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Here, a protein known as MX2 is shown to be a major effector of interferon-α-mediated resistance to HIV-1 infection: susceptibility of the HIV-1 virus to inhibition by MX2 is dictated by the Capsid region of the viral Gag protein, and inhibition occurs at a late post-entry step of infection. Human MX2 protein is an HIV-1 resistance factor Two groups report in this issue of Nature that the human interferon-induced GTP-binding protein MX2 is a potent inhibitor of human immunodeficiency virus type 1 (HIV-1) and a number of other lentiviruses. For some years it had been known that the related protein MX1 can inhibit HIV-1 replication in humans, but MX2 was thought to be devoid of antiviral activity. The anti-HIV-1 action of MX2 is much less dependent on GTPase activity than is the broader antiviral activity of MX1, pointing to possible mechanistic differences between them. Animal cells harbour multiple innate effector mechanisms that inhibit virus replication. For the pathogenic retrovirus human immunodeficiency virus type 1 (HIV-1), these include widely expressed restriction factors 1 , such as APOBEC3 proteins 2 , TRIM5-α 3 , BST2 (refs 4 , 5 ) and SAMHD1 (refs 6 , 7 ), as well as additional factors that are stimulated by type 1 interferon (IFN) 8 , 9 , 10 , 11 , 12 , 13 , 14 . Here we use both ectopic expression and gene-silencing experiments to define the human dynamin-like, IFN-induced myxovirus resistance 2 (MX2, also known as MXB) protein as a potent inhibitor of HIV-1 infection and as a key effector of IFN-α-mediated resistance to HIV-1 infection. MX2 suppresses infection by all HIV-1 strains tested, has equivalent or reduced effects on divergent simian immunodeficiency viruses, and does not inhibit other retroviruses such as murine leukaemia virus. The Capsid region of the viral Gag protein dictates susceptibility to MX2, and the block to infection occurs at a late post-entry step, with both the nuclear accumulation and chromosomal integration of nascent viral complementary DNA suppressed. Finally, human MX1 (also known as MXA), a closely related protein that has long been recognized as a broadly acting inhibitor of RNA and DNA viruses, including the orthomyxovirus influenza A virus 15 , 16 , does not affect HIV-1, whereas MX2 is ineffective against influenza virus. MX2 is therefore a cell-autonomous, anti-HIV-1 resistance factor whose purposeful mobilization may represent a new therapeutic approach for the treatment of HIV/AIDS.

Anthracyclines can induce a type 1 interferon response in tumor cells that may predict clinical response to these drugs. Some of the anti-neoplastic effects of anthracyclines in mice originate from the induction of innate and T cell–mediated anticancer immune responses. Here we demonstrate that anthracyclines stimulate the rapid production of type I interferons (IFNs) by malignant cells after activation of the endosomal pattern recognition receptor Toll-like receptor 3 (TLR3). By binding to IFN-α and IFN-β receptors (IFNARs) on neoplastic cells, type I IFNs trigger autocrine and paracrine circuitries that result in the release of chemokine (C-X-C motif) ligand 10 (CXCL10). Tumors lacking Tlr3 or Ifnar failed to respond to chemotherapy unless type I IFN or Cxcl10, respectively, was artificially supplied. Moreover, a type I IFN–related signature predicted clinical responses to anthracycline-based chemotherapy in several independent cohorts of patients with breast carcinoma characterized by poor prognosis. Our data suggest that anthracycline-mediated immune responses mimic those induced by viral pathogens. We surmise that such 'viral mimicry' constitutes a hallmark of successful chemotherapy.

Background Triple negative breast cancers (TNBC) have poor prognoses despite aggressive treatment with cytotoxic chemotherapy. Cancer-associated fibroblasts (CAFs) are prominent in tumour stroma. Our hypothesis was that CAFs modulate chemotherapy sensitivity. Methods TNBC cells and breast fibroblasts were cultured; survival after chemotherapeutics was assessed using luciferase or clonogenic assays. Signalling was investigated using transcriptomics, reporters, recombinant proteins and blocking antibodies. Clinical relevance was investigated using immunohistochemistry. Results Breast CAFs dose-dependently protected TNBC cell lines MDA-MB-231 and MDA-MB-157, but not MDA-MB-468s, from chemotherapy. CAF-induced protection was associated with interferon (IFN) activation. CAFs were induced to express IFNβ1 by chemotherapy and TNBC co-culture, leading to paracrine activation in cancer cells. Recombinant IFNs were sufficient to protect MDA-MB-231 and MDA-MB-157 but not MDA-MB-468 cells. In TNBC patients, IFNβ1 expression in CAFs correlated with cancer cell expression of MX1, a marker of activated IFN signalling. High expression of IFNβ1 (CAFs) or MX1 (tumour cells) correlated with reduced survival after chemotherapy, especially in claudin-low tumours (which MDA-MB-231 and MDA-MB-157 cells represent). Antibodies that block IFN receptors reduced CAF-dependent chemoprotection. Conclusions CAF-induced activation of IFN signalling in claudin-low TNBCs results in chemoresistance. Inhibition of this pathway represents a novel method to improve breast cancer outcomes.

