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| Open AccessOxygen enhances antiviral innate immunity through maintenance of EGLN1-catalyzed proline hydroxylation of IRF3
Oxygen is an essential requirement for aerobic organisms. Here the authors explore the role of oxygen in the antiviral innate response in multiple models of infection and suggest oxygen enhances the antiviral innate response via EGLN1 hydroxylation of IRF3.
- Xing Liu
- , Jinhua Tang
- & Wuhan Xiao
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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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| Open AccessPrior flavivirus immunity skews the yellow fever vaccine response to cross-reactive antibodies with potential to enhance dengue virus infection
Flavivirus infection or vaccination can induce cross-reactive immune responses. Here, the authors show how previous immunization with the tick-borne encephalitis virus vaccine affects the immune response to the yellow fever vaccine, suggesting that the yellow fever vaccine virus conceals epitopes shared with other flaviviruses in flavivirus-naive but not flavivirus-pre-exposed individuals.
- Antonio Santos-Peral
- , Fabian Luppa
- & Simon Rothenfusser
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| Open AccessSkin muscle is the initial site of viral replication for arboviral bunyavirus infection
Here, the authors provide evidence that, unlike other arboviruses, the initial site of orthobunyavirus replication is the panniculus carnosus muscle layer within the skin. However, virus infection does not damage or kill these cells, allowing them to produce virus over a longer period of time.
- Christine A. Schneider
- , Jacqueline M. Leung
- & Karin E. Peterson
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Article
| 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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| Open AccessDisparate macrophage responses are linked to infection outcome of Hantan virus in humans or rodents
Hantaan virus is carried and transmitted by rodents and results in asymptomatic infection, yet transmission to humans’ results in symptomatic disease and development of hemorrhagic fever with renal syndrome. Here the authors explore the disparate effects in myeloid cells from mice and humans.
- Hongwei Ma
- , Yongheng Yang
- & Fanglin Zhang
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Article
| Open AccessCleavage-intermediate Lassa virus trimer elicits neutralizing responses, identifies neutralizing nanobodies, and reveals an apex-situated site-of-vulnerability
Gorman et al. designed a Lassa virus prefusion-stabilized soluble glycoprotein complex trimer (GPC), with which they identified a Lassa virus-neutralizing nanobody that bound the GPC apex and elicited neutralizing antibody responses in guinea pigs.
- Jason Gorman
- , Crystal Sao-Fong Cheung
- & Peter D. Kwong
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| Open AccessBacterial-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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Article
| Open AccessThe poxvirus F17 protein counteracts mitochondrially orchestrated antiviral responses
Poxviruses replicate in the cytoplasm, making them vulnerable to detection by host nucleic acid sensors. Here the authors show that poxvirus replication induces mitochondrial hyperfusion, resulting in the release of mitochondrial DNA, but that the poxvirus F17 protein counteracts ensuing cGAS activation and increase in glycolysis.
- Nathan Meade
- , Helen K. Toreev
- & Derek Walsh
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Article
| Open AccessZika virus targets human trophoblast stem cells and prevents syncytialization in placental trophoblast organoids
The pathological effects of Zika virus (ZIKV) infection on placental trophoblast progenitor cells in early human embryos are not well understood. In this study, using human trophoblast stem cells (hTSCs), Wu et al. show that hTSCs are readily infected by ZIKV, but that there is increasing resistance to the virus as differentiation towards mature lineages proceeds.
- Hao Wu
- , Xing-Yao Huang
- & Cheng-Feng Qin
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Article
| Open AccessPersistent symptoms after COVID-19 are not associated with differential SARS-CoV-2 antibody or T cell immunity
Authors utilise a cohort of healthcare workers, infected during the first wave of the SARS-CoV-2 pandemic, to assess symptom persistence and humoral and cellular immunity.
- Daniel M. Altmann
- , Catherine J. Reynolds
- & Rosemary J. Boyton
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Article
| Open AccessCellular state landscape and herpes simplex virus type 1 infection progression are connected
The heterogeneity of single cell responses during infection have been reported to influence disease outcome. Here, Pietilä et al characterize cellular heterogeneity during Herpes Simplex Virus 1 infection using a multimodal approach that resolves gene expression, proteomic and spatial details at the single cell level.
