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Human cytomegalovirus exploits STING signaling and counteracts IFN/ISG induction to facilitate infection of dendritic cells
Human cytomegalovirus (HCMV) is a ubiquitous pathogen associated with morbidity and mortality in the immunocompromised or immunonaive context. Here the authors show that HCMV exploits STING signalling and subverts the interferon response to support infection of monocyte derive dendritic cells.
- Bibiana Costa
- , Jennifer Becker
- & Ulrich Kalinke
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| Open Access
Longitudinal 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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15-Lipoxygenase promotes resolution of inflammation in lymphedema by controlling Treg cell function through IFN-β
Specialised pro-resolving lipid mediators can reduce inflammatory responses and may be active in lymphedema. Here the authors show that in a mouse model 15-LO derived lipid mediators are reduced during inflammation and that a lack of the 15-LO producing enzyme aggravated disease and addition of 15-LO enzyme or Treg cells reduced disease.
- A. Zamora
- , M. Nougué
- & B. Garmy-Susini
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Cullin5 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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Maternal antibiotic exposure enhances ILC2 activation in neonates via downregulation of IFN1 signaling
Treatment of pregnant animals with antibiotics can have unexpected effects on offspring. Here the authors use mouse models to show that antibiotic treatment of mothers leads to changes in ILC2 phenotype in neonatal lungs accompanied by changes in the microbiota and microbiota derived butyrate.
- Haixu Xu
- , Xianfu Yi
- & Jie Zhou
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Bacterial-induced or passively administered interferon gamma conditions the lung for early control of SARS-CoV-2
The role of interferon-γ (IFNγ) in anti-viral immunity has been unclear. Here the authors show that bacterial-induced or intranasally administered IFNγ effectively restricts SARS-CoV-2 infection in mice through effects on non-hematopoietic cells.
- Kerry L. Hilligan
- , Sivaranjani Namasivayam
- & Alan Sher
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Dimethyl fumarate and 4-octyl itaconate are anticoagulants that suppress Tissue Factor in macrophages via inhibition of Type I Interferon
Infectious disease associated with excessive inflammation can result in coagulopathy. Here the authors show use of the clinically approved therapy dimethyl fumarate, as well as the pre-clinical tool compound 4- octyl itaconate, modulate tissue factor related coagulopathy via inhibition of the myeloid type I interferon pathway-tissue factor axis.
- Tristram A. J. Ryan
- , Alexander Hooftman
- & Luke A. J. O’Neill
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Neutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignancies
B cell malignancies resistant to conventional treatments are potentially sensitive to CAR-T cell immune therapy, but its clinical applicability is limited by immune related adverse effects. Here authors show in a humanized mouse model that blocking IFNγ with the monoclonal antibody emapalumab mitigates the adverse effects of CAR.CD19-T cells without compromising their anti-lymphoma efficacy.
- Simona Manni
- , Francesca Del Bufalo
- & Concetta Quintarelli
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Translation factor eIF5a is essential for IFNγ production and cell cycle regulation in primary CD8+ T lymphocytes
The translational elongation factor eIF5a may have a function in T cell protein translation. Here the authors show that hypusination of eIF5a or deletion of eIF5a alters the profile of mRNA translation in T cells and that eIF5 regulates the proliferation and effector function of these T cells.
- Thomas C. J. Tan
- , Van Kelly
- & Rose Zamoyska
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| Open Access
Myeloid cells promote interferon signaling-associated deterioration of the hematopoietic system
Innate and adaptive immune cells function in the homeostasis of haematopoietic stem cells (HSC). Here the authors show that myeloid cells are able to reduce the function of HSCs via interferon signaling through a neutrophil-NK cell dependent process.
- Jacqueline Feyen
- , Zhen Ping
- & Marc H. G. P. Raaijmakers
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Article
| Open Access
Interruption of post-Golgi STING trafficking activates tonic interferon signaling
Microbial DNA is recognized by the cGAS-STING pathway, which leads to a type I interferon response. Here authors show that a basal flux of interferon activation could also be triggered by interference with STING trafficking from the Golgi apparatus to the lysosomes.
