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| Open AccessA common human MLKL polymorphism confers resistance to negative regulation by phosphorylation
MLKL is regarded as an executor of the necroptotic inflammatory cell death pathway. Here authors show, by introducing a mutation into mouse MLKL representing a frequently occurring human single nucleotide polymorphism, that MLKL mutations could critically alter the inflammatory response and the clearance of Salmonella from organs upon infection.
- Sarah E. Garnish
- , Katherine R. Martin
- & Joanne M. Hildebrand
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Article
| Open AccessNLRP6 potentiates PI3K/AKT signalling by promoting autophagic degradation of p85α to drive tumorigenesis
The crosstalk between innate immunity and autophagy plays a critical role in cancer. Here, the authors report that an immune receptor NLRP6 potentiates the PI3K/AKT pathway by selective degradation of p85α. The NLRP6-p85α interaction offers a potential therapeutic target for tumor treatment.
- Feng Zhi
- , Bowen Li
- & Jun Cui
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Article
| Open AccessModulation of lytic molecules restrain serial killing in γδ T lymphocytes
γδ T cells are unique T lymphocytes with cytotoxic functions, targeting infections and tumours. Here authors show that the target killing function of γδ T cells is tightly regulated at the level of the availability of lytic molecules granzyme B and perforin.
- Patrick A. Sandoz
- , Kyra Kuhnigk
- & Björn Önfelt
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Article
| Open AccessFEAST: A flow cytometry-based toolkit for interrogating microglial engulfment of synaptic and myelin proteins
When and how microglia engulf synapses and myelin is still unclear. Here, the authors provide a suite of flow cytometry-based approaches to quantify engulfment, paving the way for high-throughput assessment of microglial function in health and disease.
- Lasse Dissing-Olesen
- , Alec J. Walker
- & Beth Stevens
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Article
| Open AccessOrai inhibition modulates pulmonary ILC2 metabolism and alleviates airway hyperreactivity in murine and humanized models
The regulation and intracellular transport of Ca2+ in immune cells involves Ca2+ release-activated Ca2+ (CRAC) channels. Here the authors show targeting CRAC components Orai1 and Orai2 modulates pulmonary ILC2 cells altering their metabolism, function and is linked to alleviation of immunopathology in a murine model of allergic airway disease.
- Emily Howard
- , Benjamin P. Hurrell
- & Omid Akbari
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Article
| Open AccessPrevious infection with seasonal coronaviruses does not protect male Syrian hamsters from challenge with SARS-CoV-2
Here, the authors analysed immune response to two consecutive coronavirus infections and observed that hamsters infected with seasonal coronaviruses were not protected from COVID-19 despite cross-reactive antibodies. Antiviral and germinal center B cell responses were suppressed but not during SARS-CoV-2 variant infections.
- Magen E. Francis
- , Ethan B. Jansen
- & Alyson A. Kelvin
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Article
| Open AccessTracing immune cells around biomaterials with spatial anchors during large-scale wound regeneration
Skin scarring devoid of dermal appendages has unfavorable effects on aesthetic and physiological functions. Here, the authors present a treatment based on extracellular matrix scaffolds and perform multimodal analysis to highlight the role of Tregs recruited by the biomaterial in mitigating tissue fibrous by suppressing excessive inflammation.
- Yang Yang
- , Chenyu Chu
- & Yili Qu
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Article
| Open AccessMyo9b mutations are associated with altered dendritic cell functions and increased susceptibility to autoimmune diabetes onset
Type 1 diabetes (T1D) results from autoimmune destruction of pancreatic islet β cells. Here the author show, by comparing the diabetes-sensitive NOD mouse strain with its congenic, diabetes-resistant ALR strain, and by genomic analyses of T1D patients and control, that mutations in the Myo9b gene may alter dendritic cells to contribute to autoimmune diabetes onset.
