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| Open AccessAn esophagus cell atlas reveals dynamic rewiring during active eosinophilic esophagitis and remission
Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus with unclear immune cell involvement. Here the authors generate a single cell transcriptomic dataset with 400k cells from the esophageal mucosa of active EoE patients, remission EoE patients, and healthy individuals to characterise esophageal cellular composition, phenotype and interaction in this disease.
- Jiarui Ding
- , John J. Garber
- & Ramnik J. Xavier
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Article
| Open AccessEarly-life exercise induces immunometabolic epigenetic modification enhancing anti-inflammatory immunity in middle-aged male mice
Exercise could affect the immune system, but whether early-life exercise could benefit immune health in adulthood is not fully understood. Here the authors show that early-life exercise promotes epi-metabolic changes in the liver to potentially benefit immunity in older age and characterise the involvement of pipecolic acid in this process.
- Nini Zhang
- , Xinpei Wang
- & Feng Gao
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Article
| Open AccessDermal injury drives a skin to gut axis that disrupts the intestinal microbiome and intestinal immune homeostasis in mice
The microbial community in the intestine can affect other organs such as the skin but it is not clear if the opposite can occur. Here the authors show that skin wounding affects the microbial composition of the intestinal flora which then enhances DSS induced colitis and intestinal inflammation.
- Tatsuya Dokoshi
- , Yang Chen
- & Richard L. Gallo
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Article
| Open AccessGasdermin D promotes influenza virus-induced mortality through neutrophil amplification of inflammation
Gasdermin D (GSDMD) is a pore forming protein activated by inflammasome derived caspases. Here the authors characterize the function of GSDMD in mouse influenza virus infection and show that immunopathology is reduced in the absence of GSDMD and involves changes in neutrophil function.
- Samuel Speaks
- , Matthew I. McFadden
- & Jacob S. Yount
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Article
| Open AccessCholesterol-binding motifs in STING that control endoplasmic reticulum retention mediate anti-tumoral activity of cholesterol-lowering compounds
Cholesterol lowering medication positively affects anti-cancer immune response, but the underpinning mechanism is not fully known. Here authors show that the effect is mediated by specific cholesterol binding motifs in STING, a key mediator of inflammation, via regulating its trafficking to Golgi.
- Bao-cun Zhang
- , Marlene F. Laursen
- & Martin R. Jakobsen
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Article
| Open AccessiNOS is necessary for GBP-mediated T. gondii clearance in murine macrophages via vacuole nitration and intravacuolar network collapse
IFNγ-inducible guanylate binding proteins (GBPs) recognize the Toxoplasma gondii vacuole during infection. Here, the authors report that inducible nitric oxide synthase (iNOS) is necessary for efficient parasite clearance by GBPs and that reactive nitrogen species produced by iNOS lead to nitration of the parasite vacuole and collapse of the intravacuolar network space, preventing parasite escape from GBP targeting.
- Xiao-Yu Zhao
- , Samantha L. Lempke
- & Sarah E. Ewald
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| Open AccessAn OLD protein teaches us new tricks: prokaryotic antiviral defense
Reporting in Nature Communications, Huo and colleagues provide three-dimensional structures of a bacterial immune defense system called Gabija. This work builds on recently published structural and functional studies and contributes strong evidence that protein assembly formation is essential for antiviral function.
- Eirene Marie Q. Ednacot
- & Benjamin R. Morehouse
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Article
| Open AccessParechovirus infection in human brain organoids: host innate inflammatory response and not neuro-infectivity correlates to neurologic disease
In comparison to PeV-A1, infection with PeV-A3 is associated with neurological illness in infants. Here, using brain organoids, the authors suggest that the innate inflammatory response as the underlying reason, and not replication kinetics.
- Pamela E. Capendale
- , Inés García-Rodríguez
- & Katja C. Wolthers
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Article
| Open AccessBacteriophage DNA induces an interrupted immune response during phage therapy in a chicken model
Bacteriophage are potential therapeutics to target bacterial infections, but recent studies suggest that bacteriophage may induce immune responses in eukaryotic cells. Here the authors show that bacteriophage DNA induces interrupted host immunity in a chicken infection model.
