Featured
-
-
Article
| Open AccessEbola virus VP30 and nucleoprotein interactions modulate viral RNA synthesis
Ebola virus (EBOV) VP30 is a multifunctional protein that plays a role in transcription, but molecular details remain unknown. Here, using X-ray crystallography and minigenome assays, Xuet al. define the interaction between VP30 and a portion of NP that is critical for optimal EBOV RNA synthesis.
- Wei Xu
- , Priya Luthra
- & Gaya K. Amarasinghe
-
Article
| Open AccessPentavalent HIV-1 vaccine protects against simian-human immunodeficiency virus challenge
A previous human HIV-1 vaccine clinical trial, boosting with HIV envelope protein from two strains, demonstrated moderate vaccine efficacy. Here, Bradleyet al. show that a pentavalent HIV envelope protein boost improves protection from viral challenge in non-human primates and they identify immune correlates of protection.
- Todd Bradley
- , Justin Pollara
- & Barton F. Haynes
-
Article
| Open AccessPyrin-only protein 2 limits inflammation but improves protection against bacteria
Pyrin-only proteins (POPs) are primate-specific negative regulators of inflammasome activation. Here the authors generate transgenic mice expressing POP2 under the control of the human promoter, and show that POP2 is important for balancing antibacterial inflammatory responsesin vivo.
- Sivakumar Periasamy
- , Kristen A. Porter
- & Jonathan A. Harton
-
Article
| Open AccessAdenovirus prime, Env protein boost vaccine protects against neutralization-resistant SIVsmE660 variants in rhesus monkeys
Protection from neutralization-resistant SIV variants is particularly difficult to achieve by vaccination. Here, Keeleet al. use sieve analysis and show that TRIM5a restrictive rhesus monkeys are protected from neutralization-resistant SIVsmE660 variants by an adenovirus prime, env protein boost vaccine.
- Brandon F. Keele
- , Wenjun Li
- & Dan H. Barouch
-
Article
| Open AccessEvolutionary dynamics and genomic features of the Elizabethkingia anophelis 2015 to 2016 Wisconsin outbreak strain
Elizabethkingia anophelis is an emerging pathogen of high antimicrobial resistance. Perrin and colleagues sequenced isolates of a 2015/2016 E. anophelis outbreak in Wisconsin and found substantial genetic diversity, accelerated evolutionary rate and a disruptive mutation in the DNA repair gene mutY.
- Amandine Perrin
- , Elise Larsonneur
- & Sylvain Brisse
-
Article
| Open AccessA tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance
Artemisinin-resistantPlasmodium is an increasing problem. Here, using a medicinal chemistry programme, the authors identify a tetraoxane-based drug candidate that shows no cross-resistance with an artemisinin-resistant strain (PfK13-C580Y) and is efficient in Plasmodiummouse models.
- Paul M. O’Neill
- , Richard K. Amewu
- & Stephen A. Ward
-
Article
| Open AccessExploiting the kinesin-1 molecular motor to generate a virus membrane penetration site
How non-enveloped viruses cross host membranes is incompletely understood. Here, Ravindranet al. show that polyomavirus SV40 recruits kinesin-1 to construct a penetration site on the ER membrane.
- Madhu Sudhan Ravindran
- , Martin F. Engelke
- & Billy Tsai
-
Article
| Open AccessCovalently linked dengue virus envelope glycoprotein dimers reduce exposure of the immunodominant fusion loop epitope
The immunodominant epitope of dengue virus envelope protein (E) induces poorly neutralizing antibodies, which poses a problem for vaccine development. Here, the authors engineer covalently locked E dimers exposing an epitope that has been shown to induce potent and broadly neutralizing antibodies.
- Alexander Rouvinski
- , Wanwisa Dejnirattisai
- & Gavin R. Screaton
-
Article
| Open AccessRules of engagement between αvβ6 integrin and foot-and-mouth disease virus
Foot-and-mouth disease virus binds αvβ6 integrin, via a conserved RGD motif in the flexible, exposed GH loop of capsid protein VP1, for cell entry. Here Kotechaet al.visualize this interaction with the VP1 GH loop extending away from the viral surface, engaging αvβ6 in an open, active state.
- Abhay Kotecha
- , Quan Wang
- & David I. Stuart
-
Article
| Open AccessHundreds of dual-stage antimalarial molecules discovered by a functional gametocyte screen
There is a need forPlasmodium transmission blocking drugs for malaria elimination. Here, Miguel-Blanco et al. screen >10,000 compounds against stage V female gametocytes, identify active compounds belonging to 57 chemotypes and confirm transmission blocking activity of four selected compounds in vitro.