- Jing Zhang
- , Yuan Zou
- & Cong-Yi Wang
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Article
| Open AccessA Glycolipidated-liposomal peptide vaccine confers long-term mucosal protection against Streptococcus pyogenes via IL-17, macrophages and neutrophils
Vaccines that specifically induce immunity against bacterial pathogens are required. Here the authors produce and characterize an intranasal liposomal vaccine against a peptide antigen from Streptococcus pyogenes and show that it induces a strong mucosal IgA response lasting for over one year, and that protection is dependent on cellular immunity mediated through IL-17, macrophages and neutrophils.
- Victoria Ozberk
- , Mehfuz Zaman
- & Manisha Pandey
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Article
| Open AccessBlockade of interferon signaling decreases gut barrier integrity and promotes severe West Nile virus disease
In this study, Lin and Zhao et al. show that type I IFN autoantibodies promote West Nile virus infection in enterocytes, which correlates with encephalitis disease risk in humans; while in mice, type I IFN signaling defects associate with gastrointestinal tract and blood-brain barrier permeability and disease severity.
- Shih-Ching Lin
- , Fang R. Zhao
- & Michael S. Diamond
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Article
| Open AccessTHBS1-producing tumor-infiltrating monocyte-like cells contribute to immunosuppression and metastasis in colorectal cancer
Thrombospondin-1 (THBS1) is a matricellular protein highly expressed in inflammatory processes, including cancer. Here the authors show that bone-marrow derived monocyte-like cells are the primary source of THBS1 in colorectal cancer, associated with mesenchymal characteristics, immunosuppression and a poor prognosis.
- Mayuki Omatsu
- , Yuki Nakanishi
- & Hiroshi Seno
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Article
| Open AccessMonkeypox virus-infected individuals mount comparable humoral immune responses as Smallpox-vaccinated individuals
In this work, Otter et al. compared the humoral immune responses induced by MPXV infection and Smallpox vaccination. Although comparable responses were observed, infection- or vaccination specific serological markers were identified enabling discrimination between vaccinated and infected individuals.
- Ashley D. Otter
- , Scott Jones
- & Bassam Hallis
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Article
| Open AccessTumor-intrinsic expression of the autophagy gene Atg16l1 suppresses anti-tumor immunity in colorectal cancer
Patients with MMR-proficient, microsatellite stable (MSS) colorectal cancer (CRC) are highly resistant to immune-checkpoint inhibitors. Here the authors report that tumor intrinsic expression of the autophagy gene ATG16L1 is associated with resistance to anti-tumor immunity in preclinical CRC models and that elevated ATG16L1 expression predicts poor immunotherapy response in Kras-mutant CRC patients.
- Lucia Taraborrelli
- , Yasin Şenbabaoğlu
- & Aditya Murthy
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Article
| Open AccessBifidobacteria shape antimicrobial T-helper cell responses during infancy and adulthood
The human immune system changes with age which impacts pathogen clearance. Here, Vogel et al. probe how CD4 + T-cells from different age groups respond to bacteria and show that activation with staphylococcal antigen induces T cells to become Th1-like cells, whilst stimulation with Bifidobacterium infantis induces a regulatory phenotype.
- Katrin Vogel
- , Aditya Arra
- & Monika C. Brunner-Weinzierl
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Article
| Open AccessCREB1-driven CXCR4hi neutrophils promote skin inflammation in mouse models and human patients
The mechanistic functions of neutrophils in skin inflammation are not fully understood. Here the authors use human psoriasis samples and a mouse model of skin inflammation to study neutrophils and find a CXCR4hi population of NET-forming, phagocytic neutrophils whose induction depends on the transcription factor CREB1.
- Jiaoling Chen
- , Yaxing Bai
- & Shuai Shao
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Article
| Open AccessDefining a TCF1-expressing progenitor allogeneic CD8+ T cell subset in acute graft-versus-host disease
Graft-versus-host disease (GvHD) is mediated by activated T cells. Here the authors study mouse models of allogeneic and xenogeneic GvHD, and define T cell factor-1 (TCF1)+ and TCF1- T cell subsets with distinct functions and differentiation pathways that participate in GvHD pathogenesis.