- Magdalena Podlacha
- , Lidia Gaffke
- & Alicja Węgrzyn
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Article
| Open AccessNINJ1 mediates inflammatory cell death, PANoptosis, and lethality during infection conditions and heat stress
Fevers are known to be both beneficial and detrimental in disease, but the fundamental innate immune mechanisms driving pathology in this context remain unclear. Here, the authors show that a combination of LPS and heat stress induces inflammatory cell death, PANoptosis, that is dependent on the executioner molecule Ninjurin 1 (Ninj1) to release inflammatory molecules and drive pathogenesis.
- Joo-Hui Han
- , Rajendra Karki
- & Thirumala-Devi Kanneganti
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Article
| Open AccessS-nitrosothiol homeostasis maintained by ADH5 facilitates STING-dependent host defense against pathogens
The generation of reactive oxygen and nitrogen species is an critical part of host defense against microbial infection. Here, Jia et al, characterize the mechanisms by which reactive nitrogen species can modulate innate immunity.
- Mutian Jia
- , Li Chai
- & Wei Zhao
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Article
| Open AccessChronic endoplasmic reticulum stress in myotonic dystrophy type 2 promotes autoimmunity via mitochondrial DNA release
Myotonic dystrophy type 2 is characterized by large CCUG repeats in the CNBP gene that result in myopathy. Here, the authors show that recognition of aberrant protein translation derived from these repeats leads to ER stress and mitochondrial DNA release, leading to cGAS/STING activation and type-I IFN responses.
- Sarah Rösing
- , Fabian Ullrich
- & Claudia Günther
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Article
| Open AccessHeat shock protein gp96 drives natural killer cell maturation and anti-tumor immunity by counteracting Trim28 to stabilize Eomes
Natural killer (NK) cell maturation and function are regulated by multiple transcription factors (TF), but detailed molecular insights are scarce. Here the authors show that a TF, Eomes, is important for NK cell responses and cancer surveillance, in which Eomes expression is regulated by gp96 and Trim28 via the ubiquitination and degradation pathways.
- Yuxiu Xu
- , Xin Li
- & Songdong Meng
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Article
| Open AccessLeukaemia exposure alters the transcriptional profile and function of BCR::ABL1 negative macrophages in the bone marrow niche
The function of macrophages in myeloid leukaemia can be difficult to assess because of lack of differentiation between transformed and non-transformed cells. Here the authors use a chimeric mouse model to characterise the effect of myeloid leukaemia on bystander macrophages noting altered functional properties of these cells.
- Amy Dawson
- , Martha M. Zarou
- & G. Vignir Helgason
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| Open AccessEosinophils preserve bone homeostasis by inhibiting excessive osteoclast formation and activity via eosinophil peroxidase
Eosinophils are traditional immune effectors involved in tissue homeostasis. In this study, eosinophils emerge as key regulators of bone homeostasis by interacting with osteoclasts, inhibiting their differentiation and pathological bone loss.
- Darja Andreev
- , Katerina Kachler
- & Aline Bozec
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Article
| Open AccessBystander activated CD8+ T cells mediate neuropathology during viral infection via antigen-independent cytotoxicity
Many viral infections are linked to the development of neurological disorders. Here, Balint et al use a mouse model of Zika virus infection to show that it is immune cells (NKG2D+CD8+ T cells) that cause infection-associated paralysis, rather than the virus itself.
- Elizabeth Balint
- , Emily Feng
- & Ali A. Ashkar
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Article
| Open AccessResolvin T4 enhances macrophage cholesterol efflux to reduce vascular disease
Specialized pro-resolving mediators (SPM) are involved in the reprogramming of immune responses. Here the authors show that resolvin (RvT) 4 limits the progression of vascular disease in mouse models of arthritis exacerbated atherosclerotic inflammation.