- Celia Miguel-Blanco
- , Irene Molina
- & Esperanza Herreros
-
Article
| Open AccessIn vitro evolution of an influenza broadly neutralizing antibody is modulated by hemagglutinin receptor specificity
Broadly neutralizing antibodies (bnAbs) against influenza hemagglutinin (HA) have yielded insights for antiviral development. Here, the authors employ saturated mutagenesis of the paratope region of a bnAb combined with yeast display screening using H1 and H3 HAs, and find that a tradeoff exists between Ab affinity and breadth that influenced by disparate modes of receptor binding.
- Nicholas C. Wu
- , Geramie Grande
- & Ian A. Wilson
-
Article
| Open AccessAssociation between a common immunoglobulin heavy chain allele and rheumatic heart disease risk in Oceania
Rheumatic heart disease (RHD) is a chronic auto-inflammatory reaction to group A streptococcal infection, and frequently occurs in individuals from the South Pacific. This study finds a novel association between an immunoglobulin heavy chain allele and risk of RHD in Pacific Islanders and South Asians.
- Tom Parks
- , Mariana M. Mirabel
- & Brenton Ward
-
Article
| Open AccessTCF1+ hepatitis C virus-specific CD8+ T cells are maintained after cessation of chronic antigen stimulation
Virus-specific CD8+T cells lose effector function over the course of chronic infection, a process called ‘exhaustion’, but the fate of these cells after treatment-induced antigen elimination is unknown. Here the authors show that exhausted cells persist in patients even after direct-acting antiviral therapy removes antigen exposure, and that these cells are responsive on re-exposure to antigen.
- Dominik Wieland
- , Janine Kemming
- & Robert Thimme
-
Article
| Open AccessSimilarity in viral and host promoters couples viral reactivation with host cell migration
The coevolution of viruses and host cells can be mapped with interactomics. Here the authors identify coupling of human and viral promoters, and show that HIV-reactivation from dormancy is coincident with migration of HIV-infected cells owing to coupling of human CXCR4 and HIV LTR promoters.
- Kathrin Bohn-Wippert
- , Erin N. Tevonian
- & Roy D. Dar
-
Article
| Open AccessFacile access to potent antiviral quinazoline heterocycles with fluorescence properties via merging metal-free domino reactions
Heterocycles are ubiquitous in bioactive compounds and routes to different substitution patterns are important to access the full substrate space. Here the authors report a route to 4,5,7,8-substituted antiviral fluorescent quinazolines, to allow cellular uptake visualization without external marker.
- Felix E. Held
- , Anton A. Guryev
- & Svetlana B. Tsogoeva
-
Article
| Open AccessNear-atomic structure of Japanese encephalitis virus reveals critical determinants of virulence and stability
Japanese encephalitis virus (JEV) is a Flavivirus responsible for thousands of deaths every year for which there are no specific anti-virals. Here, Wang et al. report the cryo-EM structure of mature JEV at near-atomic resolution and identify structural elements that modulate stability and virulence.
- Xiangxi Wang
- , Shi-Hua Li
- & Zihe Rao
-
Article
| Open AccessAdrenergic-mediated loss of splenic marginal zone B cells contributes to infection susceptibility after stroke
Risk of infection is high after stroke, but the causes are not clear. Here the authors implicate altered beta–adrenergic signalling after stroke that results in a reduction in IgM-mediated protection by marginal zone B cells.
- Laura McCulloch
- , Craig J. Smith
- & Barry W. McColl
-
Article
| Open AccessGlobal site-specific N-glycosylation analysis of HIV envelope glycoprotein
The analysis of site-specific glycosylation of HIV Envelope glycoprotein (Env) is challenging as it contains 25–30 glycosylation sites with multiple glycan forms at each site. Here the authors present a generally applicable mass spectrometry-based method for site-specific analysis of protein glycosylation that they apply to the analysis of the HIV-1 Env.
- Liwei Cao
- , Jolene K. Diedrich
- & James C. Paulson
-
Article
| Open AccessSingle-cell tracking of flavivirus RNA uncovers species-specific interactions with the immune system dictating disease outcome
Analysis of virus replication on a single-cell level is often hampered by a lack of specific or sensitive enough reagents. Here, Douamet al. use RNA-flow technique to track (+) and (−) strand RNA of yellow fever virus in hematopoietic cells in mouse models and identify virus-host interactions that affect disease outcome.