- Solhwi Lee
- , Kunhee Lee
- & Se Jin Im
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Article
| Open AccessCamel nanobody-based B7-H3 CAR-T cells show high efficacy against large solid tumours
Chimeric antigen receptor T (CAR-T) cells represent an emerging form of immune therapy but success, especially in solid tumors, is limited by the scarcity of suitable target epitopes. Here authors show that a distinct epitope motif on the transmembrane protein B7-H3, recognized by a camel nanobody, triggers robust activation and anti-tumor function in cognate CAR-T cells.
- Dan Li
- , Ruixue Wang
- & Mitchell Ho
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Article
| Open AccessmRNA vaccines encoding fusion proteins of monkeypox virus antigens protect mice from vaccinia virus challenge
The authors report mRNA vaccines encoding a fusion protein of MPXV A35R extracellular domain and full-length M1R and observe improved anti-M1R antibody response. The vaccines show enhanced active and passive protection in female mice challenged with a lethal dose of vaccinia virus.
- Fujun Hou
- , Yuntao Zhang
- & Xiaoming Yang
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Article
| Open AccessLarge T cell clones expressing immune checkpoints increase during multiple myeloma evolution and predict treatment resistance
Myelomagenesis progresses through well-defined pre-malignant states. Here, using single-cell RNA sequencing and T cell receptor repertoire analysis of bone marrow T cells in patients at different stages of myelomagenesis, the authors identify large clonotypic expansions characterized by the expression of multiple immune checkpoints.
- Cirino Botta
- , Cristina Perez
- & Bruno Paiva
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Article
| Open AccessmRNA-1273 bivalent (original and Omicron) COVID-19 vaccine effectiveness against COVID-19 outcomes in the United States
Bivalent mRNA COVID-19 vaccines have been developed to provide broader protection against SARS-CoV-2 variants. In this cohort study based on electronic health records from the United States, the authors estimate the effectiveness of bivalent, compared to monovalent, vaccines and no vaccination against a range of COVID-19-related outcomes.
- Hung Fu Tseng
- , Bradley K. Ackerson
- & Lei Qian
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Article
| Open AccessNLRP3 selectively drives IL-1β secretion by Pseudomonas aeruginosa infected neutrophils and regulates corneal disease severity
Bacterial infection of immune cells can result in engagement of different immunological pathways. Here the authors show that a Pseudomonas aeruginosa type three secretion system exoenzyme is linked to the differential selection of inflammasome usage between macrophages and neutrophils.
- Martin S. Minns
- , Karl Liboro
- & Eric Pearlman
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Article
| Open AccessGlycerol contributes to tuberculosis susceptibility in male mice with type 2 diabetes
Patients with diabetes mellitus have an increased risk of developing tuberculosis. Here the authors show that increased blood levels of glycerol in mice with type 2 diabetes contributes to their susceptibility to infection, as glycerol is one of the main carbon sources for the bacteria.
- Nuria Martinez
- , Lorissa J. Smulan
- & Hardy Kornfeld
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Article
| Open AccessA CCL2+DPP4+ subset of mesenchymal stem cells expedites aberrant formation of creeping fat in humans
Extra-intestinal “creeping fat” is a hallmark of Crohn’s disease. Here, using single-cell transcriptomics and lipid metabolomics, the authors identify a subset of mesenchymal stem cells that promote adipogenesis in creeping fat formation.
- Fengfei Wu
- , Fangting Wu
- & Lan Bai
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Article
| Open AccessEpithelial plasticity and innate immune activation promote lung tissue remodeling following respiratory viral infection
After respiratory viral infection and in fibrotic lung disease, repair and remodeling processes particularly affect airway basal cell (BC) and alveolar epithelial cell populations. Here, using single cell transcriptomics and lineage tracing, the authors characterize this process and define roles for innate immune activation in the regulation of BC fate and alveolar remodeling.
- Andrew K. Beppu
- , Juanjuan Zhao
- & Barry R. Stripp
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Article
| Open AccessPharmacological inhibition of TBK1/IKKε blunts immunopathology in a murine model of SARS-CoV-2 infection
TANK-binding kinase-1 (TBK1) and its homologue IκB kinase-ε (IKKε) are critical in the induction of the interferon response and the response to infection by pathogens. Here the authors show that pharmacological targeting of TBK1 AND IKKε reduces the immunopathology seen in a murine model of SARS-COV-2 infection.
