Innate immunity

  • Article
    | Open Access

    Interferon (IFN) is an important component of antiviral immunity, but can also be exploited by bacteria for immune evasion. Here the authors show that Listeria monocytogenes (Lm) induces type I IFN to suppress the degradation of Lm virulence proteins, ActA and LLO, and promote Lm infection in an IFITM3-dependent manner, thereby hinting at a potential target for antimicrobial therapy.

    • Joel M. J. Tan
    • , Monica E. Garner
    •  & John H. Brumell
  • Article
    | Open Access

    Post-translational modifications are important regulators of NLRP3 inflammasome activity. Here the authors show that the E3 ligase TRIM28 can SUMOylate NLRP3, thereby limiting its proteasomal degradation and increasing NLRP3 inflammasome activity.

    • Ying Qin
    • , Qi Li
    •  & Wei Zhao
  • Article
    | Open Access

    SAMHD1 is a cellular dNTPase proposed to inhibit HIV-1 reverse transcription in non-cycling immune cells by limiting dNTP substrate supply; its anti-viral but not dNTPase function is downregulated by phosphorylation of T592. Here, Martinat et al. describe an additional SUMOylation at residue K595, which promotes the dNTPase-independent restriction activity.

    • Charlotte Martinat
    • , Arthur Cormier
    •  & Alessia Zamborlini
  • Article
    | Open Access

    IRF5 is a potential target for therapy in systemic lupus erythematosus (SLE). Here the authors show using mouse SLE-like models that genetic or chemical inhibition of IRF5 after SLE onset could be more effective than, or an add on for, currently utilised type I interferon inhibition.

    • Tatsuma Ban
    • , Masako Kikuchi
    •  & Tomohiko Tamura
  • Article
    | Open Access

    Toll-like receptor 8 (TLR8) plays essential roles in the innate immune response to viral single-stranded RNA (ssRNA), so small molecule modulators of TLR8 are of interest, however adverse effects limit their use. Here, the authors report a tetrasubstituted imidazole CU-CPD107 with dichotomous behaviour, which inhibits R848-induced TLR8 signaling, but shows synergistic activity in the presence of ssRNA, making it a potential antiviral agent.

    • Yi Yang
    • , Adam Csakai
    •  & Hang Yin
  • Article
    | Open Access

    Lipid droplets (LDs) are recognized as dynamic organelles and scaffolding platforms to regulate signalling cascades. Here, Monson et al. provide evidence that LDs are involved in regulation of an early antiviral immune response specifically through the enhanced modulation of IFN following viral infection in vitro and in vivo.

    • E. A. Monson
    • , K. M. Crosse
    •  & K. J. Helbig
  • Article
    | Open Access

    The human voltage-gated proton channel (hHv1) maintains intracellular pH and membrane potential in sperm and neutrophils. Here, the authors show that albumin activates hHv1, by binding to the channel voltage sensor domains to enhance open probability and increases proton current, and that activation is required to trigger sperm to allow oocyte fertilization and to sustain production and release of immune inflammatory mediators during the neutrophil respiratory burst.

    • Ruiming Zhao
    • , Hui Dai
    •  & Steve A. N. Goldstein
  • Article
    | Open Access

    Yeast form part of the host microbiome with known impact on host immunity. Here the authors identify and investigate the impact of commensal yeast-derived polysaccharides in modulating host inflammation, and show its potential for inhibiting inflammation in a number of models of inflammatory diseases.

    • Changhon Lee
    • , Ravi Verma
    •  & Sin-Hyeog Im
  • Article
    | Open Access

    P53 is a well-known tumour suppressor, however its role in intestinal type 2 immunity is currently unclear. Here authors report that during parasitic infections, p53 triggers tuft cell Ca2+ influx and IL-25 release, and shows a regulatory role for p53 in intestinal type 2 immunity via transcriptional regulation of the Lrmp gene.

    • Chun-Yuan Chang
    • , Jianming Wang
    •  & Wenwei Hu
  • Article
    | Open Access

    Ubiquitination has an important function in the regulation of antiviral immunity involving the signalling molecule MAVS. Here the authors investigate deubiquitinating enzymes and show USP18 regulates MAVS mediated antiviral signalling through modulating the ubiquitination of MAVS via promotion of interaction between MAVS and TRIM31.

    • Jinxiu Hou
    • , Lulu Han
    •  & Chengjiang Gao
  • Article
    | Open Access

    IFNy can polarize macrophages in the tumour microenvironment to an inflammatory state and thereby contributes to their anti-tumour function. Here the authors show an underlying mechanism in this process is IFNy-driven STAT1 occupancy and activation of NRE1, a regulatory region within the NAMPT gene, thereby implicating inducible NAD salvage synthesis in TAM functions.

    • Thomas B. Huffaker
    • , H. Atakan Ekiz
    •  & Ryan M. O’Connell
  • Article
    | Open Access

    MAL and MyD88 are downstream adaptors of Toll-like receptors (TLR) and the MAL TIR domain forms filaments in vitro, which in turn nucleate the assembly of crystalline arrays of the MyD88 TIR domain. Here, the authors present the structure of these MyD88 TIR crystalline arrays solved by both microcrystal electron diffraction and serial femtosecond crystallography, and they show with mutagenesis experiments that MyD88 interface residues are important for TLR4 signaling in vivo.