- Mary E. Walker
- , Roberta De Matteis
- & Jesmond Dalli
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Article
| Open AccessGestational diabetes augments group B Streptococcus infection by disrupting maternal immunity and the vaginal microbiota
Here, Marcado-Evans et al show that gestational diabetes enhances group B Streptococcus infection through altering host-microbe dynamics, disrupting maternal immunity, and perturbing the vaginal microbiota in a murine pregnancy model.
- Vicki Mercado-Evans
- , Marlyd E. Mejia
- & Kathryn A. Patras
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| Open AccessOmicron Spike confers enhanced infectivity and interferon resistance to SARS-CoV-2 in human nasal tissue
Shi and Li et al. show that SARS-CoV-2 Omicron subvariants have increased capacity to infect primary human nasal tissue using a distinct entry route that depends on matrix metalloproteinases as opposed to TMPRSS2 used by previous variants, which enables evasion from antiviral factors.
- Guoli Shi
- , Tiansheng Li
- & Alex A. Compton
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| Open AccessUBR5 promotes antiviral immunity by disengaging the transcriptional brake on RIG-I like receptors
The RIG-I like receptors sense RNA viruses and initiate antiviral immunity. Here the authors screen 375 definite ubiquitin ligases and propose UBR5 promotes RLR transcription by disengaging the TRIM28-imposed brake on the RLR promoters.
- Duomeng Yang
- , Tingting Geng
- & Penghua Wang
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Article
| Open AccessExosomal secreted SCIMP regulates communication between macrophages and neutrophils in pneumonia
In this work, authors report on SCIMP-positive exosomes secreted by macrophages, that play a crucial anti-inflammatory role in pneumonia. Exosomal SCIMP primarily achieves bacterial clearance by the SCIMP-FPRs-neutrophils chemotaxis.
- Xiaolei Pei
- , Li Liu
- & Sizhou Feng
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| Open AccessLongitudinal single cell atlas identifies complex temporal relationship between type I interferon response and COVID-19 severity
Single cell transcriptomics can reveal at high resolution the body’s response to infection. Here the authors have applied this technology to a longitudinal SARS-CoV-2 infected cohort and identified gene expression changes that may predict disease severity and reveal the underlying molecular mechanisms.
- Quy Xiao Xuan Lin
- , Deepa Rajagopalan
- & Shyam Prabhakar
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| Open AccessSingle-molecule localization microscopy reveals STING clustering at the trans-Golgi network through palmitoylation-dependent accumulation of cholesterol
Stimulator of interferon genes (STING) is known to translocate from ER to Golgi while orchestrating type I interferon responses to DNA. Here, the authors show single-molecule resolution images of STING clustering at the trans-Golgi network, where it acts as a scaffold to trigger downstream signaling.
- Haruka Kemmoku
- , Kanoko Takahashi
- & Tomohiko Taguchi
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| Open AccessCullin5 drives experimental asthma exacerbations by modulating alveolar macrophage antiviral immunity
Asthma may be exacerbated by respiratory viral infection, but the cellular and molecular mechanisms are still unclear. Here the authors show, using mouse models of asthma with influenza infection, that asthma-induced cullin5 in alveolar macrophages suppresses IFN-β production to promote neutrophilic inflammation but dampens antiviral immunity.
- Haibo Zhang
- , Keke Xue
- & Lei Sun
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Article
| Open AccessSystems-based identification of the Hippo pathway for promoting fibrotic mesenchymal differentiation in systemic sclerosis
Systemic sclerosis (SSc) is an autoimmune disease causing skin fibrosis and organ inflammation. Here the authors generate and analyze SSc skin single cell RNA sequencing data to propose contributions from both myofibroblasts and endothelial-to-mesenchymal -transitioning cells (EndoMT) to skin fibrosis, and to implicate the involvement of Hippo signaling pathways.
- Feiyang Ma
- , Pei-Suen Tsou
- & Johann E. Gudjonsson
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Article
| Open AccessMucosal TLR5 activation controls healthspan and longevity
Understanding how the immune system’s functionality declines with age is crucial for addressing aging-related health issues. Here, the authors demonstrate that activating TLR5 in the mucosal layer can significantly improve healthspan and longevity, suggesting a novel approach for aging interventions.