- Tomalika R. Ullah
- , Matt D. Johansen
- & Michael P. Gantier
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Article
| Open AccessMetabolic Reprogramming via ACOD1 depletion enhances function of human induced pluripotent stem cell-derived CAR-macrophages in solid tumors
The functional-metabolic state of macrophages fundamentally influences the tumour microenvironment, making adoptive cell therapy with pro-inflammatory macrophages an attractive anti-tumour approach. Here authors introduce pluripotent stem cell-derived CAR-macrophage that are depleted of ACOD1, an essential gene in itaconate metabolism, which reprograms them to a pro-inflammatory state enabling enhanced anti-tumour function.
- Xudong Wang
- , Siyu Su
- & Jin Zhang
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Article
| Open AccessAedes aegypti Argonaute 2 controls arbovirus infection and host mortality
Aedes mosquitoes are the major vectors of the human viral diseases dengue, Zika and yellow fever, but do not succumb to infection with these pathogens due to their anti-viral small interfering RNA pathway. Here, the authors show that disruption of this pathway also impacts DNA repair mechanisms and the autophagy pathway which promotes mosquito death.
- Shengzhang Dong
- & George Dimopoulos
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Article
| Open AccessIntracellular Fusobacterium nucleatum infection attenuates antitumor immunity in esophageal squamous cell carcinoma
Fusobacterium nucleatum (Fn) is an oncogenic bacterium reported to promote esophageal squamous cell carcinoma (ESCC). Here the authors show that the virulence factor of Fn, Fn-Dps upregulates PD-L1 and that Fn promotes cell death in T-cells, hence, limiting the efficacy of immunotherapy in ESCC.
- Yiqiu Li
- , Shan Xing
- & Ge Zhang
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Article
| Open AccessDiscovery and pharmacophoric characterization of chemokine network inhibitors using phage-display, saturation mutagenesis and computational modelling
Ticks inject evasins at the bite site to bind multiple redundant chemokines and inhibit inflammation allowing blood feeding. Here, the authors identify evasin derived short peptides with broad spectrum anti-chemokine activity that could be used to develop new treatments for inflammatory disease.
- Serena Vales
- , Jhanna Kryukova
- & Shoumo Bhattacharya
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Article
| Open AccessStressed target cancer cells drive nongenetic reprogramming of CAR T cells and solid tumor microenvironment
The emergency of a high frequency of early memory T cells has been associated with clinical success of CAR T cell therapy. Here the authors show that target cancer cells stressed by disulfiram/copper complexes and ionizing radiation favour the reprogramming of CAR T cells that acquire memory-like characteristics, associated with prolonged anti-tumor response in preclinical solid tumor models.
- Yufeng Wang
- , David L. Drum
- & Xinhui Wang
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Article
| Open AccessActivation of melanocortin-1 receptor signaling in melanoma cells impairs T cell infiltration to dampen antitumor immunity
Aberrant G protein-coupled receptor (GPCR) signaling has been associated with tumor progression and metastasis. Here the authors show that depletion of the GPCR melanocortin-1 receptor (MC1R) in melanoma cells is associated with enhanced T cell infiltration and anti-tumor immune responses.
- Yazhong Cui
- , Yang Miao
- & Ting Han
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Article
| Open AccessGerminal center output is sustained by HELLS-dependent DNA-methylation-maintenance in B cells
Loss-of-function mutations in the chromatin remodelling protein HELLS result in humoral immune deficiency. Authors here show in a conditional knockout mouse model that HELLS controls the kinetics of a typical germinal center response by DNA methylation, its absence leading to either the appearance of memory-B cell markers or a metabolic state change typical of plasma cells.
