerosis is poorly understood. Here the authors describe a protective subset of vascular macrophages expressing the C-type lectin receptor CLEC4A2, which licenses monocytes to join the resident vascular macrophage pool and ensures vascular homeostasis.
- Inhye Park
- , Michael E. Goddard
- & Claudia Monaco
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Article
| Open AccessDistinct roles of KLF4 in mesenchymal cell subtypes during lung fibrogenesis
The pluripotency factor KLF4 has been described as pro-fibrotic or anti-fibrotic in various diseases. Herein, the authors show that during lung fibrosis, these distinct effects can be attributed to mesenchymal cell-type specific functions of KLF4.
- Rachana R. Chandran
- , Yi Xie
- & Daniel M. Greif
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Article
| Open AccessDelayed induction of type I and III interferons mediates nasal epithelial cell permissiveness to SARS-CoV-2
The innate immune response in epithelial cells after SARS-CoV-2 infection is not fully understood. Here the authors use human air-liquid interface culture and show single cell transcription changes and delayed type I Interferon responses after SARS-CoV-2 infection compared with other respiratory viruses.
- Catherine F. Hatton
- , Rachel A. Botting
- & Christopher J. A. Duncan
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Article
| Open AccessA human fetal liver-derived infant MLL-AF4 acute lymphoblastic leukemia model reveals a distinct fetal gene expression program
It is unknown why infant acute lymphoblastic leukemia (ALL) produced by MLL rearrangements leads to worse outcomes than childhood ALL. Here the authors develop a CRISPR-Cas9-induced human xenograft model of MLL-AF4 infant-ALL that faithfully replicates the disease and reveals that fetal-specific genes are potential infant-ALL drivers.
- Siobhan Rice
- , Thomas Jackson
- & Anindita Roy
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Review Article
| Open AccessEmerging technologies and infection models in cellular microbiology
Cellular microbiology is a field that combines the study of infection and cell biology. In this review, we highlight emerging technologies and infection models that recently transformed our understanding of the infected cell and may inspire future medicine.
- Ana Teresa López-Jiménez
- & Serge Mostowy
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Article
| Open AccessClinical practices underlie COVID-19 patient respiratory microbiome composition and its interactions with the host
Here, the authors profile the respiratory microbiome of COVID-19 patients and link clinical practices, such as mechanical ventilation, with vast changes in the microbiota. In the lungs, oral bacteria are found physically associated with proinflammatory immune cells, thus possibly contributing to exacerbated immune responses in severe disease
- Verónica Lloréns-Rico
- , Ann C. Gregory
- & Jeroen Raes
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Article
| Open AccessRegulatory T cells promote cancer immune-escape through integrin αvβ8-mediated TGF-β activation
TGFβ is secreted in an inactive form in the tumor microenvironment. Authors here show that although TGFβ is produced mainly by cancer cells, regulatory T cells are necessary for its activation via expression of the b8 chain of avb8 integrin. Thus, both cell types contribute to TGFβ dependent tumor growth.
- Alexandra Lainé
- , Ossama Labiad
- & Julien C. Marie
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Article
| Open AccessThe GPR171 pathway suppresses T cell activation and limits antitumor immunity
Proliferative and effector functions of T cells are determined by T cell receptor signalling and modulated by activator and inhibitory co-receptors. Authors report here that the G-protein-coupled receptor GPR171 functions as a co-inhibitor of T cell signalling and might serve as a target for cancer immunotherapy.
- Yuki Fujiwara
- , Robert J. Torphy
- & Yuwen Zhu
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Article
| Open AccessIdentification of limb-specific Lmx1b auto-regulatory modules with Nail-patella syndrome pathogenicity
Nail-patella syndrome (NPS) is characterized by nail dysplasia, absent/hypoplastic patellae, chronic kidney disease, and glaucoma and can be caused by haploinsufficiency of LMX1B; however, not all patients harbor pathogenic LMX1B mutations. Here the authors show that loss-of-function variations in upstream enhancer sequences are responsible for a limb specific form of human NPS.
- Endika Haro
- , Florence Petit
- & Kerby C. Oberg
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Article
| Open AccessOral immune dysfunction is associated with the expansion of FOXP3+PD-1+Amphiregulin+ T cells during HIV infection
Anti-retroviral treatment does not fully resolve mucosal dysfunction and systemic inflammation in HIV infected individuals. Authors show here that an unusual population of regulatory T cells, distinguished by Amphiregulin expression and the incapability to suppress CD4 T cells might contribute to disrupted oral immune protection in HIV patients.