- Florian Douam
- , Gabriela Hrebikova
- & Alexander Ploss
-
Article
| Open AccessE3 ligase FBXW7 is critical for RIG-I stabilization during antiviral responses
The innate immune response to many RNA viruses depends on recognition of viral RNA by RIG-I. Here the authors show that, upon virus infection, FBXW7 interacts with RIG-I and inhibits ubiquitin-mediated degradation of RIG-I, resulting in increased interferon signallingin vitro and in vivo.
- Yinjing Song
- , Lihua Lai
- & Qingqing Wang
-
Article
| Open AccessA potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue
Benzoxaboroles have been shown to be active against different pathogens. Here, the authors show that the benzoxaborole AN3661 inhibitsPlasmodium falciparum in vitroand in mouse models, and identify a homologue of a mammalian cleavage and polyadenylation specificity factor as a drug target.
- Ebere Sonoiki
- , Caroline L. Ng
- & Philip J. Rosenthal
-
Article
| Open AccessEnsemble forecast of human West Nile virus cases and mosquito infection rates
Since its introduction to the US in 1999, the West Nile virus (WNV) has become endemic in the Americas. Here, the authors develop a model of WNV transmission dynamics between birds, mosquitoes and humans, which they integrate in conjunction with data assimilation methods, mosquito infection data and reported human cases in a New York county to show its utility for forecasting infection rates.
- Nicholas B. DeFelice
- , Eliza Little
- & Jeffrey Shaman
-
Article
| Open AccessAllograft inflammatory factor 1 is a regulator of transcytosis in M cells
M cells are intestinal epithelial cells that are specialized to transcytose antigens and bacteria from the intestinal lumen to antigen presenting cells on the other side. Here the authors show that the actin-binding protein Aif1 is highly expressed by intestinal M cells and regulates this transcytosis.
- Sari Kishikawa
- , Shintaro Sato
- & Hiroshi Kiyono
-
Article
| Open AccessIntrauterine Zika virus infection of pregnant immunocompetent mice models transplacental transmission and adverse perinatal outcomes
Zika virus infection of pregnant women is associated with congenital neurological disorders. Here, Vermillionet al. develop an immunocompetent mouse model for identification of factors at the maternal-fetal interface that contribute to adverse perinatal outcomes.
- Meghan S. Vermillion
- , Jun Lei
- & Irina Burd
-
Article
| Open AccessArylmethylamino steroids as antiparasitic agents
Steroid units can facilitate membrane permeation and bioavailability in drugs. Here, using a medicinal chemistry program, Krieget al. identify an arylmethylamino steroid that kills Plasmodium parasites, likely through a chelate-based quinone methide mechanism, and has activity against Schistosoma mansoni.
- Reimar Krieg
- , Esther Jortzik
- & Katja Becker
-
Article
| Open AccessInfection-derived lipids elicit an immune deficiency circuit in arthropods
The insect IMD signalling pathway detects invading pathogens. Here the authors show that ticks have an alternative IMD system that lacks peptidoglycan receptors, IMD and FADD, and is instead reliant on interaction of the E3 ligase XIAP with the E2 conjugating enzyme Bendless.
- Dana K. Shaw
- , Xiaowei Wang
- & Joao H. F. Pedra
-
Article
| Open AccessIFI16 and cGAS cooperate in the activation of STING during DNA sensing in human keratinocytes
The role of IFI16 as a DNA sensor is highly controversial. With support from aNature Communications back-to-back publication from Jønsson et al., the authors here provide functional evidence that IFI16 is involved in DNA sensing via the cGAS-STING pathway in human keratinocytes.
- Jessica F. Almine
- , Craig A. J. O’Hare
- & Leonie Unterholzner
-
Article
| Open AccessIFI16 is required for DNA sensing in human macrophages by promoting production and function of cGAMP
The role of IFI16 as a DNA sensor is highly controversial. With support from a Nature Communications back-to-back publication from Almineet al. the authors here provide functional evidence that IFI16 is required for DNA sensing via the cGAS-STING pathway in human macrophages.
- K. L. Jønsson
- , A. Laustsen
- & M. R. Jakobsen
-
Article
| Open AccessP113 is a merozoite surface protein that binds the N terminus of Plasmodium falciparum RH5
The secretedPlasmodium falciparum protein RH5 is essential for invasion of erythrocytes and is a promising vaccine candidate. Here, Galaway et al. show that the N-terminal region of RH5 binds the GPI-anchored merozoite surface protein P113 and can elicit invasion-blocking antibodies.
- Francis Galaway
- , Laura G. Drought
- & Gavin J. Wright
-
Article
| Open AccessComparative influenza protein interactomes identify the role of plakophilin 2 in virus restriction
Protein interaction networks can identify host proteins that affect virus replication. Here, the authors compare the protein interactomes of several influenza A virus strains and identify plakophilin 2 as a restriction factor that inhibits formation of the viral polymerase complex.