- Clara Cousu
- , Eléonore Mulot
- & Sébastien Storck
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Article
| Open AccessPro-phagocytic function and structural basis of GPR84 signaling
GPR84 is an important GPCR regulating macrophage function. Here, the authors show the pro-phagocytic function of the GPR84-Gi signaling axis in native macrophages and determine a cryo-EM structure of the GPR84-Gi complex with a synthetic agonist.
- Xuan Zhang
- , Yujing Wang
- & Cheng Zhang
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Article
| Open AccessHMGB2 regulates the differentiation and stemness of exhausted CD8+ T cells during chronic viral infection and cancer
T cells can become exhausted during chronic virus infection or repeated stimulation by tumour antigens. Here the authors show that High-Mobility Group Box 2 (HMGB2) protein promotes CD8+ T cell memory cell generation in acute viral infection and exhaustion stemness in chronic infection.
- Emily N. Neubert
- , Julia M. DeRogatis
- & Roberto Tinoco
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Article
| Open AccessGut barrier defects, intestinal immune hyperactivation and enhanced lipid catabolism drive lethality in NGLY1-deficient Drosophila
NGLY1 mutations cause a multisystem developmental disorder. Here they show that this enzyme is required for normal gut barrier function, and when mutated, causes immune and metabolic abnormalities, contributing to lethality.
- Ashutosh Pandey
- , Antonio Galeone
- & Hamed Jafar-Nejad
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Article
| Open AccessMultifunctional human monoclonal antibody combination mediates protection against Rift Valley fever virus at low doses
There are currently no treatment options for infection with Rift Valley fever virus (RVFV). Here, Chapman et al., show that a combination of human monoclonal antibodies targeting two different steps in early virus cell entry enhances protection in a mouse model and is effective at low doses.
- Nathaniel S. Chapman
- , Ruben J. G. Hulswit
- & James E. Crowe Jr.
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Article
| Open AccessMetabolic heterogeneity of tissue-resident macrophages in homeostasis and during helminth infection
Gauging the in vivo metabolism of immune cells at the single-cell level has proven challenging. Here the authors use spectral flow cytometry to investigate metabolic profiles in tissue-resident macrophages from several organs and changes in response to helminth infection.
- Graham A. Heieis
- , Thiago A. Patente
- & Bart Everts
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Article
| Open AccessSolar ultraviolet B radiation promotes α-MSH secretion to attenuate the function of ILC2s via the pituitary–lung axis
Allergic asthma is episodic and associated with seasonal changes which may have links with UV exposure levels. Here the authors propose a link between UVB exposure and ILC2 function through α-MSH released from the pituitary gland which accumulates in the serum and alters ILC2 function through the MC5R receptor.
- Yuying Huang
- , Lin Zhu
- & Bing Sun
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Article
| Open AccessLangerhans cells shape postnatal oral homeostasis in a mechanical-force-dependent but microbiota and IL17-independent manner
In postnatal life, oral mucosal immunity is shaped by microbiota and the interrelating immune cells. Here, the authors show that although microbial factors facilitate the differentiation of oral Langerhans cells, their function in surveillance of mucosal epithelial barriers and capacity to induce adaptive immunity is predominantly governed by masticatory mechanical forces.
- Yasmin Jaber
- , Yasmine Netanely
- & Avi-Hai Hovav
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Article
| Open AccessPrevious immunity shapes immune responses to SARS-CoV-2 booster vaccination and Omicron breakthrough infection risk
In this study, the authors investigate immune responses following a third (booster) SARS-CoV-2 vaccination dose in a cohort of healthcare professionals in Denmark. They find stronger immune responses among those with a prior infection, and correlation between lower antibody responses and higher risk of subsequent breakthrough infection.
- Laura Pérez-Alós
- , Cecilie Bo Hansen
- & Peter Garred
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Article
| Open AccessLet-7 enhances murine anti-tumor CD8 T cell responses by promoting memory and antagonizing terminal differentiation
Effective CD8+ T cell immunity requires the generation of a long-lived memory pool and the maintenance of a non-exhausted effector T cell pool. The implementation of immune checkpoint blockade can reduced levels of exhaustion but lacks the ability to support memory formation in the effector pool. Here the authors suggest a role for Let-7 in the enhancement of the anti-tumor CD8+ T cell response by supporting memory via modulation of metabolic and differentiation state.