- Xintao Tu
- , Ting-Ting Chu
- & Nan Yan
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MYC promotes immune-suppression in triple-negative breast cancer via inhibition of interferon signaling
Tripe-negative breast cancers poorly respond to immune checkpoint inhibition therapy, due to their immune-hostile tumour microenvironment. Authors here show that the oncogene MYC plays a pivotal role in suppressing anti-tumour immunity via directly regulating the transcription of interferon signalling genes.
- Dario Zimmerli
- , Chiara S. Brambillasca
- & Jos Jonkers
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Single-cell profiling reveals distinct adaptive immune hallmarks in MDA5+ dermatomyositis with therapeutic implications
Anti-melanoma differentiation-associated gene 5-positive dermatomyositis is a severe autoimmune disease with largely unknown aetiology. Here authors identify the key immune cell types that contribute to the disease phenotype and implicate type I interferons signalling in the patho-mechanism.
- Yan Ye
- , Zechuan Chen
- & Xiaoming Zhang
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Viral coinfection promotes tuberculosis immunopathogenesis by type I IFN signaling-dependent impediment of Th1 cell pulmonary influx
Viral coinfection alongside mycobacterium tuberculosis (Mtb) infection may lead to immune complications or interference with immune responses. Here the authors show that in mice infected with Mtb and LCMV virus the specific TH1 response to MTb is reduced through a type I IFN response to the infecting virus.
- Tae Gun Kang
- , Kee Woong Kwon
- & Sung Jae Shin
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Inhibition of type 1 immunity with tofacitinib is associated with marked improvement in longstanding sarcoidosis
Sarcoidosis is a heterogenous disorder often treated with glucocorticoids. Here the authors show, in an open label, non-randomized, single arm clinical trial involving 10 patients, that treatment with tofacitinib, a Janus kinase inhibitor, is associated with improved clinical symptoms and reduced activity of Th1 cytokines such as IFN-γ and IL-12.
- William Damsky
- , Alice Wang
- & Brett King
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Discovery of a signaling feedback circuit that defines interferon responses in myeloproliferative neoplasms
Interferon alpha (IFNalpha) therapy is showing promising results to treat myeloproliferative neoplasms (MPNs). Here, the authors show that IFNalpha response requires ULK1 phosphorylation to induce p38-MAPK signalling but it is counteracted by ROCK1-2 activation suggesting combination therapy of IFNalpha-ROCK1-2 inhibition may improve MPNs treatment.
- Diana Saleiro
- , Jeremy Q. Wen
- & Leonidas C. Platanias
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Identification and establishment of type IV interferon and the characterization of interferon-υ including its class II cytokine receptors IFN-υR1 and IL-10R2
Interferons are critical soluble components of the inflammatory process and are composed of three types with associated receptor complexes. Here the authors identify and characterise the type IV interferon, IFN-υ, and identify its associated receptors, denote functionality during in vivo infection and ascertain its genomic localisation.
- Shan Nan Chen
- , Zhen Gan
- & Pin Nie
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An instructive role for Interleukin-7 receptor α in the development of human B-cell precursor leukemia
Activating mutations in Interleukin-7 receptor alpha (IL7Ra) have been reported in B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) but its role in leukaemogenesis is not clear. Here, the authors show that activation of IL7Ra in primary human hematopoietic progenitors initiates preleukaemia and cooperates with CDKN2A silencing to develop BCP-ALL.
- Ifat Geron
- , Angela Maria Savino
- & Shai Izraeli
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Myeloid cell nuclear differentiation antigen controls the pathogen-stimulated type I interferon cascade in human monocytes by transcriptional regulation of IRF7
The interferon response is a critical component of the innate immune response. Here the authors implicate MNDA in the regulation of type I interferon responses to pathogen infection.