- N. Bhaskaran
- , E. Schneider
- & P. Pandiyan
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Article
| Open AccessA broadly neutralizing humanized ACE2-targeting antibody against SARS-CoV-2 variants
Here the authors report the isolation and structural and biological characterization of a humanized angiotensin-converting enzyme 2 (ACE2)-blocking antibody, which exterts potent inhibitory activity against SARS-CoV and circulating global SARS-CoV-2 lineages both in vitro and in hACE2 mouse model.
- Yanyun Du
- , Rui Shi
- & Jinghua Yan
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Article
| Open AccessSkeletal stem and progenitor cells maintain cranial suture patency and prevent craniosynostosis
Cranial sutures are major growth centers for the skull vault and premature fusion leads to pathological fusion, craniosynostosis. Here the authors isolate Wnt responsive skeletal stem and progenitor cells from sutures, that can be transplanted together with Wnt3a protein to repair craniosynostosis in a mouse model.
- Siddharth Menon
- , Ankit Salhotra
- & Natalina Quarto
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Article
| Open AccessIFITM proteins promote SARS-CoV-2 infection and are targets for virus inhibition in vitro
IFITM proteins can inhibit several viruses, but effects on SARS-CoV-2 infection are not well understood. Here, the authors show that endogenous IFITMs support SARS-CoV-2 infection in different in vitro models by binding spike and enhancing virus entry.
- Caterina Prelli Bozzo
- , Rayhane Nchioua
- & Frank Kirchhoff
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Article
| Open AccessIn vivo evolution of an emerging zoonotic bacterial pathogen in an immunocompromised human host
Bordetella hinzii is an emerging pathogen with zoonotic risk to humans, known to be able to cause respiratory tract infection, bacteremia and endocarditis. Here, applying whole genome sequencing to bacterial isolates, the authors characterize the mechanisms driving adaptive evolution in B. hinzii in a patient with interleukin-12 receptor β1 deficiency, suggesting a role for host immune phenotype in shaping within-host pathogen evolution following zoonotic infection.
- A. Launay
- , C.-J. Wu
- & J. P. Dekker
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Article
| Open AccessTargeting the latent human cytomegalovirus reservoir for T-cell-mediated killing with virus-specific nanobodies
Human cytomegalovirus (HCMV) can evade immune responses in latent reservoirs, which is a specific problem during transplantation. Here the authors develop a bivalent nanobody that is specific for US28, a viral receptor required by latent HCMV, and show it can partially reactivate the virus and make it susceptible to killing by T cells.
- Timo W. M. De Groof
- , Elizabeth G. Elder
- & Martine J. Smit
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Article
| Open AccessChronic lung diseases are associated with gene expression programs favoring SARS-CoV-2 entry and severity
Patients with chronic lung disease (CLD) have an increased risk for severe coronavirus disease-19 and poor outcomes. Here the authors compare the transcriptomes of single cells isolated from healthy and CLD lungs to identify molecular characteristics of lung cells that may account for worse COVID-19 outcomes in these patients.
- Linh T. Bui
- , Nichelle I. Winters
- & Laure Emmanuelle Zaragosi
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Article
| Open AccessMonocyte-driven atypical cytokine storm and aberrant neutrophil activation as key mediators of COVID-19 disease severity
The host immune response plays a critical role in the immunopathology of SARS-CoV2. Here the authors combine a systems biology approach to implicate monocytes as key drivers of cytokine storm and disturbed neutrophil activation in COVID-19 disease severity.
- L. Vanderbeke
- , P. Van Mol
- & J. Wauters
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Article
| Open AccessIron-dependent apoptosis causes embryotoxicity in inflamed and obese pregnancy
Iron is essential during pregnancy for embryo and placental development and maternal health. However, in this study using mouse models, the authors demonstrate that excess maternal iron causes adverse embryo outcomes in pregnancies with underlying systemic inflammation.
- Allison L. Fisher
- , Veena Sangkhae
- & Elizabeta Nemeth
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Article
| Open AccessSARS-CoV-2 infection and transmission in the North American deer mouse
Deer mice are natural hosts for a number of human pathogens. Here, Griffin et al. report that intranasal exposure of the North American deer mouse to SARS-CoV-2 results in virus replication and shedding, despite causing only mild or asymptomatic illness. Additionally, infected deer mice can transmit SARS-CoV-2 to naïve deer mice.
- Bryan D. Griffin
- , Mable Chan
- & Darwyn Kobasa
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Article
| Open AccessDrug repurposing screens identify chemical entities for the development of COVID-19 interventions
Here, the authors perform repurposing screens of the ReFRAME drug library in two cell lines and identify inhibitors of SARS-CoV-2 infection. Antiviral activity of prodrug MK-4482 is confirmed in hamsters.