Mx proteins are key factors of the innate intracellular defense mechanisms that act against viruses induced by type I/III interferons. The family Peribunyaviridae includes many viruses of veterinary importance, either because infection results in clinical disease or because animals serve as reservoirs for arthropod vectors. According to the evolutionary arms race hypothesis, evolutionary pressures should have led to the selection of the most appropriate Mx1 antiviral isoforms to resist these infections. Although human, mouse, bat, rat, and cotton rat Mx isoforms have been shown to inhibit different members of the Peribunyaviridae, the possible antiviral function of the Mx isoforms from domestic animals against bunyaviral infections has, to our knowledge, never been studied. Herein, we investigated the anti-Schmallenberg virus activity of bovine, canine, equine, and porcine Mx1 proteins. We concluded that Mx1 has a strong, dose-dependent anti-Schmallenberg activity in these four mammalian species.

Blood transcriptional biomarkers of acute viral infections typically reflect type 1 interferon (IFN) signalling, but it is not known whether there are biological differences in their regulation that can be leveraged for distinct translational applications. We use high frequency sampling in the SARS-CoV-2 human challenge model to show induction of IFN-stimulated gene (ISG) expression with different temporal and cellular profiles. MX1 gene expression correlates with a rapid and transient wave of ISG expression across all cell types, which may precede PCR detection of replicative infection. Another ISG, IFI27 , shows a delayed but sustained response restricted to myeloid cells, attributable to gene and cell-specific epigenetic regulation. These findings are reproducible in experimental and naturally acquired infections with influenza, respiratory syncytial virus and rhinovirus. Blood MX1 expression is superior to IFI27 expression for diagnosis of early infection, as a correlate of viral load and for discrimination of virus culture positivity. Therefore, MX1 expression offers potential to stratify patients for antiviral therapy or infection control interventions. Blood IFI27 expression is superior to MX1 expression for diagnostic accuracy across the time course of symptomatic infection and thereby, offers higher diagnostic yield for respiratory virus infections that incur a delay between transmission and testing. It’s not always clear whether blood biomarkers are differentially expressed in the time course of viral infections. In this SARS-CoV-2 human challenge study, the authors identify distinct single-gene blood transcriptional biomarkers for early stages of infection or for symptomatic infection.

Background Breast cancer (BC) is a disease with variable morphology, clinical behaviour and response to therapy. Identifying factors associated with the progression of early-stage BC can help understand the risk of metastasis and guide treatment decisions. Myxovirus resistance 1 (MX1), which is involved in the cellular antiviral mechanism, plays a role in some solid tumours; however, its role in invasive BC remains unknown. In this study, we aimed to explore the clinicopathological and prognostic significance of MX1 in BC. Methods MX1 was assessed at the protein level using tissue microarrays from a large well-annotated BC cohort ( n  = 845). The expression of MX1 mRNA was assessed at the transcriptomic level using the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC; n  = 1980) and validated using three publicly available cohorts on Breast Cancer Gene-Expression Miner (bc-GenExMiner version 4.4). The associations between MX1 expression and clinicopathological factors, and outcome were evaluated. Results High MX1 protein expression was associated with features of aggressiveness, including large tumour size, high tumour grade, high Nottingham prognostic index scores, hormone receptor negativity and high Ki67 expression. High MX1 expression showed an association with poor patient outcome and it was an independent predictor of short BC-specific survival ( p  = 0.028; HR = 1.5; 95% CI = 1.0–2.2). Consistent with the protein results, high MX1 mRNA levels showed an association with features of aggressive behaviour and with shorter survival. Conclusion This study identified MX1 as an independent predictor of poor outcome in patients with BC. Further functional studies are needed to investigate the biological role of MX1 in BC and its potential value as a therapeutic target.