- Lili Gu
- , David Casserly
- & Andrew G. Bowie
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Proteomic profiling of MIS-C patients indicates heterogeneity relating to interferon gamma dysregulation and vascular endothelial dysfunction
Multi-inflammatory syndrome in children (MIS-C) can be associated with SARS-CoV-2 infection but can also be similar to other inflammatory syndromes. Here the authors characterise the plasma proteome phenotype in MIS-C and compare to other SARS-CoV-2 related syndromes and find disproportionately high IFN-γ responses in MIS-C patients.
- Caroline Diorio
- , Rawan Shraim
- & Edward M. Behrens
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Delayed 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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Cross-species analysis of viral nucleic acid interacting proteins identifies TAOKs as innate immune regulators
Whether there are conserved nucleic acid (NA) binding proteins across species is not fully known. Using data from human, mouse and fly, the authors identify common binders, implicate TAOKs and show that these kinases bind NAs across species and promote virus defence in mammalian cells.
- Friederike L. Pennemann
- , Assel Mussabekova
- & Andreas Pichlmair
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A non-canonical, interferon-independent signaling activity of cGAMP triggers DNA damage response signaling
Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) is normally induced by innate immunity sensing for protection from pathogens. Here the authors show that cGAMP is also upstream of DNA damage signaling by activating ATM-CHK2-mediated repair pathway, while simultaneously suppressing the homology-directed repair.
- Daipayan Banerjee
- , Kurt Langberg
- & Nagaraj Kerur
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Self-reactivity controls functional diversity of naive CD8+ T cells by co-opting tonic type I interferon
There is heterogeneity in the response to self-ligands within the naïve CD8+ T cell pool and the consequences of this are unclear. Here the authors show subsets of naïve CD8+ T cells which differ in expression of Ly6C and CD5 and response to viral infection through regulation by type I IFN signalling.
- Young-Jun Ju
- , Sung-Woo Lee
- & Jae-Ho Cho
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Cleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory triggering by multiple sensors
Loss of function polymorphisms of phospholipase D3 and D4 are associated with inflammatory diseases and their function is unclear. Here the authors show that PLD3/4 function as RNAses and deletion of these proteins in mice leads to accumulation of ssRNA which exacerbates inflammation through TLR signalling.
- Amanda L. Gavin
- , Deli Huang
- & David Nemazee
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Infection-induced type I interferons critically modulate the homeostasis and function of CD8+ naïve T cells
Infections induce activation of naïve T cells for protective immunity, but insights for this host-pathogen crosstalk are still missing. Here the authors show that infection-induced type I interferon (IFN-I) signaling promote the differentiation, expansion and functional maturation of naïve CD8 T cells, particularly for low affinity clones, to enhance anti-microbial immunity.
- Mladen Jergović
- , Christopher P. Coplen
- & Janko Nikolich-Žugich
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Listeria exploits IFITM3 to suppress antibacterial activity in phagocytes
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
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Interferon lambda 4 impairs hepatitis C viral antigen presentation and attenuates T cell responses
A genetic variant in the IFN-lambda 4 gene has been associated with poor hepatitis C virus prognosis but it is not clear how this functions. Here the authors show that IFN-lambda 4 promotes ER stress and inhibits presentation of HCV epitopes to CD8+ T cells.
- Qian Chen
- , Mairene Coto-Llerena
- & Markus H. Heim
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| Open Access
Critical role of interferons in gastrointestinal injury repair
Despite being prevalent yet well studied, ulcerative colitis still has poorly characterized pathophysiology. Here the authors use mouse colitis models to find that type I and III interferon (IFN) both contribute to ameliorating the disease, with IFN signaling in either the epithelial or hematopoietic compartment sufficient for this protective effect.
- Constance McElrath
- , Vanessa Espinosa
- & Sergei V. Kotenko
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Type I interferons affect the metabolic fitness of CD8+ T cells from patients with systemic lupus erythematosus
Lupus pathogenesis is associated with high type 1 interferon stimulated gene (ISG) expression. Here, the authors correlate ISG expression in CD8+ T cells from lupus nephritis patients with abnormal mitochondrial function, implicating increased NAD consumption and reduced cell viability in the pathogenesis.