- Lingyan Wang
- , Bishi Fu
- & Shitao Li
-
Article
| Open AccessHost-inherent variability influences the transcriptional response of Staphylococcus aureus during in vivo infection
Drugs inhibiting virulence factors of bacterial pathogens are under development. Here, Thänertet al. analyse the transcriptomes of host and pathogen during Staphylococcus aureusinfection of two mouse strains, and show that virulence determinants are differentially expressed in different mouse strains.
- Robert Thänert
- , Oliver Goldmann
- & Eva Medina
-
Article
| Open AccessA defined syphilis vaccine candidate inhibits dissemination of Treponema pallidum subspecies pallidum
There are no vaccines for the prevention of syphilis, a disease caused by the bacteriumTreponema pallidum subsp. pallidum. Here, the authors use an animal model of infection to show that immunization with the Tp0751 bacterial protein inhibits the pathogen’s spread within the body.
- Karen V. Lithgow
- , Rebecca Hof
- & Caroline E. Cameron
-
Article
| Open AccessSC83288 is a clinical development candidate for the treatment of severe malaria
Severe malaria is a life-threatening infection with limited treatment options. Here, using a medicinal chemistry approach starting from amicarbalide, Pegoraroet al. identify a compound that, when delivered intravenously, can cure Plasmodium falciparuminfection in a humanized mouse model.
- Stefano Pegoraro
- , Maëlle Duffey
- & Michael Lanzer
-
Article
| Open AccessThe tumour suppressor APC promotes HIV-1 assembly via interaction with Gag precursor protein
The tumour suppressor APC is a multifunctional protein implicated in intracellular localization of mRNAs and WNT signalling. Here, Miyakawaet al. show that, via interaction with the HIV Gag precursor protein, APC promotes membrane targeting of viral components and cell-to-cell spread of HIV.
- Kei Miyakawa
- , Mayuko Nishi
- & Akihide Ryo
-
Article
| Open AccessmTORC2 signalling regulates M2 macrophage differentiation in response to helminth infection and adaptive thermogenesis
mTORC1 and mTORC2 are alternatively required for differentiation of T cells into Th1/Th17 or Th2 cells. Here the authors show mTORC2 signalling is also needed for IL-4-induced M2 activation with functional evidence provided by aN. brasiliensisinfection model and cold challenge to model adaptive thermogenesis.
- R. W. Hallowell
- , S. L. Collins
- & M. R. Horton
-
Article
| Open AccessDrug regimens identified and optimized by output-driven platform markedly reduce tuberculosis treatment time
Current antibiotic therapies for tuberculosis are lengthy and onerous. Here, the authors use an output-driven approach to optimize drug doses for two experimental drug regimens in a mouse model of tuberculosis, leading to improved regimens that reduce treatment time by 75%.
- Bai-Yu Lee
- , Daniel L. Clemens
- & Marcus A. Horwitz
-
Article
| Open AccessEsterase mutation is a mechanism of resistance to antimalarial compounds
Pepstatin is a known inhibitor of malarial proteases, but its activity varies between sources. Here, Istvanet al. identify a pepstatin ester as the active component of pepstatin preparations and show that this prodrug is activated by a Plasmodiumesterase, mutation of which can confer resistance to pepstatin and other compounds.
- Eva S. Istvan
- , Jeremy P. Mallari
- & Daniel E. Goldberg
-
Article
| Open AccessThe mito-DAMP cardiolipin blocks IL-10 production causing persistent inflammation during bacterial pneumonia
Non-resolving bacterial pneumonia results in lung tissue damage owing to overactive inflammation. Here the authors show that the mitochondrial DAMP cardiolipin contributes to persistent inflammation by SUMOylating PPARγ, which promotes binding of the corepressor NCOR/HDAC3 complex to the IL-10 promoter.
- Krishnendu Chakraborty
- , Mahesh Raundhal
- & Prabir Ray
-
Article
| Open AccessHepatitis C virus has a genetically determined lymphotropism through co-receptor B7.2
Infection of B cells by hepatitis C virus (HCV) is poorly understood, but is thought to result in lymphoproliferative disorders. Here, Chenet al. identify CD86 as co-receptor for lymphotropic HCV and show that HCV infection inhibits memory B-cell function.