- Maija K. Pietilä
- , Jana J. Bachmann
- & Cornel Fraefel
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| Open AccessAn immunostimulatory glycolipid that blocks SARS-CoV-2, RSV, and influenza infections in vivo
7DW8-5 is a glycolipid that binds CD1d and stimulates invariant natural killer T (iNKT) cells. Here the authors show that 7DW8-5, when administered intranasally, provides prophylactic anti-viral effects against influenza, RSV, and SARS-CoV-2 in mice or hamsters, and that this effect is mediated by iNKT cells and IFN-γ.
- Moriya Tsuji
- , Manoj S. Nair
- & David D. Ho
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| Open AccessHigh body temperature increases gut microbiota-dependent host resistance to influenza A virus and SARS-CoV-2 infection
The ambient environmental temperature changes the extent or severity of a virus infection. Here the authors show that influenza and SARS-CoV-2 infection at higher temperatures promotes gut microbiota derived deoxycholic acid signalling which increases host resistance to infection.
- Minami Nagai
- , Miyu Moriyama
- & Takeshi Ichinohe
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Article
| Open AccessIdentification of age-specific gene regulators of La Crosse virus neuroinvasion and pathogenesis
La Crosse Virus predominantly causes encephalitis in children. Here, Basu et al. use transcriptomics and targeted siRNA screening to identify that age-dependent expression of EphrinA2 and Connexin43 by brain capillary endothelial cells is important for neuroinvasion.
- Rahul Basu
- , Sundar Ganesan
- & Iain D. C. Fraser
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Article
| Open AccessSingle-cell RNA sequencing reveals the fragility of male spermatogenic cells to Zika virus-induced complement activation
Zika virus poses a potential threat to male reproductive health but the underlying mechanisms remain obscure. To address this question, the study by Yang et al performs single-cell RNA sequencing with ZIKV-infected mice testes. The authors find that spermatogenic cells are fragile to ZIKV infection and the complement system components produced by infiltrated S100A4 + monocytes/macrophages are crucial for the injury of spermatogenic cells.
- Wei Yang
- , Li-Bo Liu
- & Pei-Gang Wang
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| Open AccessType I interferon shapes brain distribution and tropism of tick-borne flavivirus
Here the authors combine a multimodal imaging-snRNAseq transcriptomics strategy to provide insight into the distribution of a neurotropic tick-borne flavivirus in the brain, and show that absence of interferon signaling increases infection of resident microglia.
- Nunya Chotiwan
- , Ebba Rosendal
- & Anna K. Överby
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Article
| Open AccessFactor Xa cleaves SARS-CoV-2 spike protein to block viral entry and infection
The serine protease factor Xa (FXa) is upregulated in COVID-19 patients and functions in the coagulation pathway. Here, Dong et al characterise the basis of its antiviral activity in the context of SARS-CoV-2 pandemic variants.
- Wenjuan Dong
- , Jing Wang
- & Jianhua Yu
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| Open AccessAPOBEC3B drives PKR-mediated translation shutdown and protects stress granules in response to viral infection
APOBEC’s are a family of cytidine deaminases that induce mutations in viruses to inhibit their replication and maintain cell integrity. Here, Manjunath et al show that APOBEC3B also inhibits viral replication by stimulating the innate immune sensor protein kinase R causing translational shutdown and stress granule formation independently of its cytidine deaminase activity.
- Lavanya Manjunath
- , Sunwoo Oh
- & Rémi Buisson
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Article
| Open AccessOncolytic Parapoxvirus induces Gasdermin E-mediated pyroptosis and activates antitumor immunity
Oncolytic viruses are able to target tumours and thought to induce apoptosis while remodelling the tumour immune microenvironment. Here authors show in an oncolytic parapoxvirus ovis model that pyroptosis, a highly immunogenic Gasdermin-E-dependent cell death mechanism, is the dominant cell death pathway during virotherapy.
- Jing Lin
- , Shihui Sun
- & Wenqi He
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| Open AccessHomotypic and heterotypic immune responses to Omicron variant in immunocompromised patients in diverse clinical settings
Immunocompromised individuals are predisposed to severe SARS-CoV-2 infection, with transplant recipients typically displaying impaired immune response to pathogens, due to typical life-long immunosuppressive treatment. In this work, the authors evaluate the immune response to Omicron subvariants BA.1 and BA.2 in organ transplant recipients across a diverse clinical spectrum.