    • Max T. B. Clabbers
    • , Susannah Holmes
    •  & Thomas Ve
  • Article
    | Open Access

    Conventional T cell subsets are selected in the thymus by peptide bearing MHC expressed by cortical epithelial cells, in contrast cortical thymocytes express non-peptide bearing MHC molecules including CD1d and MR1 and select iNKT and MAIT cell populations respectively. Here, the authors generate a novel inducible MHC class-I trasnactivator murine system and suggest the absence of peptide-MHC on thymocytes is involved in the selection of non-peptide specific lymphocytes.

    • Hristo Georgiev
    • , Changwei Peng
    •  & Kristin A. Hogquist
  • Article
    | Open Access

    Mycobacterial cell wall lipids can drive immunoevasion, but underlying mechanisms are incompletely understood. Here the authors show TREM2 is a pattern recognition receptor that binds non-glycosylated mycolic acid-containing lipids and inhibits Mincle-induced anti-mycobacterial macrophage responses.

    • Ei’ichi Iizasa
    • , Yasushi Chuma
    •  & Hiromitsu Hara
  • Article
    | Open Access

    PU.1 is a master regulator of myeloid development but its role in disease-relevant neutrophils is not well known. Here, the authors look at primary neutrophils from a human population and find that genetic variants affecting binding of PU.1 are associated with cell count and disease susceptibility.

    • Stephen Watt
    • , Louella Vasquez
    •  & Nicole Soranzo
  • Article
    | Open Access

    KIR2DL2 and KIR2DL3 are two inhibitory members of the killer-cell immunoglobulin-like receptors (KIR) family that share a common HLA-I preference in binding HLA from the C1 group. However, it is still unclear to what extent binding and function is equivalent between KIR2DL2 and 2DL3. Here, the authors present the crystal structures of KIR2DL2 and 2DL3 in complex with HLA-C*07:02 and observe differences in HLA-C recognition between KIR2DL2 and 2DL3, which correlates with differences in HLA-C binding preference as they show with mutagenesis and binding studies.

    • Shoeib Moradi
    • , Sanda Stankovic
    •  & Julian P. Vivian
  • Article
    | Open Access

    Mito-SEPs are small peptides that can modulate oxidative metabolism in mitochondria. Here the authors show that C15ORF48 encodes a mito-SEP, MOCCI, capable of altering mitochondria respiration to suppress inflammation, while C15ORF48 3’ untranslated region also contains a miRNA, miR-147b, that synergizes with MOCCI to modulate host anti-viral responses.

    • Cheryl Q. E. Lee
    • , Baptiste Kerouanton
    •  & Lena Ho
  • Article
    | Open Access

    N6-methyladenosine (m6A) RNA modification regulates RNA metabolism, and has been implicated in immune regulation. Here, the authors show that the m6A methyltransferase, METTL3, translocates into the cytoplasm to increase viral RNA m6A modification, decreases viral ds RNA content, and thereby dampens the RIG/MDA5-induced anti-viral immunity.

    • Weinan Qiu
    • , Qingyang Zhang
    •  & Pengyuan Yang
  • Article
    | Open Access

    NF-κB signalling is critical to TLR mediated cytokine release in various immune responses. Here the authors show how N4BP1 inhibits NEMO signalling and subsequent NF-κB activation and how this pathway is negatively regulated by caspase-8 cleavage of N4BP1.

    • Hexin Shi
    • , Lei Sun
    •  & Bruce Beutler
  • Article
    | Open Access

    Secreted peptides and cell-surface localized receptor kinases allow plants to modify growth and development according to external cues. Here, Rhodes et al. show that the MIK2 receptor perceives the SERINE RICH ENDOGENOUS PEPTIDE (SCOOP) family of phytocytokines and is capable of recognising Fusarium-derived SCOOP-like peptides.

    • Jack Rhodes
    • , Huanjie Yang
    •  & Cyril Zipfel
  • Article
    | Open Access

    Macrophages can be polarized by in vitro culture stimuli into M1 or M2 cells, but microenvironments in vivo are more complex. Here the authors analyze cultured macrophages stimulated with a combination of M1 and M2 stimuli by single-cell RNA sequencing, machine learning, and single-cell secretion profiling to show a surprising level of heterogeneity of response.

    • Andrés R. Muñoz-Rojas
    • , Ilana Kelsey
    •  & Kathryn Miller-Jensen
  • Article
    | Open Access

    Pathogen triggered N-terminal degradation of NLRP1 and CARD8 by the proteasome releases their C-terminal UPA-CARD fragments (CT) to form the inflammasome, which in turn activates caspase-1. Here, the authors present the cryo-EM structures of the NLRP1-CT and CARD8-CT helical filaments as well as the ASCcaspase-1 octamer structure, which together with in vitro and cell based assays provide further insights into the architecture and specificity of the active NLRP1 and CARD8 inflammasomes.