- Norzawani Buang
- , Lunnathaya Tapeng
- & Marina Botto
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β-arrestin 2 as an activator of cGAS-STING signaling and target of viral immune evasion
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
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Early-onset autoimmunity associated with SOCS1 haploinsufficiency
SOCS1 is a potent suppressor of JAK-STAT signalling responses to IFNγ and γ-chain cytokines and thereby limits inflammation. Here the authors identify and characterize heterozygous SOCS1 mutations in 10 patients from 5 unrelated families with autoimmune diseases.
- Jérôme Hadjadj
- , Carla Noemi Castro
- & Frédéric Rieux-Laucat
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Activation and evasion of type I interferon responses by SARS-CoV-2
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
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Oncolytic virus-derived type I interferon restricts CAR T cell therapy
Oncolytic viruses promote an inflammatory response and elicit anti-tumor immunity. Here the authors show, unexpectedly, that the oncolytic virus, VSVIFNβ, induces type I interferon responses that, when combined with chimeric antigen receptor (CAR) T therapy, lead to the attrition of both CAR T and conventional T cells, thus dampening their anti-tumor activity.
- Laura Evgin
- , Amanda L. Huff
- & Richard Vile
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Identification of interferon-stimulated genes that attenuate Ebola virus infection
Here, Kuroda et al. screen a library of nearly 400 interferon-stimulated genes (ISGs) and identify several ISGs that inhibit Ebola virus entry, viral transcription/replication, or virion formation. The study provides insights into interactions between Ebola and the host cells.
- Makoto Kuroda
- , Peter J. Halfmann
- & Yoshihiro Kawaoka
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Type I interferon sensing unlocks dormant adipocyte inflammatory potential
White adipose inflammation can occur in obesity and is at least in part mediated by inflammatory immune cells. Here the authors show that the Type I Interferon/Interferon alpha-beta receptor axis promotes an inflammatory, glycolysis associated adipocyte phenotype.
- Calvin C. Chan
- , Michelle S. M. A. Damen
- & Senad Divanovic
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| Open Access
Sex-specific innate immune selection of HIV-1 in utero is associated with increased female susceptibility to infection
Sex differences in the immune response to vaccines and infections have been well described in children and adults. Here the authors describe, in a cohort of 177 HIV-infected infants, innate immune sex differences in fetal life that increase female susceptibility to intrauterine HIV infection and increase the chances of subsequent HIV remission in infected males.
- Emily Adland
- , Jane Millar
- & Philip Goulder
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| Open Access
Regulation of the linear ubiquitination of STAT1 controls antiviral interferon signaling
LUBAC is involved in adding linear ubiquitin chains to important immune signaling proteins. Here the authors show that this mechanism is effective in inhibiting STAT1-mediated interferon signaling, and that the deubiquitinase OTULIN can remove these linear ubiquitins from STAT1 to reactivate this antiviral signaling pathway.
- Yibo Zuo
- , Qian Feng
- & Hui Zheng
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Article
| Open Access
Innate immunity limits protective adaptive immune responses against pre-erythrocytic malaria parasites
Here, Minkah et al. show that, while immunization with replication-competent Plasmodium parasites can confer sterile protection against infection, it also induces a type I interferon response that adversely affects anti-malaria immunity by affecting numbers of protective hepatic CD8 T cells and CD8 T cell function.
- Nana K. Minkah
- , Brandon K. Wilder
- & Stefan H. I. Kappe
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| Open Access
IFN-γ selectively suppresses a subset of TLR4-activated genes and enhancers to potentiate macrophage activation
Macrophage activation is synergistically controlled by lipopolysaccharide (LPS) and interferon-γ (IFN-γ). Here the authors show that IFN-γ promotes macrophage activation not only by activating STAT1-dependent genes, but also by suppressing STAT3-dependent negative feedback regulation downstream of LPS signaling.
- Kyuho Kang
- , Mahesh Bachu
- & Lionel B. Ivashkiv
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| Open Access
A molecular switch from STAT2-IRF9 to ISGF3 underlies interferon-induced gene transcription
A rapid cellular response to interferons (IFNs) is critical for establishing antimicrobial immunity, but how cells switch from from homeostasis to IFN signaling is not fully understood. Here, the authors provide evidence that IFNs induce gene expression by alternating subunits of transcription factor ISGF3.