- Victor H. Ferreira
- , Javier T. Solera
- & Atul Humar
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| Open AccessCAF08 adjuvant enables single dose protection against respiratory syncytial virus infection in murine newborns
Respiratory syncytial virus is a major pathogen with burden observed and associated with childhood infection. Here the authors characterise a cationic adjuvant formulation and show single immunisation results in protection in a murine neonate model of respiratory syncytial virus infection.
- Simon D. van Haren
- , Gabriel K. Pedersen
- & Ofer Levy
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| Open AccessImmune responses in Omicron SARS-CoV-2 breakthrough infection in vaccinated adults
The SARS-CoV-2 Omicron variant possess many mutations within the receptor binding domain of the Spike protein, which confer increased transmissibility and higher antibody escape. Here, the authors carry out analysis of the serological and cellular immune responses of individuals with Omicron breakthrough infection.
- Hassen Kared
- , Asia-Sophia Wolf
- & Siri Mjaaland
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Article
| Open AccessLeukocyte cell-derived chemotaxin 2 is an antiviral regulator acting through the proto-oncogene MET
The innate antiviral immune response is an important defense against infection. Here, the authors show that leukocyte cell-derived chemotaxin 2 (LECT2) promotes RIG-I-mediated innate immune responses by preventing its degradation, and inhibits lymphocytic choriomeningitis virus replication in the liver.
- Takayoshi Shirasaki
- , Satoshi Yamagoe
- & Masao Honda
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| Open AccessProfiling of hMPV F-specific antibodies isolated from human memory B cells
Here, Xiao et al. isolate a large panel of antibodies against human metapneumovirus fusion protein from human B cells, and characterize their epitopes, neutralization activities, and antigen binding specificity, providing a useful framework for understanding the immune response against hMPV.
- Xiao Xiao
- , Arthur Fridman
- & Lan Zhang
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| Open AccessTransient viral exposure drives functionally-coordinated humoral immune responses in HIV-1 post-treatment controllers
A rare sub-population of people living with HIV-1 experience long-lasting viral remission after interrupting antiretroviral therapy and are considered post-treatment controllers. Here the authors characterise the humoral immune response to HIV-1 in a cohort of post-treatment controllers.
- Luis M. Molinos-Albert
- , Valérie Lorin
- & Laetitia Laine
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| Open AccessNeutralizing antibodies induced in immunized macaques recognize the CD4-binding site on an occluded-open HIV-1 envelope trimer
Neutralizing antibodies (bNAbs) against HIV-1 are exclusively directed against the viral envelope protein (Env) and mainly target Env in a closed, prefusion state. Here, Yang et al. structurally characterize two heterologously-neutralizing CD4-binding site (CD4bs) antibodies isolated from sequentially immunized macaques, and show that these antibodies recognize the CD4bs on Env trimers in an „occluded-open‟ conformation between closed, as targeted by bNAbs, and fully-open, as recognized by CD4.
- Zhi Yang
- , Kim-Marie A. Dam
- & Pamela J. Bjorkman
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| Open AccessBroadly neutralizing anti-HIV-1 antibodies tether viral particles at the surface of infected cells
Broadly neutralizing antibodies (bNAbs) neutralize HIV-1 and exert Fc-dependent activities against infected cells. Here, Dufloo et al. show that bNAbs also block HIV-1 release by trapping viral particles at the surface of infected cells.
- Jérémy Dufloo
- , Cyril Planchais
- & Timothée Bruel
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| Open AccessAge-dependent pathogenic characteristics of SARS-CoV-2 infection in ferrets
Here, Kim et al. characterize SARS-CoV-2 infection in juvenile, young, and old aged ferrets to provide a further understanding of differences in COVID-19 severity in humans at different ages. Aged ferrets have higher viral loads, shed virus longer, and mimic the transcriptomic profile of severely infected patients.
- Young-Il Kim
- , Kwang-Min Yu
- & Young Ki Choi
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| Open AccessGain-of-function genetic screening identifies the antiviral function of TMEM120A via STING activation
Understanding the interplay between host and viral factors during infection is essential for the interactome of infection. Here the authors perform a gain-of-function screen to identify factors involved during Zika virus infection and identify TMEM120A as a key factor in the STING mediated immune responses.