- Alexandria C. Wells
- , Kaito A. Hioki
- & Leonid A. Pobezinsky
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Article
| Open AccessCD8+ tissue-resident memory T-cell development depends on infection-matching regulatory T-cell types
Type-1 regulatory T cells promoted the generation of CD8+ tissue-resident memory T (TRM) cells during intracellular infections in the gut. Here, the authors show that the establishment TRM cells more broadly depends on the presence of regulatory T cells matching the type of infection.
- Leandro Barros
- , Daryna Piontkivska
- & Cristina Ferreira
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Article
| Open AccessPre-clinical validation of a pan-cancer CAR-T cell immunotherapy targeting nfP2X7
The scarcity of targetable proteins broadly expressed on cancer cells, but not on healthy cells, is an obstacle for chimeric antigen receptor (CAR)-T cell therapy. Here the authors establish that a functionally impaired version of P2X purinoceptor 7, non-functional P2X7 (nfP2X7), fulfils these criteria, and demonstrate that CAR-T cells targeting nfP2X7 efficiently and selectively kill breast and prostate cancer cells in mouse models.
- Veronika Bandara
- , Jade Foeng
- & Simon C. Barry
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Article
| Open AccessPlant immunity suppression by an exo-β-1,3-glucanase and an elongation factor 1α of the rice blast fungus
Fungal cell walls release β-1,3-glucan fragments that trigger plant immunity. Here, the authors show that a glucanase (Ebg1) of the blast fungus Magnaporthe oryzae suppresses plant immunity by hydrolyzing β-1,3-glucan. At the same time, Ebg1 induces plant immune responses that are dampened by a fungal protein that interacts with Ebg1.
- Hang Liu
- , Xunli Lu
- & You-Liang Peng
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Article
| Open AccessA cytotoxic T cell inspired oncolytic nanosystem promotes lytic cell death by lipid peroxidation and elicits antitumor immune responses
Different types of lytic cell death can trigger an anti-tumor immune response. Here the authors report the design of a near infrared light controllable micron-scale oncolytic system, triggering lipid peroxidation and lytic cell death in tumors as well anti-tumor immunity in preclinical cancer models.
- Zhigui Zuo
- , Hao Yin
- & Qinyang Wang
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Article
| Open AccessEffect of SARS-CoV-2 prior infection and mRNA vaccination on contagiousness and susceptibility to infection
It is unclear whether SARS-CoV-2 immunity decreases transmission through reduction in contagiousness of cases or susceptibility of contacts. Here, the authors use testing and contact data from Geneva, Switzerland and find that increased protection of contacts was the main driver of reduced transmission.
- Denis Mongin
- , Nils Bürgisser
- & Delphine Sophie Courvoisier
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Article
| Open AccessOptogenetic engineering of STING signaling allows remote immunomodulation to enhance cancer immunotherapy
Optogenetics makes use of light-sensitive proteins to control biological processes using light. Here, the authors present an optogenetic system that regulates the cGAS/STING pathway remotely and demonstrate its efficacy in murine tumour models.
- Yaling Dou
- , Rui Chen
- & Yun Huang
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Article
| Open AccessA tissue-intrinsic IL-33/EGF circuit promotes epithelial regeneration after intestinal injury
Mechanisms promoting epithelial regeneration after intestinal injury are poorly understood. Here, authors report that intestinal stem cells produce IL-33 after radiation injury, which induces Paneth cells to produce EGF and promote regeneration.
- Marco Calafiore
- , Ya-Yuan Fu
- & Alan M. Hanash
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Article
| Open AccessNeutrophil metalloproteinase driven spleen damage hampers infection control of trypanosomiasis
Trypanosoma brucei infection is characterised by activation of neutrophil associated genes. Here, Pham et al. further dissect the role neutrophils play in tissue pathology, disease outcome and maintenance of adaptive immunity.
- Hien Thi Thu Pham
- , Stefan Magez
- & Magdalena Radwanska
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