- Ekaterini Platanitis
- , Duygu Demiroz
- & Thomas Decker
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| Open Access
STAT1 signaling shields T cells from NK cell-mediated cytotoxicity
The JAK-STAT signaling pathway is important for cytokine responses and CD4 T-cell differentiation. Here the authors show that Stat1 also serves to protect CD4 T cells from natural killer cell-mediated killing, potentially by promoting the expression of Nlrc5 and MHC-I, to preserve the induction of experimental colitis via the adoptive transfer of CD4 T cells.
- Yu Hui Kang
- , Amlan Biswas
- & Scott B. Snapper
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| Open Access
Genotype specific pathogenicity of hepatitis E virus at the human maternal-fetal interface
Hepatitis E virus (HEV) infection can result in severe placental disease, but mechanisms underlying pathogenicity are poorly understood. Here, the authors develop an ex vivo model for HEV infection at the maternal-fetal interface and compare pathogenicity of different HEV genotypes.
- Jordi Gouilly
- , Qian Chen
- & Hicham El Costa
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| Open Access
An information-theoretic framework for deciphering pleiotropic and noisy biochemical signaling
Signalling responses are marked by substantial cell-to-cell variability. Here, the authors propose an information theoretic framework that accounts for multiple inputs and temporal dynamics to analyse how signals flow through shared network components.
- Tomasz Jetka
- , Karol Nienałtowski
- & Michał Komorowski
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| Open Access
Bone protection by inhibition of microRNA-182
Osteoclasts mediate bone disruption in a number of degenerative bone diseases. Here, the authors show that miR-182 regulates osteoclastogenesis via PKR and IFN-beta signaling, is correlated with rheumatoid arthritis, and that its ablation or inhibition is protective against bone erosion in mouse models of osteoporosis or inflammatory arthritis.
- Kazuki Inoue
- , Zhonghao Deng
- & Baohong Zhao
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| Open Access
Plasmodium co-infection protects against chikungunya virus-induced pathologies
Chikungunya virus (CHIKV) and Plasmodium co-infections have been reported in humans, but effects of the two pathogens on each other are unclear. Here, Teo et al. show in mice that Plasmodium infection affects CHIKV-specific T and B cell responses, leading to reduced joint inflammation.
- Teck-Hui Teo
- , Fok-Moon Lum
- & Lisa F. P. Ng
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| Open Access
LY6E mediates an evolutionarily conserved enhancement of virus infection by targeting a late entry step
The interferon-induced gene LY6E increases virus infection, but the underlying mechanism is poorly understood. Here, Mar et al. show that LY6E enhances uncoating of influenza A virus after endosomal escape and that viral enhancement by LY6E is conserved across evolution.
- Katrina B. Mar
- , Nicholas R. Rinkenberger
- & John W. Schoggins
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| Open Access
Altered thymic differentiation and modulation of arthritis by invariant NKT cells expressing mutant ZAP70
Invariant natural killer T (iNKT) cells can be subsetted based on their cytokine productions. Here the authors show, using Zap70 mutant mice, that interferon-γ secreting (IFN-γ) iNKT cells may be induced by hampered T cell receptor signallings to help ameliorate interleukin-17-mediated joint inflammation.
- Meng Zhao
- , Mattias N. D. Svensson
- & Mitchell Kronenberg
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| Open Access
MxB is an interferon-induced restriction factor of human herpesviruses
MxB is an interferon-induced GTPase that inhibits HIV replication. Here, Crameri et al. show that MxB restricts replication of herpesviruses by inhibiting delivery of incoming viral DNA into the nucleus, and this antiviral activity depends on MxB’s GTPase activity.
- Michel Crameri
- , Michael Bauer
- & Jovan Pavlovic
Malaria blood stage infection suppresses liver stage infection via host-induced interferons but not hepcidin