    • L. Robert Hollingsworth
    • , Liron David
    •  & Hao Wu
  • Article
    | Open Access

    COPA regulates Golgi to ER transport, and mutations lead to autoinflammation and disease through poorly understood mechanisms. Here, the authors show that disease-causing COPA variants prevent STING transport from the Golgi to the ER, leading to cGAS-independent activation of the STING pathway.

    • Kojiro Mukai
    • , Emari Ogawa
    •  & Tomohiko Taguchi
  • Article
    | Open Access

    Histones, proteins that bind DNA, are toxic for pathogens outside cells but can also cause multi-organ damage as seen in sepsis. Here the authors develop small negatively charged molecules that can be used as histone antidotes, and show that they improve the phenotype in mouse models with histone-related pathologies.

    • Connor H. O’ Meara
    • , Lucy A. Coupland
    •  & Christopher R. Parish
  • Article
    | Open Access

    lncRNAs are transcriptional regulators, but little is known of them functioning as negative feedback regulators of inflammation in humans. Here, the authors show that the human lncRNA LUCAT1 sequesters STAT1 to limit JAK/STAT signaling and the inflammatory response to viral infection or TLR stimulation in myeloid cells.

    • Shiuli Agarwal
    • , Tim Vierbuchen
    •  & Katherine A. Fitzgerald
  • Article
    | Open Access

    Here, Fahlberg et al. describe the cellular immune response during acute, resolving or progressive COVID-19 in SARS-CoV-2 infected non-human primates. The study identifies associations of monocytes and macrophage subtypes in lungs with disease outcome, IL-6 and IL-10 ratio in plasma, and viral replication in bronchial brushes.

    • M. D. Fahlberg
    • , R. V. Blair
    •  & M. Vaccari
  • Article
    | Open Access

    Excessive interferon (IFN) responses often follow viral infection to induce pathology or even death. Here the authors show that a signaling adaptor, β-arrestin 2, enhances the cGAS/STING innate immunity signaling pathway to promote IFN-β production, but may be degraded in infected cells to serve as a target of viral immune evasion.

    • Yihua Zhang
    • , Manman Li
    •  & Dapeng Yan
  • Article
    | Open Access

    The human skin is a highly complex organ comprising multiple tissue layers and diverse cell types. Here, the authors present a spatially-resolved quantitative proteomic atlas of the healthy human skin, characterizing the protein profiles of four skin layers and nine cell types.

    • Beatrice Dyring-Andersen
    • , Marianne Bengtson Løvendorf
    •  & Matthias Mann
  • Article
    | Open Access

    MAVS and MITA are adapter proteins that play distinct roles in the context of the host response to RNA and DNA viruses, respectively. Here the authors implicate RNF115 in dual temporal and spatial mechanisms of interacting and catalyzing distinct ubiquitination of MAVS and MITA to modulate RNA and DNA antiviral immune responses.

    • Zhi-Dong Zhang
    • , Tian-Chen Xiong
    •  & Bo Zhong
  • Article
    | Open Access

    How mutations in the microbial receptor NOD2 induce Blau syndrome in humans and related uveitis is unclear. Here the authors show, using Nod2-deficient mice and experimental uveitis, that Nod2 negatively regulates T cell activation and transcription of autoimmunity-related genes to suppress Th17 responses and uveitis.

    • Ruth J. Napier
    • , Ellen J. Lee
    •  & Holly L. Rosenzweig
  • Article
    | Open Access

    A series of Toll-like receptor 7 (TLR7)-specific antagonists and extensive structural analysis reveal the open conformation of the receptor and the structural basis of TLR7 antagonism. One of the compounds shows efficacy in treating mouse model of systemic lupus erythematosus.

    • Shingo Tojo
    • , Zhikuan Zhang
    •  & Toshiyuki Shimizu
  • Article
    | Open Access

    Macrophages survey their surroundings using macropinocytosis, but its regulation is unclear. Here, the authors report that SLIT2, a known inhibitor of Rac GTPases, is an endogenous inhibitor of macropinocytosis, and that SLIT2 limits the uptake of NOD2 ligands into immune cells and subsequent release of the inflammatory chemokine, CXCL1, in vivo.

    • Vikrant K. Bhosle
    • , Tapas Mukherjee
    •  & Lisa A. Robinson
  • Article
    | Open Access

    The pandemic of SARS-CoV-2 post a significant threat to public health. Here the authors show, by screening 23 viral proteins, that both structural and non-structural SARS-CoV-2 proteins are capable of modulating host innate immunity and type interferon responses, with this information serves to warrant further studies on SARS-CoV-2 pathogenesis.

    • Xiaobo Lei
    • , Xiaojing Dong
    •  & Jianwei Wang
  • Article
    | Open Access

    TLR4 signalling can reprogram the metabolism of macrophages to be more glycolytic and proinflammatory. Here the authors show that LPS and TLR4 signalling results in recruitment of TBK1, which in turn phosphorylates serine 727 on STAT3 to enable a proinflammatory switch via an effect on mitochondrial metabolism.

    • Jesse J. Balic
    • , Hassan Albargy
    •  & Ashley Mansell