- Chia-Lin Chen
- , Jeffrey Y. Huang
- & Keigo Machida
-
Article
| Open AccessTargeting dendritic cells to accelerate T-cell activation overcomes a bottleneck in tuberculosis vaccine efficacy
A delay in T cell responses is postulated as a possible explanation for the limited efficacy of vaccines against tuberculosis. Here the authors demonstrate this T-cell block and remove it by activating endogenous dendritic cells or delivering activated dendritic cells to the lungs, enhancing immunity of mice toMycobacterium tuberculosis.
- Kristin L. Griffiths
- , Mushtaq Ahmed
- & Shabaana A. Khader
-
Article
| Open AccessA large-scale genome-wide association and meta-analysis identified four novel susceptibility loci for leprosy
Previous studies have shown genetic associations between leprosy and 18 different genes/loci. Here, Wang and colleagues perform genome-wide association study in Han Chinese leprosy patients and describe four novel loci to be associated to the disease.
- Zhenzhen Wang
- , Yonghu Sun
- & Furen Zhang
-
Article
| Open AccessHuman antibody 3E1 targets the HA stem region of H1N1 and H5N6 influenza A viruses
Treatment of influenza A viruses with broadly neutralizing monoclonal antibodies is an area of active research. Here, the authors characterise a human monoclonal antibody called 3E1 that was reactive against both H1 and H5 viruses in vitroand demonstrated some treatment efficacy in mice.
- Wenshuai Wang
- , Xiaoyu Sun
- & Bing Sun
-
Article
| Open AccessSensing of HSV-1 by the cGAS–STING pathway in microglia orchestrates antiviral defence in the CNS
The cGAS–STING pathway is an important immune defence pathway against viral infection, including HSV-1. Here the authors use an HSV-1 encephalitis model and show microglia are the main producers of type 1 interferons that induce antiviral activity in neurons and prime the TLR3-interferon pathway in astrocytes.
- Line S. Reinert
- , Katarína Lopušná
- & Søren R. Paludan
-
Article
| Open AccessGrowth inhibition of cytosolic Salmonella by caspase-1 and caspase-11 precedes host cell death
Inflammatory caspases restrict microbial growth by inducing cytokine production and pyroptosis, but other caspase-induced mechanisms are thought to contribute. Here the authors use time-lapse microscopy of single cells to show that caspase1/11 has anti-Salmonella functions that occur in advance of cell death induction.
- Teresa L. M. Thurston
- , Sophie A. Matthews
- & David W. Holden
-
Article
| Open AccessIrreversible inhibitors of the 3C protease of Coxsackie virus through templated assembly of protein-binding fragments
Molecular fragments are useful tools in drug-discovery but they might be hard to identify due to their weak affinity to the targets. Here, the authors use a protein-templated assembly to design high affinity inhibitors of Coxsackie virus 3C protease, a pharmacological target against enteroviral infections.
- Daniel Becker
- , Zuzanna Kaczmarska
- & Jörg Rademann
-
Article
| Open AccessCARD9 negatively regulates NLRP3-induced IL-1β production on Salmonella infection of macrophages
IL-1β is important for control of bacterial infections, but when deregulated can lead to excessive inflammation. The authors show that the adaptor protein CARD9 suppresses levels of IL-1β and is downregulated during S. Typhimuriuminfection, thus facilitating an inflammatory response
- Milton Pereira
- , Panagiotis Tourlomousis
- & Clare E. Bryant
-
Article
| Open AccessThe structural basis for CD36 binding by the malaria parasite
Targeting of the CD36 scavenger receptor by the malaria parasite effector PfEMP1 prevents splenic clearance of infected erythrocytes. Here, the authors propose that diverse PfEMP1 achieve this by binding to a conserved phenylalanine residue in CD36 that is also required for lipoprotein binding.
- Fu-Lien Hsieh
- , Louise Turner
- & Matthew K. Higgins
-
Article
| Open AccessA conserved influenza A virus nucleoprotein code controls specific viral genome packaging
The nucleotide sequence of the eight genomic RNA segments of influenza A virus provides essential packaging signals, but how these sequences are recognized is unknown. Here, Moreira et al. identify conserved amino acids in the viral nucleoprotein that regulate packaging of RNA segments.
- Étori Aguiar Moreira
- , Anna Weber
- & Mindaugas Juozapaitis
-
Article
| Open AccessA broadly neutralizing anti-influenza antibody reveals ongoing capacity of haemagglutinin-specific memory B cells to evolve
A major goal of vaccine design is to protect against a broad range of pathogen strains. Here the authors isolate a new broadly neutralizing antibody against influenza haemagglutinin from human memory B cells, and identify mutations that increase and broaden the neutralization towards H5 HA subtype.
- Ying Fu
- , Zhen Zhang
- & Wayne A. Marasco