- Malina A. Bakowski
- , Nathan Beutler
- & Thomas F. Rogers
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Article
| Open AccessDistinctive genetic structure and selection patterns in Plasmodium vivax from South Asia and East Africa
The genetic diversity of Plasmodium vivax strains in South Asia isn’t well described. Here, the authors sequence P. vivax from returning UK travelers and establish South Asian isolates as subpopulation distinct from East African and South East Asian isolates.
- Ernest Diez Benavente
- , Emilia Manko
- & Taane G. Clark
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Article
| Open AccessPPDPF alleviates hepatic steatosis through inhibition of mTOR signaling
Non-alcoholic fatty liver disease (NAFLD) has become a prevalent chronic liver disease, however, drugs to treat this disease are still lacking. Here, the authors show that PPDPF inhibits the development of hepatic steatosis by negatively regulating mTORC1-S6K-SREBP1 signaling, which provides a potential therapeutic candidate for NAFLD treatment.
- Ning Ma
- , Yi-Kang Wang
- & Dong Xie
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Article
| Open AccessPerfluoroalkyl substance pollutants activate the innate immune system through the AIM2 inflammasome
The double-stranded DNA receptor AIM2 is able to sense the environmental pollutant perfluorooctane sulfonate, a prototypical perfluoro-alkyl substrate. Activation of the AIM2 pathway leads to inflammation and tissue damage via IL-1β secretion and pyroptosis of affected innate immune cells.
- Li-Qiu Wang
- , Tao Liu
- & Jun Cui
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Article
| Open AccessGenetic fate-mapping reveals surface accumulation but not deep organ invasion of pleural and peritoneal cavity macrophages following injury
Body cavity macrophages reside on the serous surfaces of organs and believed to participate in organ repair following injury. Here the authors show with a fate-mapping reporter system that these cells, although accumulate at the surfaces of injured liver or lung, don’t penetrate deeply into the tissue.
- Hengwei Jin
- , Kuo Liu
- & Bin Zhou
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Article
| Open AccessIdentification of poly(ADP-ribose) polymerase 9 (PARP9) as a noncanonical sensor for RNA virus in dendritic cells
Innate immune cells play critical roles patrolling for and detecting viral infection by expression of a range of nucleic acid sensors. Here the authors implicate PARP9 in the detection of viral RNA and the induction of the IFN pathway via PI3K/AKT3.
- Junji Xing
- , Ao Zhang
- & Zhiqiang Zhang
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Article
| Open AccessNeutralizing antibody responses to SARS-CoV-2 in symptomatic COVID-19 is persistent and critical for survival
Antibody responses are critical for protection from developing severe COVID-19 following SARS-CoV-2 infection. Here the authors show that antibody responses against SARS-CoV-2 spike protein correlate with neutralizing capacity and protection, are not affected by heterologous boosting of influenza or common cold immunity, and can last up to 8 months.
- Stefania Dispinseri
- , Massimiliano Secchi
- & Gabriella Scarlatti
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Article
| Open AccessEnhanced influenza A H1N1 T cell epitope recognition and cross-reactivity to protein-O-mannosyltransferase 1 in Pandemrix-associated narcolepsy type 1
Narcolepsy type 1 (NT1) is a severe sleep disorder with strong association to the HLA type DQB1*0602 and increased incidence among children vaccinated with the Influenza A vaccine Pandemrix. Here the authors show that these children develop T and B cell autoimmunity against protein-O-mannosyltransferase 1 via cross-reactivity.
- A. Vuorela
- , T. L. Freitag
- & O. Vaarala
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Article
| Open AccessSystems serology detects functionally distinct coronavirus antibody features in children and elderly
Antibody responses to SARS-CoV-2 are critical in the immune response to infection, but the potential cross-reactivity to other human corona viruses is poorly appreciated. Here the authors apply a systems based approach to characterise the antibody response in pre-pandemic cohorts and assess heterotypic reactivity to SARS-CoV-2.
- Kevin J. Selva
- , Carolien E. van de Sandt
- & Amy W. Chung
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Article
| Open AccessStatistics of pathogenic bacteria in the search of host cells
Chemotaxis may generally be thought to determine bacterial virulence and identification of appropriate host cells. Here, Otte, Ipiña et al. show that if this process is studied in vitro, purely mechanistic random search strategies must be included to explain the experimental results.
- Stefan Otte
- , Emiliano Perez Ipiña
- & Fernando Peruani