- Shuo Li
- , Nianchao Qian
- & Xu Tan
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Article
| Open AccessMolecular mechanisms of the CdnG-Cap5 antiphage defense system employing 3′,2′-cGAMP as the second messenger
Many bacterial cyclic-oligonucleotide-based antiphage signaling systems (CBASS) employ effectors with SAVED domains. Here, the authors present a biochemical and structural characterization of two such CBASS, providing mechanistic insights into bacterial antiphage defense.
- Shirin Fatma
- , Arpita Chakravarti
- & Raven H. Huang
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| Open AccessIncreased lethality in influenza and SARS-CoV-2 coinfection is prevented by influenza immunity but not SARS-CoV-2 immunity
Influenza A virus (IAV) and SARS-CoV-2 coinfection is a possible scenario during influenza season. Here, the authors show in a mouse model that IAV infection increases the risk of severe disease upon SARS-CoV-2 infection two days later. IAV vaccination, especially antibody-dependent, protects from severe disease during coinfection.
- Hagit Achdout
- , Einat. B. Vitner
- & Tomer Israely
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| Open AccessOPTN is a host intrinsic restriction factor against neuroinvasive HSV-1 infection
During herpesvirus infection, most individuals intrinsically suppress a primary infection and therewith preclude potential damage or neurodegeneration of the CNS. Here, Ames et al. show that Optineurin (OPTN), a conserved autophagy receptor, restricts HSV-1 spread, degrades viral VP16 through autophagy and is neuroprotective against HSV infection in vivo.
- Joshua Ames
- , Tejabhiram Yadavalli
- & Deepak Shukla
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| Open AccessSARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation
SARS-CoV-2 infection has been shown to drive NLRP3 inflammasome activation and thereby cytokine storm, but how it does so is unclear. Here the authors show that the viral N protein can bind to NLRP3, resulting in enhanced interaction with ASC and thereby with the NLRP3 inflammasome.
- Pan Pan
- , Miaomiao Shen
- & Jianguo Wu
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Article
| Open AccessBroadly cross-reactive human antibodies that inhibit genogroup I and II noroviruses
Noroviruses can cause gastroenteritis and there is currently no licensed vaccine or specific treatment available. Here, the authors isolate human monoclonal antibodies and characterize one antibody (NORO-320) with broad reactivity to genogroup I and II noroviruses.
- Gabriela Alvarado
- , Wilhelm Salmen
- & James E. Crowe Jr.
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Article
| Open AccessIntracellular lipid droplet accumulation occurs early following viral infection and is required for an efficient interferon response
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
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Article
| Open AccessType II alveolar cell MHCII improves respiratory viral disease outcomes while exhibiting limited antigen presentation
Type II alveolar cells play central roles in multiple aspects of lung biology. Here the authors show that type II alveolar cells also constitutively express MHCII, exhibit limited MHCII antigen presentation capacity, and are a component of the host response to respiratory viral infection.
- Sushila A. Toulmin
- , Chaitali Bhadiadra
- & Laurence C. Eisenlohr
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Article
| Open AccessIL-21 and IFNα therapy rescues terminally differentiated NK cells and limits SIV reservoir in ART-treated macaques
Infection of African green monkeys with SIV is associated with reduced pathogenicity. Here the authors explore the requirement of differentiated NK cell populations in a pathogenic Rhesus macaque model of SIV infection and show administration of IL-21 and IFNα rescues terminally differentiated NK cells, similarly to what found in African green monkeys, and limits the SIV reservoir in antiretroviral therapy treated macaques.
- Justin Harper
- , Nicolas Huot
- & Mirko Paiardini
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Article
| Open AccessVirus-specific memory T cell responses unmasked by immune checkpoint blockade cause hepatitis
Checkpoint blocking therapies are used to treat metastatic melanoma, but can have adverse immune-mediated effects, including liver pathology. Here the authors identify an expanded pool of CD4+ effector memory T cells resulting from prior CMV exposure as a risk factor for this adverse effect in these patients.
- James A. Hutchinson
- , Katharina Kronenberg
- & Sebastian Haferkamp
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Article
| Open AccessAntibody affinity maturation and plasma IgA associate with clinical outcome in hospitalized COVID-19 patients
SARS-CoV2 infection has been linked to a wide range of clinical severities and the immunopathology is still under intense scrutiny. Here, the authors uncover an association of antibody affinity maturation and plasma IgA levels with clinical outcome in patients with COVID-19 disease.