- Jae Sung Lim
- , Eun Jae Jeon
- & Kyung A Cho
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| Open AccessInnate immune and proinflammatory signals activate the Hippo pathway via a Tak1-STRIPAK-Tao axis
The evolutionally conserved Hippo pathway regulates essential developmental, homeostatic and regenerative processes, and is involved in the host defense against pathogens. Here authors show that in Drosophila Melanogaster and mammalian cells, innate immune stimuli activate Hippo via a pathway emanating from the Tak1 kinase and cascading down to Hippo via STRIPAK-Tao-Hpo signaling.
- Yinan Yang
- , Huijing Zhou
- & Bo Liu
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Article
| Open AccessEpithelial SIRT6 governs IL-17A pathogenicity and drives allergic airway inflammation and remodeling
IL-17 mediated inflammation in the lung is mediated by different effector molecules. Here the authors show that the epigenetic regulator epithelial sirtuin 6 (Sirt6) is associated with lung inflammation in asthma patients and that Sirt6 contributes to promotion of inflammation in mouse asthma models.
- Jingyun Quan
- , Xiaoxia Wen
- & Tianwen Lai
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Article
| Open AccessNuclear RPSA senses viral nucleic acids to promote the innate inflammatory response
Innate immune responses are the first line of defence against viral pathogens. Here, Jiang et al show that the nuclear located 40S ribosomal protein SA senses viral nucleic acids to selectively enhance proinflammatory cytokine gene expression through epigenetic modification.
- Yan Jiang
- , Siqi Sun
- & Xuetao Cao
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Article
| Open AccessInflammasome activity is controlled by ZBTB16-dependent SUMOylation of ASC
Inflammasomes are multiprotein complexes, including the protein ASC, that assemble in response to inflammatory stimulation. Here the authors characterise the regulation of ASC during inflammasome formation and show the involvement of SUMOylation and zinc-finger and BTB domain-containing protein 16 (ZBTB16).
- Danfeng Dong
- , Yuzhang Du
- & Dakang Xu
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Article
| Open AccessAcetylation is required for full activation of the NLRP3 inflammasome
The NLRP3 inflammasome is activated in two steps, priming and assembly, in response to endogenous, microbial, and other environmental danger signals. Here authors show that the assembly step is regulated by acetylation, and inhibition of this post-translational modification prevents full activation of the inflammasome.
- Yening Zhang
- , Ling Luo
- & Kai Zhao
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Article
| Open AccessHuman and mouse neutrophils share core transcriptional programs in both homeostatic and inflamed contexts
Difficulties can be encountered when translating research between cells from animals and humans because of gene expression differences. Here the authors perform an integrative transcriptomic analysis from human and mouse neutrophils and identify a core inflammation program shared across inflamed contexts.
- Nicolaj S. Hackert
- , Felix A. Radtke
- & Ricardo Grieshaber-Bouyer
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| Open AccessInteraction dynamics between innate and adaptive immune cells responding to SARS-CoV-2 vaccination in non-human primates
Innate immune responses to mRNA vaccines are less well understood than adaptive immunity. Here, the authors comprehensively characterize the innate and adaptive immune responses to mRNA-1273 vaccinations in rhesus macaques and show how the vaccine activates interactions among components of the two systems.
- Chaim A. Schramm
- , Damee Moon
- & Daniel C. Douek
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| Open AccessDermis resident macrophages orchestrate localized ILC2 eosinophil circuitries to promote non-healing cutaneous leishmaniasis
Tissue resident macrophages are intricately involved in homeostatic processes but also in tissue repair. Here Lee and colleagues show dermis-resident macrophages are a source of thymic stromal lymphopoietin and CCL24, which act on type 2 innate lymphoid cells and eosinophils respectively, to maintain their M2 properties and promote non-healing cutaneous leishmaniasis.