Myxovirus resistance (Mx) proteins are products of interferon stimulated genes (ISGs) and Mx proteins of different species have been reported to mediate antiviral activity against a number of viruses, including influenza A viruses (IAV). Ferrets are widely considered to represent the ‘gold standard’ small animal model for studying pathogenesis and immunity to human IAV infections, however little is known regarding the antiviral activity of ferret Mx proteins. Herein, we report induction of ferret (f)Mx1/2 in a ferret lung cell line and in airway tissues from IAV-infected ferrets, noting that fMx1 was induced to higher levels that fMx2 both in vitro and in vivo. Overexpression confirmed cytoplasmic expression of fMx1 as well as its ability to inhibit infection and replication of IAV, noting that this antiviral effect of fMx1was modest when compared to cells overexpressing either human MxA or mouse Mx1. Together, these studies provide the first insights regarding the role of fMx1 in cell innate antiviral immunity to influenza viruses. Understanding similarities and differences in the antiviral activities of human and ferret ISGs provides critical context for evaluating results when studying human IAV infections in the ferret model.

Background: Oestrogen receptor-negative (ER−) breast cancer is intrinsically sensitive to chemotherapy. However, tumour response is often incomplete, and relapse occurs with high frequency. The aim of this work was to analyse the molecular characteristics of residual tumours and early response to chemotherapy in patient-derived xenografts (PDXs) of breast cancer. Methods: Gene and protein expression profiles were analysed in a panel of ER− breast cancer PDXs before and after chemotherapy treatment. Tumour and stromal interferon-gamma expression was measured in xenografts lysates by human and mouse cytokine arrays, respectively. Results: The analysis of residual tumour cells in chemo-responder PDX revealed a strong overexpression of IFN -inducible genes, induced early after AC treatment and associated with increased STAT1 phosphorylation, DNA-damage and apoptosis. No increase in IFN -inducible gene expression was observed in chemo-resistant PDXs upon chemotherapy. Overexpression of IFN-related genes was associated with human IFN- γ secretion by tumour cells. Conclusions: Treatment-induced activation of the IFN/STAT1 pathway in tumour cells is associated with chemotherapy response in ER− breast cancer. Further validations in prospective clinical trials will aim to evaluate the usefulness of this signature to assist therapeutic strategies in the clinical setting.

There have been several reports of skin manifestations in patients with coronavirus disease 2019 (COVID-19). However, it is unclear whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA can be detected on the skin surface, including the sebum, of these patients. In this study, SARS-CoV-2 RNA was detected using real-time reverse-transcription polymerase chain reaction (RT-PCR) assay of skin surface lipids (SSLs) collected using an oil-blotting film from the faces of hospitalized patients with COVID-19. Human transcriptome analysis was also performed using the same samples. In facial SSLs of patients with COVID-19, the RT-PCR positivity rate was 84.6% (11/13 samples) within 5 days and 30.4% (7/23 samples) by 6–10 days of symptom onset. In the transcriptome analysis, the most characteristic SSL-RNA profile was the upregulation of interferon-stimulated gene (ISG)-related genes, such as ISG15 , IFITM1 , and MX1 . This study presents an alternative technique using SSLs for non-invasive SARS-CoV-2 RNA detection and simultaneous analysis of human molecular pathogenesis in patients with COVID-19.

Human myxovirus resistance protein 1 (MxA) restricts a wide range of viruses and is closely related to the membrane-remodelling GTPase dynamin. The functions of MxA rely on domain rearrangements coupled with GTP hydrolysis cycles. To gain insight into this process, we studied real-time domain dynamics of MxA by single-molecule fluorescence resonance energy transfer. We find that the GTPase domain-bundle-signalling-element (BSE) region can adopt either an ‘open’ or a ‘closed’ conformation in all nucleotide-loading conditions. Whereas the open conformation is preferred in nucleotide-free, GDP·AlF 4 − -bound and GDP-bound forms, loading of GTP activates the relative movement between the two domains and alters the conformational preference to the ‘closed’ state. Moreover, frequent relative movement was observed between BSE and stalk via hinge 1. On the basis of these results, we suggest how MxA molecules within a helical polymer collectively generate a stable torque through random GTP hydrolysis cycles. Our study provides mechanistic insights into fundamental cellular events such as viral resistance and endocytosis. MxA (myxovirus resistance protein A) is a viral restriction factor whose activity depends on self-assembly into polymeric rings and helical filaments. Here the authors reveal the conformational movements involved in generating torque within polymeric MxA molecules and the dynamic conformational changes that occur upon GTP loading and hydrolysis.