- Juanjie Tang
- , Supriya Ravichandran
- & Surender Khurana
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Article
| Open AccessE3 ligase Nedd4l promotes antiviral innate immunity by catalyzing K29-linked cysteine ubiquitination of TRAF3
Ubiquitination is a prevalent post translational modification. Here, the authors show a pivotal role for Nedd4l in the regulation of antiviral immunity via promotion of ubiquitination of TRAF3 and go on to show disruption of Nedd4l both in vitro and in vivo perturbs the antiviral immune response.
- Peng Gao
- , Xianwei Ma
- & Huazhang An
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Article
| Open AccessA systematic review of antibody mediated immunity to coronaviruses: kinetics, correlates of protection, and association with severity
Antibody mediated immunity to SARS-CoV-2 will affect future transmission and disease severity. This systematic review on antibody response to coronaviruses, including SARS-CoV-2, SARS-CoV, MERS-CoV and endemic coronaviruses provides insights into kinetics, correlates of protection, and association with disease severity.
- Angkana T. Huang
- , Bernardo Garcia-Carreras
- & Derek A. T. Cummings
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Article
| Open AccessEntamoeba and Giardia parasites implicated as hosts of CRESS viruses
Metagenomics allows virus genome discovery, but the viral hosts are often not identified. Here, Kinsella et al. use recombination events between virus genomes, statistical association of viruses to hosts in clinical samples, and analysis of endogenous viral elements in host genomes to identify probable hosts of three CRESS virus families.
- Cormac M. Kinsella
- , Aldert Bart
- & Lia van der Hoek
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Article
| Open AccessBroadly neutralizing plasma antibodies effective against autologous circulating viruses in infants with multivariant HIV-1 infection
Some infants develop broadly neutralizing antibodies (bnAbs) to HIV in a shorter time frame than adults, but the reasons aren’t well understood. Here, the authors study a cohort of 51 HIV-1 clade C perinatally infected infants of Indian origin and find that multivariant infection is associated with bnAbs in elite neutralizers.
- Nitesh Mishra
- , Shaifali Sharma
- & Kalpana Luthra
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| Open AccessInfluenza A virus M2 protein triggers mitochondrial DNA-mediated antiviral immune responses
Cytosolic mitochondrial DNA (mtDNA) plays a role in innate antiviral immunity but how this is triggered during infection remains unclear. Here, the authors provide evidence that the Influenza virus protein M2 stimulates translocation of mtDNA into the cytosol in a MAVS-dependent manner.
- Miyu Moriyama
- , Takumi Koshiba
- & Takeshi Ichinohe
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Article
| Open AccessTime elapsed between Zika and dengue virus infections affects antibody and T cell responses
Here, the authors show that the time elapsed between Zika infection and subsequent dengue virus infection affects the magnitude and durability of the antibody and cell-mediated immune responses against dengue virus, but not viremia. This research in non-human primates has implications for co-endemic regions and vaccination.
- Erick X. Pérez-Guzmán
- , Petraleigh Pantoja
- & Carlos A. Sariol
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Article
| Open AccessCircadian control of lung inflammation in influenza infection
The circadian clock affects immune responses, but its role in influenza infection is not well understood. Here, Sengupta et al. show that time of infection and the circadian clock have no effect on lung virus titers, but affect inflammation, morbidity and mortality.
- Shaon Sengupta
- , Soon Y. Tang
- & Garret A. FitzGerald
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| Open AccessExposure of an occluded hemagglutinin epitope drives selection of a class of cross-protective influenza antibodies
Antibody cross-reactivity can help to prevent escape mutations from enabling viral escape, but underlying mechanisms are unclear. Here the authors identify influenza hemagglutinin epitopes that are exposed during viral replication and which result in the generation of a class of protective cross-reactive antibodies.
- Yu Adachi
- , Keisuke Tonouchi
- & Yoshimasa Takahashi
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Article
| Open AccessZIKV infection induces robust Th1-like Tfh cell and long-term protective antibody responses in immunocompetent mice
Here, the authors show that Zika virus (ZIKV) infection induces Th1-like Tfh cells that depend on T-bet for their development and are essential for class switching of ZIKV-specific IgG2c antibodies and maintenance of long-term neutralizing antibody responses.
- Huabin Liang
- , Jinyi Tang
- & Haikun Wang