- Sang Hun Lee
- , Byunghyun Kang
- & David L. Sacks
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Article
| Open AccessPTK2B promotes TBK1 and STING oligomerization and enhances the STING-TBK1 signaling
TBK1 plays a central role in the antiviral innate response. Here the authors identify PTK2B as an interacting protein linked to TBK1 and STING oligomerisation and the activation of STING-TBK1 signaling.
- Yongfang Lin
- , Jing Yang
- & Qinmiao Sun
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Article
| Open AccessTLR7 promotes smoke-induced experimental lung damage through the activity of mast cell tryptase
Toll-like receptor 7 (TLR7) normally recognizes exogenous single-stranded RNA for the activation of innate immunity. Here the authors show that TLR7 may also contribute, via the modulation of mast cell functions, to experimental, cigarette smoke-induced mouse models of emphysema, thereby hinting TLR7 as a potential therapeutic target for human lung inflammation.
- Gang Liu
- , Tatt Jhong Haw
- & Philip M. Hansbro
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Article
| Open AccessThe E3 ligase Riplet promotes RIG-I signaling independent of RIG-I oligomerization
Riplet conjugates K63-Ub chain to RIG-I in order to induce a robust antiviral response, but the mechanism of action remains unclear. Here, the authors show that Riplet recognizes RIG-I regardless of its RNA-bound status and promotes RIG-I signaling independent of RIG-I oligomerization.
- Wenshuai Wang
- , Benjamin Götte
- & Anna Marie Pyle
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Article
| Open AccessCryo-electron tomography of NLRP3-activated ASC complexes reveals organelle co-localization
The authors characterized puncta in the ASC complex by correlative light microscopy and cryo-ET in cells and propose an ultrastructure of the ASC filament network.
- Yangci Liu
- , Haoming Zhai
- & Yorgo Modis
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Article
| Open AccessARF1 prevents aberrant type I interferon induction by regulating STING activation and recycling
Self-derived DNA may trigger interferon-driven autoinflammation mediated by the cGAS-STING axis. Here, the authors find that mutations in the GTPase ARF1 cause an interferonopathy by promoting aberrant mitochondrial DNA release and impairing STING recycling.
- Maximilian Hirschenberger
- , Alice Lepelley
- & Konstantin M. J. Sparrer
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Article
| Open AccessAn interferon-integrated mucosal vaccine provides pan-sarbecovirus protection in small animal models
Here, the authors report the generation of a live but defective SARS-CoV-2 virus that is envelope-deficient and expresses human interferon beta. They show that nasal vaccination enhances mucosal and lung T cell response and provides pan-sarbecovirus protection in small animals.
- Chun-Kit Yuen
- , Wan-Man Wong
- & Kin-Hang Kok
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Article
| Open AccessC-type lectin receptor 2d forms homodimers and heterodimers with TLR2 to negatively regulate IRF5-mediated antifungal immunity
Receptor dimerization can modulate immune responses during various microbial infections. Here, the authors show that C-type lectin receptor-2d (CLEC2D) negatively regulates antifungal immunity through forming homodimers or heterodimers with TLR2.
- Fan Li
- , Hui Wang
- & Xin-Ming Jia
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Article
| Open AccessA conformation-locking inhibitor of SLC15A4 with TASL proteostatic anti-inflammatory activity
The authors identify feeblin, an inhibitory compound of the proinflammatory TLR7/8/9-IRF5 pathway with therapeutic potential, which acts by binding SLC15A4 via an allosteric mechanism mediating degradation of its signaling partner TASL.
- Andras Boeszoermenyi
- , Léa Bernaleau
- & Giulio Superti-Furga
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Article
| Open AccessObesity dysregulates the pulmonary antiviral immune response
Obesity is a risk factor for severe influenza infection. Here, Almond et al show that increased susceptibility is due to increased airway concentrations of the hormone leptin which dampens interferon responses and facilitates severe infection.
- Mark Almond
- , Hugo A. Farne
- & Aran Singanayagam
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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 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 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 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 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